GMP Manual

PHARMACEUTICAL QUALITY SYSTEM GMP MANUAL
1.A Preface
Author: Lothar Hartmann Ph. D. / Update 09
The GMP Manual contains three chapters related to quality:
Pharmaceutical Quality System (chapter 1)

Quality Unit (chapter 19)
Continual Improvement (chapter 20)
The reason for this structure is to distinguish between the different levels of regulatory applicability.
chapter 1 Pharmaceutical Quality System (PQS) represents the paradigm change that is currently
taking place in the pharmaceutical industry as a result of the ICH process (ICH Q10, see chapter E.10).
It reflects current thinking and describes the conceptual environment towards which the pharmaceutical
industry needs to develop according to ICH Q10, especially the switch to process orientated thinking
based on the ISO 9000:2000 principles. The principles laid down in this chapter reflect regulatory
expectations at this point in time. They are not binding and alternative approaches may be used.
Nevertheless the tendency in some regions is clear towards regulatory requirement.
chapter 19 Quality Unit covers departmental aspects as well as the tasks and responsibilities of a
Quality Unit to be fulfilled in the current environment. All these aspects are clearly regulatory
requirements within the framework of GMP.
chapter 20 Continual Improvement is set up as a way to facilitate the implementation of the regulatory
requirements. It describes the various tools that are available for avoiding reoccurrence of quality
related issues and proactively improve robustness of the processes (manufacturing as well as
business). This chapter is neither a regulatory requirement nor an expectation. It is an add-on for the
users of the GMP Manual demonstrating techniques currently available to improve quality.
1.B The road to a Pharmaceutical Quality System
Here you will find answers to the following questions:

How has the concept of "quality" in the pharmaceutical industry changed over the past decades?
Pharmaceutical quality has been a long time in development. Until the 80th, the predominant
philosophy was that Quality Control (QC) testing alone could determine the quality of the medicinal
(drug) product. This concept had serious limitations. Compared with other industries, where it is
feasible to test 100 % of products, pharmaceutical testing must rely on representative samples - testing
of 100 % of pharmaceutical products would leave nothing for the patient to consume! When only
samples are tested, serious problems can go undetected. As an example, sterile products on the
market have shown microbiological contamination even though the samples were free of
microorganisms.
The realization that testing alone could not reliably determine whether a product was meeting its
predefined specifications gave rise to the concept of theQuality Assurance (QA) partnership. To judge
the quality of a pharmaceutical product, it is necessary to have additional information as to how it has
been manufactured. This awareness led to the development of measures such as batch record review,
investigation reporting and approval of manufacturing documents by the quality department.
The major drawback with the QA concepts that companies implemented was that they were reactive
rather than proactive. All activities focused on assessing the status quo and fixing problems as they
arose. At this time the pharmaceutical industry was not prepared to take the next step towards an
overall quality concept, as laid down in ISO 9001:2000 and associated documents. Compliance with
GMP regulations was the main preoccupation, and Health Authority inspections at this time supported
this narrow view.
Nevertheless, the growing complexity of the operational environment in the pharmaceutical industry,
compounded by the growing size of Pharma concerns meant that it became increasingly difficult to
achieve compliance with all aspects of GMP regulations.
The industry began to adopt the term Quality Management (QM) and to take stock of a number of
GMP topics such as change control, recall management, equipment maintenance, validation, handling
of discrepancies, etc. necessary to achieve compliance. Individual systems were developed for specific
topics, and these operated independently and side-by-side but were never seen as parts of the bigger
picture.
In a Science Board Meeting in November 2001 the FDA raised concerns about the efficiency of the
pharmaceutical industry. It was said that greater efficiency would be required to get high quality drugs
to market quickly enough to take advantage of the new drug development opportunities offered by
advances in chemistry and biology. Additionally, the FDA underlined the need for optimal use of public
and private resources to meet growing health care needs while obtaining global competitiveness for
the pharmaceutical industry.
In conclusion, the status quo was no longer tenable: pharmaceutical manufacturers could do much
better. Furthermore, traditional metrics were said to be hiding poor performance, and compliance
"infrastructure" with quality-related costs currently running in excess of 20 percent, was uneconomical.
The agency's findings showed that too often, processes were not fully understood, and that this was
still the case once scaled up for commercial production. This problem, they maintained, was
compounded by a lack of scientific basis for deeper process understanding.
In 2004, the FDA introduced its "GMP initiative for the 21st century". This would bring the
pharmaceutical industry to the next level of understanding in terms of quality, with the introduction
of Quality Management Systems (QMS). At this point it is disgraceful to note that the pharmaceutical
industry was presumably one of the last industries to recognize the benefits of a QMS. Since many
years, the QMS concept helped other industries to increase their process robustness and thus bring
down the price of quality.
The basic philosophy of this concept for the pharmaceutical industry was finally laid down in the ICH
Q10 document Pharmaceutical Quality Systems (2008, see chapter E.10). This document heralded a
paradigm change across the industry. We now take a holistic view of the entire organization and
embed GMP requirements into the overall system.
This approach will allow the pharmaceutical industry to take the quantum leap from reactive to
proactive behavior, to recognize discrepancies and not only fix them, but introduce measures that
prevent reoccurrence. As a consequence, the pharmaceutical industry will move into a loop of
continual improvement and finally increase the robustness of its processes, in production as well as in
business.
A Quality Management System enables a company to implement effective, efficient, transparent and
simple processes and structures to achieve continual compliance. In addition, this will benefit the
company's business in terms of improved quality, optimized costs, inspection readiness and customer
satisfaction.
Summary
Pharmaceutical organizations became more and more complex over the past decades and thus needed to adapt the
concept of "quality" from "Quality Control" to modern approaches like Pharmaceutical Quality Systems as laid
down in ICH Q10.
1.C Introduction to the PQS


What are the fundamentals of a PQS?
What is the role of senior management within the concept of a PQS
What is the central document of a PQS?
What are basic documentation requirements?
1.C.1 General requirements
The overall aim of implementing a Pharmaceutical Quality System (PQS) is to continually improve the
effectiveness and efficiency of the organization's performance and thus achieve compliance with GMP
regulations around the world.
A PQS must be led in a systematic and visible manner and involve people at all levels.
A company performs many internal activities such as manufacturing, research, development, clinical
trials, registration, marketing, purchasing, warehousing and distribution, to name but a few. Activities
need to be addressed in a PQS which describes all the processes that have to be managed.
All these activities should be embedded in a life cycle approach, as laid down in ICH Q10
(see chapter E.10):
Development
Technology Transfer
Commercial Manufacturing
Product Discontinuation
Implementing a PQS has a significant impact on the "classical" organization of a company. It

necessitates:
Process-oriented thinking
Definitions of the responsibilities within a process
Identification of interfaces, within and between different processes
The nomination of process owners for the processes identified
The establishment of Key Performance Indicators (KPIs) for measuring the
effectiveness of a process and thus the value it brings to the company
The routine assessment of process performance and identification of potential
improvements.
A PQS requires the systematic involvement of senior management in the functioning and success of a
PQS. In practice, senior management directs the organization towards its quality objectives by:
Determining responsibilities within the organization (global, regional, local)

Providing sufficient resources (infrastructure - e.g. offices, manufacturing, IT - time and
personnel) to support the processes
Defining information and communication flow at all levels of the organization
Integrating the concept of Quality Risk management at all levels of the organization
Implementing a concept of Knowledge Management
Fostering all initiatives that lead to improved process robustness (production processes
as well as business processes)
Encouraging the implementation of concepts that will enable continual improvement at
all levels
Using the (regular) Management Review to direct the PQS and thus the organization.
It must be stressed that outsourced operations and related activities also need to be covered by the
PQS.
1.C.2 Documentation
1.C.2.1 General
A documentation system remains a fundamental component of a PQS. The objective of such

documentation is to identify and describe what needs to be in place. It is an essential tool to keep all
processes in a state of control and it must satisfy GMP requirements.
Senior management defines the documentation that is required to run a PQS and support effective and
efficient operation of the processes.
It basically includes:
senior management's commitment to quality,

a quality manual,
documented procedures,
documents and records needed for an efficient PQS.
GMP documentation, especially regarding Master Production Instructions and laboratory

documentation, provides detailed information as laid down in the respective regulations. GMP
requirements need to be reflected in the PQS for reasons of compliance.
The documentation created to run a PQS and to comply with GMP requirements should fulfill criteria
with respect to:
functionality,
user-friendliness,
the structure of the company's documentation system,
knowledge management,
interfaces between departments.
Documentation may be available in any form or media, such as paper, micro-fiche, electronic
(CD/DVD) etc., suitable to needs.
In a GMP environment, quality-related activities are to be recorded at the time that they are performed.
Deviations from established procedures need to be documented and explained and/or investigated: a
complaint and recall procedure has to be in place (seechapter 1.D.4 Evaluation activities).
Contract manufacturing (including laboratories) needs to be carefully managed, e.g. through evaluation,
assessment and documentation (including a quality agreement). All (GMP) activities and
responsibilities have to be defined in writing (see chapter 17 Contractors and Suppliers).
1.C.2.2 Quality manual
The central document of a PQS is the Quality Manual. Although it is a company's decision how
detailed this should be, the quality manual should be made as comprehensive as possible.
The main elements to be incorporated include:
the scope of the PQS (see chapter 1.D Main elements of a PQS for an example),
senior management's quality commitment (quality policy, quality objectives, see chapter
1.C.2 Documentation),
a description of the main processes,
their interactions and
the description of major responsibilities.
1.C.2.3 Control of documents
All documents and records required by the PQS are subject to appropriate control. A documented
procedure needs to be established to define the following controls:
drafting, review, approval (Quality Unit at minimum for GMP-related documents) and
updating of documents,
handling and control of changes to documents (version control) including P & ID (Piping
& Instrumentation Diagram) schemes,
handling, control and internal distribution of external documents,
withdrawal and prevention of unintended use of obsolete documents.
1.C.2.4 Control of records
Records provide evidence of conformity to requirements. They should be legible, readily identifiable
and retrievable. A documented procedure should define the control needed for identification, storage,
protection, retrieval, retention time and disposition of records.
The control of records includes hard copies as well as electronically-stored data.
Records should be established, at least for raw materials, intermediates, labeling, packaging materials,
batch production, laboratory data (including Certificates of Analysis and stability data), calibration,
distribution, complaints and returns.
A procedure for the review of batch production and laboratory records is required (batch record review,
see chapter 15.C.5 Batch record review).
Details about GMP-conformity of documentation are given in chapter 15 Documentation.
Summary
The implementation of a PQS implies the introduction of a process-oriented thinking. The way how the PQS is
organized is laid down in the "Quality Manual". All documents and records required by the PQS are subject to
appropriate control. Senior Management is systematically involved in the PQS and directs the PQS by applying
various tools, such as the "management review".
1.D Main elements of a PQS

What are the four major processes of a PQS?
How can the GMP requirements be linked to these four processes?
What new elements that go beyond the GMP requirements are needed to run a PQS?
1.D.1 Management responsibility
1.D.1.1 Management commitment
Leadership, commitment and the active involvement of senior management are essential to the
effective functioning of the PQS.
Senior management should provide evidence of its commitment to the development and
implementation of the Pharmaceutical Quality System (PQS) by:
communicating the importance of meeting patient needs as well as regulatory (GMP)

and legal requirements, including environmental, health and safety aspects,
ensuring that the organization has knowledge of the regulatory requirements,
establishing quality policy,
ensuring that quality objectives are established,
defining responsibilities,
fostering continual improvement,
defining methods to measure the organization's performance,
conducting regular management reviews,
ensuring the availability of sufficient resources (manpower, time and infrastructure).
1.D.1.2 Quality policy
Senior management should stress the importance of compliance with regulatory/GMP requirements
and the continual improvement in performance of the PQS. This should be explained in the quality
policy.
The quality policy demonstrates senior management's commitment to quality and to the provision of
adequate resources.
Measures have to be initiated to ensure that the key statements of the quality policy become part of
daily business. Therefore, the quality policy needs to be communicated and understood at all levels
within the organization. Quality is the responsibility of all persons involved in a process.
To cope with the changes that inevitably occur in and around the organization, the quality policy should
be reviewed for continuing suitability. The responsibility for these activities is clearly allocated to senior
management.
1.D.1.3 Quality planning
Senior management is responsible for the quality planning of the organization.
Quality Planning may be driven e.g. by strategies and organizational objectives, by patient needs, by
regulatory requirements, or by risk management. This may give rise to, e.g. skill and knowledge
requirements, allocation of task responsibilities, resources (financial and infrastructure), performance
indicators and contingency plans.
Senior management should establish Quality objectives that are known and widely used at all levels
within the organization. They should be measurable and consistent with the quality policy.
The "SMART" criteria
S = Specific,
M = Measurable,
A = Achievable,
R = Relevant,
T = Time-framed
should be applied to establish quality objectives.
The outputs of quality planning should be submitted for Management review (see chapter 1.D.1.7
Management review).
1.D.1.4 Representative
Senior management should make sure that responsibilities and competencies are defined for all
profiles and that they are communicated to all levels within the organization.
People throughout the organization should be given the responsibilities and authority necessary to
enable them to contribute to the achievement of quality objectives.
Senior management should appoint a representative who, irrespective of other responsibilities, is
responsible and authorized:
to make sure that the processes needed for the PQS are established, implemented and
maintained,
to report to senior management on the performance of the PQS and any need for
improvement.
This representative should report to senior management.
1.D.1.5 Resource management
Senior management should determine and provide adequate and appropriate resources to implement
and maintain the PQS, i.e.:
human resources
financial resources
materials
infrastructure (facilities and equipment)
time.
For more detailed discussion of resource management see chapter 1.D.2 Resource management
1.D.1.6 Internal communication
Senior management should ensure that appropriate communication processes are established
between all levels of the organization. This should include the communication of GMP and regulatory
requirements as appropriate to each level in the organization. Quality issues should be considered as a
standard topic on the agenda of all appropriate meetings. Procedures should exist for notifying
responsible management of quality-critical situations in a timely manner.
1.D.1.7 Management review
Senior management should review the organization's PQS at predefined intervals to ensure its
continuing suitability, adequacy and effectiveness. This review has to include the assessment of
opportunities for improvement and the need for changes to the PQS, including the quality policy and
the quality objectives.
The review should also cover environmental, health and safety aspects. Records of management
reviews are to be maintained.
A consolidation of available data is to be provided as input to senior management review to support

their decision-making process.
These data include, but are not limited to:
audit observations/results (internal and external audits as well as inspections by

authorities),
supplier qualification,
product conformity (product quality review),
complaint, deviation and manufacturing changes
feedback from outsourced operations
risk assessments and trending
process performance, e.g. key performance indicators (KPI),
status of corrective and preventive actions (CAPA),
follow-up actions from previous management reviews,
changes that could affect the PQS,
recommendations for improvement.
The output from the management review should include any decisions and actions taken relating to:
continual improvement of the effectiveness of the PQS and its processes,

continual improvement of product (relating to customer requirements),
setting priorities of activities and
resources needed.
1.D.1.8 Outsourced operations
The management responsibilities described in this section extend to the control and review of any
outsourced activities. It has to be ensured that measures are in place to assure the quality of product
and processes:
Assessment, prior to outsourcing, of the suitability and competency of the contract

acceptor
Definition of responsibilities and communication processes for quality-related activities
laid down in a written agreement
Monitoring and review of performance of the contract acceptor.
1.D.2 Resource management
1.D.2.1 Provision of resources
Senior management should ensure that resources which are essential to the implementation of the
company's strategy and quality objectives are identified and made available.
Provision of resources is the responsibility of senior management and has to be foreseen in the
budgeting and investment processes. These processes have to be defined in writing.
Senior management needs to determine and provide the resources:
to implement and maintain the PQS and continually improve its effectiveness,
to maintain equipment and facilities,
to adequately train and educate employees,
to plan for future needs
for information management and technology.
When using external resources such as contract manufacturers (including laboratories), the external
providers are expected to provide sufficient resources as described in this chapter. The external
provision of resources should be subject to a contractual arrangement.
1.D.2.2 Human resources
Senior management has to provide an adequate number of personnel who are qualified with the
appropriate education, training, and/or experience to perform work and meet requirements.
If the targets, as measured by the company's performance indicators (e.g. timelines for calibration due
dates, deviation/investigation handling, testing, release, etc.) are missed on a recurrent basis, and that
in consequence, PQS processes do not run properly, the adequacy of human resources should be
reconsidered.
Competence, awareness and training are ensured by senior management through:
implementing an adequate and effective organization,

determining the necessary competence and education for personnel performing work
which affects quality of product and processes,
issuing job descriptions and qualifications for all functions throughout the organization,
training provided regularly by qualified individuals covering, at minimum, the particular
operations that the employee performs, and GMP as it relates to the employee's functions,
the periodical evaluation of the effectiveness of training, such as by:
o testing the actual content of procedures performed
o observing the employee performing task(s)
o checking the accuracy of the work and results
ensuring that personnel are aware of the relevance and importance of their activities
and how they contribute to the achievement of quality objectives,
maintaining appropriate records of education, training, skills and experience.
More information on this topic is given in chapter 2.B.1 Qualification requirements and chapter 2.C
Training.
1.D.2.3 Infrastructure
Senior management has to ensure that the organization determines, provides and maintains the
infrastructure needed to conduct operations (e.g. manufacturing, testing and support) according to
contemporary standards.
Infrastructure comprises buildings (including utilities and workspaces), equipment and computerized
systems.
Buildings have to:
be located, designed, and constructed to facilitate cleaning, maintenance, and

operations as appropriate to the type and stage of manufacture,
allow adequate space for the orderly placement of equipment and materials to prevent
mix-ups and contamination,
have adequate cleaning, washing and toilet facilities,
have laboratory facilities separate from production areas,
be adequately lit in all areas to facilitate cleaning, maintenance, and proper operations,
have storage areas offering suitable conditions for all types of materials (e.g.,
temperature and humidity),
include adequate laboratory facilities for the quality unit,
be properly maintained and repaired,
provide separate areas for eating, drinking and smoking,
contain the necessary utilities (such as HVAC, water, gases etc.) to perform the relevant
production operations.
Equipment should be:
of appropriate design, adequate size and be suitably located for its intended use in
order to facilitate cleaning, sanitization (where appropriate), and maintenance,
constructed so that surfaces in contact with raw materials, intermediates, APIs or drug
(medicinal) product do not alter quality beyond the official or other established specifications.
Computerized systems should be:
of appropriate design and adequate capacity,

equipped with the necessary software programs,
maintained (e.g. with program updates or exchange of hardware components),
safe against loss of data.
The infrastructure has to meet all legislative requirements as laid down by regulatory authorities (safety
issues, occupational health problems, environmental aspects, etc.).
1.D.2.4 Information
Senior management should regard data as a fundamental resource to be converted into essential
knowledge and used for making fact-based decisions. In order to manage information it is necessary
to:
identify information needs

identify access to information
identify sources of information (internal and external)
convert information into knowledge
use data, information and knowledge to fulfill strategies and meet quality objectives
ensure appropriate security and confidentiality of information.
1.D.3 Manufacturing operations
Manufacturing operations include all value-adding activities involved in the realization of the product,
from setting specifications to the transportation of the product to the user.
The majority of GMP requirements relate to this major process of a PQS.
1.D.3.1 Planning
Manufacturing operations should be planned in line with the PQS requirements of other processes.
Planning of process equipment, including laboratory equipment, is a vital part of preparations for
product realization. Equipment should be of adequate design and be appropriately qualified before use
in manufacturing (see chapter 6 Qualification).
Schedules and procedures should be established for the preventive maintenance of equipment (see
chapter 4.H Maintenance). In addition, established cleaning procedures must prevent contamination or
carry-over (see chapter 8 Cleaning Validation).
Where computerized systems are used in a GMP-relevant process, hardware and software should be
appropriately qualified and validated as per the criticality of the system (see chapter 9 Computer
Validation).
Changes to any equipment (including computer systems and laboratory equipment) should be done
under a defined change control system to maintain its qualified status (see chapter 1.D.4.3 Change
management and chapter 19.C Change control). All activities described above are subject to risk
management (see chapter 10 Risk Management).
Materials used in manufacturing operations should be defined by appropriate specifications and

acceptance criteria to ensure that processes are in a state of control and that quality is consistent. It is
necessary to define all activities from the receipt of materials to sampling and testing against defined
specifications as well as storage and release for use or rejection.
To prove the capability of the product realization process, the equipment should be qualified and the
production process validated, where appropriate, following the current GMP requirements (see chapter
7 Process Validation).
Activities not covered by the manufacturer's PQS, such as contract manufacturing (incl. laboratories),
activities of brokers or distribution, should be subject to a written contract defining, in detail, the Quality
responsibilities of each party.
1.D.3.2 Design and development
The design and development process comprises planning, determination, review and verification of
inputs and outputs and the control of changes. To achieve a robust manufacturing process, it is
mandatory to perform all of the above-mentioned steps.
1.D.3.3 Purchasing
Purchased items which could impact final product quality should be procured to defined requirements
and according to written procedures from an approved supplier.
Procedures should be written to describe the receipt, initial visual check of labels and containers,
identification, quarantine, storage, handling, sampling, testing and approval or rejection of materials.
Suppliers should be selected on the basis of their ability to supply the items. Supply chain
and/or manufacturer qualification for critical materials, utilities and services is mandatory.
Particular attention should be paid to:
Changes to the supply chain and/or the manufacturing processes which could impact
the organization's final product, e.g. changes in method might impact product purity or
performance.
Purchasing documentation, which may include data relating to the supplier's and/or
manufacturer's PQS, e.g. Good Manufacturing Practices (GMP),Hazard Analysis Critical
Control Point (HACCP). Purchasing data would also be expected to include Certificates of
Analysis/Conformity.
Verifying that the product is as ordered, so as to prevent cross-contamination or product
disruption.
Receipt of a material prompts the following actions (see also chapter 11.M.2 Stock management
system and chapter 11.M.9 Process Flow):
Initial visual check of labels and containers to verify that the material is correct and that
there is no evidence of damage, tampering or contamination.
Assignment of a unique code or batch number.
Identification of the material status.
Bulk deliveries in non-dedicated tankers require assurance of the absence of cross-
contamination.
Materials are kept under quarantine and should not be mixed with existing stocks until
approved.
Sampling and testing (see also chapter 11.M.2 Stock management system and chapter 11.M.5.4
Sampling):
Sampling is to be performed at defined locations and by procedures designed to prevent

contamination.
Containers from which samples have been withdrawn should be marked.
Samples should be representative of the batch of material from which they are taken.
Each batch should be tested for conformance with specifications unless the supplier's
Certificate of Analysis has been verified as accurate.
As a minimum requirement, an identity test on each batch is mandatory.
Processing aids, hazardous or highly toxic raw materials, and other special materials do
not need to be tested if a Certificate of Analysis shows that these materials conform to
established specifications or are shown to be suitable for the intended use.
Approval or rejection of material (see also chapter 11.M.2 Stock management system and chapter
11.M.5.5 Quarantine):
Material that conforms to specifications may be approved by the quality unit.
Rejected material should be identified and controlled under a quarantine system
designed to prevent their unauthorized use in manufacturing.
Storage and handling (see also chapter 11.M Warehouse and logistics):
Materials should be handled and stored in a manner to prevent degradation,

contamination, and cross-contamination.
Placement of stored material should allow easy cleaning and inspection.
Stored material should be used on a "first-in, first-out" principle.
Materials should be re-evaluated after prolonged storage to determine their suitability for
use.
1.D.3.4 Production and service provision
Production and service provision should be systematically planned and controlled to predetermined
conditions derived from comprehensive process understanding (e.g. specifications, process
parameters, contents and scope of service, operating procedures). Operating under these conditions
reduces the potential for non-conformities, delivers material that is fit for use and provides the basis
for continual process improvement.
In order to reduce costs of failure and to control the production process, all steps should be adequately
monitored. The techniques of process validation or - in terms of the paradigm change - continued
process verification are applied and provide documented evidence that the process can be
performed effectively and reproducibly.
Product conformity should be continually maintained throughout the supply chain by appropriate
measures for identification, handling, packaging, storage and protection.
Traceability depends on the nature of the processing e.g. in bulk silos and storage tanks, or continual
processing. It requires appropriate concepts (e.g. batch, time or volume based). Identification and
traceability are regulatory imperatives.
In the special case of contract manufacturing, specified control conditions should be observed. The
contract giver must be notified of any deviations, as per the agreement (see chapter 17.A Contract
manufacture).
GMP requirements to be considered for production and service provision are related to the following
topics:
document control, pre-approved manufacturing procedures, batch record review and

handling of deviations,
equipment qualification, process validation, analytical method validation and cleaning
validation,
change control,
production activities (chemical as well as biotech) such as in-process controls, blending,
recovery of materials, hygiene, calibration, cleaning, sanitation, maintenance, contamination
control as well as packaging and labeling of APIs and intermediates,
utilities (e.g. air, piping), water treatment and containment,
design and construction of facilities and process equipment,
sampling (including retention samples), testing and release of materials and products
storage and distribution of materials and products,
stability of drug (medicinal) products, APIs and intermediates, where appropriate,
returns.
The responsibilities for all production activities should be defined in writing. Significant changes in the
manufacturing process should be evaluated, approved and authorities notified, as appropriate, before
implementation. All quality-related complaints should be investigated according to a written procedure.
1.D.3.5 Control of monitoring and measuring devices
It is necessary to confirm that devices used to monitor product characteristics are suitable for their
intended purpose. Devices should be checked, calibrated and regularly maintained.
This includes computerized systems, laboratory instruments, reference materials, standard analytical
solutions and buffer solutions used for process controls.
1.D.4 Evaluation activities
1.D.4.1 Deviation investigation
The PQS should ensure that deviations from established procedures are identified and recorded.
Incidents that could affect the quality of the product or the reliability of records or test results should be
investigated. The Quality Unit is responsible for making sure that these deviations are investigated and
resolved. The PQS should specify the responsibilities for all functions involved in the investigation and
resolution of deviations.
Further information on this issue is given in chapter 11.K Deviations.
1.D.4.2 Product Quality Review (Annual Product Review)
The Product Quality Review itself is a GMP requirement and should be conducted annually, or if
justified, on another routine basis, to evaluate process consistency through reviews of:
in-process control and test results for trending

all batches that failed to meet established specification(s)
all critical deviations or non-conformities and related investigations
any changes made to the processes or analytical methods
results of the stability monitoring program
all quality-related returns, complaints and recalls
adequacy of corrective actions
the current impurity profile versus the established impurity profile.
The cumulative effects of changes to systems and processes should also be reviewed periodically to
determine if there is a need to revalidate. The Product Quality Review may be used to evaluate
process performance with respect to validation. More detailed information is given in chapter 15.F
Annual product review / Product quality review.
1.D.4.3 Change management
A continual improvement-focused Pharmaceutical Quality System is, by definition, a dynamic entity.

The introduction to this chapter stresses the need to adequately document quality systems
(see chapter 1.C.2 Documentation) to ensure uniformity and understanding. Changes are, therefore,
intimately linked to documentation and its control. Quality-related changes should be comprehensively
planned, carefully controlled, and fully documented. All relevant stakeholders, including regulatory
authorities, where appropriate, should be involved and/or notified of the proposed change, according to
its nature and significance.
Change control procedures
Evaluation and approval of proposed changes to specifications, test procedures, production processes,
production equipment, etc., should be controlled by written procedures.
Evaluation of a proposed change should include consideration of the following:
significance of the proposed change

effect on quality of API or final drug product
impact on drug (medicinal) product subsequently manufactured from the API (e.g.
through changes to impurity profile, crystal form, particle size, residual solvents, stability etc.)
need for operator training
need to involve regulatory authorities
need to revalidate processes.
Proposed changes should be reviewed and approved by the relevant departments and the Quality Unit.
Implementation of changes
All documents affected by the change should be identified and revised accordingly. Changes to
documents should be reviewed and approved by the same functions that performed the original review
and approval, unless specifically designated otherwise. The designated functions should have access
to pertinent background information upon which to base their review and approval.
Where appropriate, the nature of the change(s) should be identified in the revised document or
attachments. However, it is advantageous to incorporate a brief summary of previous changes in the
current version of the document (document history).
Relevant changes in documents previously submitted to regulatory authorities and/or customers should
also be notified. Any operator training needed should be satisfactorily completed and recorded. Several
batches produced following implementation of the change should be extensively evaluated. Changes
resulting from corrective and/or preventive action should be documented and adequately controlled.
Changes to existing quality critical activities should only be introduced once validation is completed,
documented and approved.
Periodic Review of Cumulative Changes
Validated processes (including computerized systems) should be monitored and/or periodically

evaluated, and previous changes assessed, to determine whether there is a need for revalidation.
1.D.4.4 Audits
Internal quality audits, covering quality system elements and GMP requirements, provide a regular and
systematic way of obtaining objective evidence about how the Pharmaceutical Quality System is
functioning. They are an effective means of highlighting activities requiring attention and are, therefore,
a means of driving continual improvement. This approach should be achieved through the use of
documented procedures for planning, implementation and follow-up of internal quality audits to verify
compliance with documented PQS activities, quality manual claims, and GMP and other regulatory
requirements. Since many GMP deficiencies are the result of a weakness in, or failure of, part of the
Pharmaceutical Quality System, an effective internal quality audit system will go a long way towards
ensuring regulatory compliance, and will facilitate continual inspection readiness.
Internal quality audits should be scheduled as part of an ongoing PQS internal audit program, covering
the scope of the quality system documented in the quality manual. The frequency with which different
parts are audited should be determined on the basis of importance to overall PQS performance (i.e.
activities with known weaknesses should be audited more frequently) and a risk-based assessment.
Internal quality audits should be planned, performed, recorded and followed up by

suitably trained staff who are independent of the area being audited. Internal quality auditors
should be experienced in quality systems and GMP in order to perform audits which benefit the
organization.
It is the responsibility of the Quality Unit to make sure that internal quality audits are
performed.
Internal quality system audit findings should be discussed with the respective
management. Agreed, time-limited remedial actions should be recorded and followed up to
completion and sign-off.
The follow-up activities should verify the effectiveness of the corrective action taken.
Output of the internal quality audit program should be summarized and periodically
submitted to senior management as an integral part of the management review process.
1.D.4.5 Complaints
All complaints should be recorded, promptly investigated and reported in accordance with a written,
approved procedure. Quality-related complaints have GMP significance, and it is the responsibility of
the Quality Unit to assure that these complaints are investigated and resolved. Records of complaints
should be reviewed as part of the product quality review (annual product review) in order to identify
trends and corrective and preventive actions.
1.D.4.6 Data analysis
Key to the successful implementation of an effective Pharmaceutical Quality System is the need to
identify, agree and use realistic criteria for routinely monitoring performance trends (KPI - Key
Performance Indicator, see chapter 1.D.4.4 Audits). Some general examples are provided below.
The nature and emphasis of performance measures will inevitably vary from one company to another.
The examples given below are not all-inclusive:
Improvement initiatives ongoing and/or completed

Quality failures, e.g. cost of production failures per month
Percentage of on-time deliveries
Failure costs per development project as a percentage of project costs
Controlled documents overdue for review
Internal audit observation trends
Complaints (numbers, response times)
Recalls and other market withdrawals
Laboratory errors and OOS results
Process deviation frequency
Staff training status
Equipment breakdowns per month
At defined intervals, senior management should review the adequacy and performance of the
Pharmaceutical Quality System to ensure that GMP and regulatory requirements, quality system
principles and quality manual claims are being routinely satisfied. The measures listed above and other
sources of relevant information such as product reviews and external inspections should be used. This
information can be used to realign resources in order to improve the Pharmaceutical Quality System.
Another application of data analysis is the control of processes. Appropriate statistical techniques
should be identified, documented and implemented to control quality-critical processes.
Trend analysis and the identification of process capabilities are likely to be the main applications of
statistical techniques in all areas. In the manufacturing and control area, statistical techniques would
apply e.g. to validation, sampling plans, stability testing and interpretation of analytical data. A
statistical perspective is essential when planning a complex investigation if maximum benefit is to be
derived.
Manufacturers should identify and document the need for, and application of, appropriate statistical
techniques. Documented procedures and adequate training should be used to control the application of
statistical techniques. Whenever possible, recognized statistical techniques should be selected for use.
If alternatives are applied, their use should be justified through traceability to basic statistical theory.
1.D.4.7 Risk management
The principles of quality risk management as laid down in ICH Q9 should be incorporated into the
Pharmaceutical Quality System as a means of focusing resources on priority issues and areas of
improvement. Also, the Pharmaceutical Quality System should take into consideration that operations
require careful planning, execution and monitoring to reduce risk and the costs of failure.
Some major operations where quality risk management could be applied are listed below:
Control should be exercised over labels used during the manufacture and filling,
including label reconciliation, to absolutely minimize the risk of label mix-ups or the use of
incorrect or out-of-date labels.
Weighing or subdivision of material prior to use should be performed in an appropriate
area to minimize the risk of cross-contamination.
Drug (medicinal) products and APIs should be handled in an environment giving
adequate protection.
Equipment should be designed, constructed, located, and used so as to minimize the
risk of contamination or mix-ups arising during manufacture.
Whilst clean-up between successive batches of the same API or drug product may not
be mandatory, equipment should be cleaned at appropriate intervals when the risk of
contamination from microbiological growth or non-acceptable material build-up becomes too
great.
Pipework and valves should be designed to minimize the risk of contamination.
Permanent pipework should be labeled with the name of the material therein and the direction
of flow, and should be located so that rusting, surface condensation, or leakage will not lead to
contamination.
Prospective validation should apply to all relevant new or modified processes. It is
usually the result of a risk analysis performed on the proposed new or modified production
process.
Computerized systems should be designed, implemented and operated so as to
minimize the risk of failures. This includes supporting computerized systems such as Enterprise
Resource Planning (e.g. SAP®) and/or Document Management Systems (e.g. Documentum®)
as well as systems used in manufacturing (e.g. SPS, DCS, LIMS).
Other examples of integrating quality risk management into current operations are given in chapter 6 of
ICH Q9 (see chapter E.9 ICH Q9: Quality Risk Management) . Principles and methods of risk
management are described in chapter 10 Considerations on Risk Management.
1.D.4.8 Corrective and Preventive Actions (CAPA)
The Pharmaceutical Quality System should aim to prevent occurrence of non-conformities, but when
they do occur, it should allow for implementation of corrective measures. A planned and structured
approach to corrective and preventive actions increases the likelihood that the root cause of actual or
potential quality problems will be identified and lasting remedial action taken. When failures occur, the
true underlying cause(s) should be established if learning points are to be identified and appropriate
corrective measures applied.
The cause(s) of actual and potential non-conformities in product, process or the quality system itself
should be identified and eliminated. Action should be appropriate to the severity of the non-
conformities. Changes resulting from corrective and/or preventive action should be documented and
adequately controlled.
Corrective action
Corrective action is intended to both rectify any existing non-conformities and avoid a
recurrence. It is, therefore, necessary to identify the underlying cause of the problem.
Corrective action may arise e.g. from complaints, recalls, audit findings, management
reviews and other situations where non-conformance is likely to be identified.
A carefully planned and timely investigation should be carried out to determine the
reason(s) for the non-conformities and agree appropriate action.
Details of the non-conformities, the associated investigation and agreed actions should
be recorded.
Progress with agreed actions resulting from the non-conformities investigation should be
closely monitored until all are satisfactorily completed.
Senior management should be notified about the costs of failure including the respective
corrective actions.
Preventive action
Preventive action is intended to avoid the initial occurrence of a non-conformity.

Preventive action may include analysis of trends in process, product, analytical data and
equipment as well as operator performance. Sources of information could include audit reports,
product quality reviews (annual product reviews), recalls, customer complaints and any other
data likely to assist in identifying areas of potential non-conformity.
As with corrective action, preventive action should be authorized, carefully planned,
implemented in a controlled manner and adequately monitored to ensure the desired outcome.
Information relevant to preventive (and corrective) actions including costs and cost
savings should be regularly collated and presented for management review in support of
maintaining and improving the effectiveness of the Pharmaceutical Quality System.
1.D.4.9 Continual improvement of the organisation
To fully benefit the company, the Pharmaceutical Quality System should involve all staff whose
activities influence quality, have a clear and unambiguous focus on continual improvement and
incorporate relevant, realistic performance measures with emphasis on reducing failure costs, and
satisfying (internal and external) customer needs.
If the Pharmaceutical Quality System is designed and implemented to emphasize continual

improvement (being driven by the effective use of internal quality audits, corrective and preventive
action, and management review), then internal efficiency will rise, leading to a sustainable reduction in
failure costs. Similarly, the effective control of nonconforming product helps to identify the root cause of
quality problems, and in so doing, provides an important improvement opportunity. A comprehensive
internal quality audit system (see chapter 1.D.4.4 Audits) is a vital health check and provides a means
of identifying issues in need of attention, while a planned and structured approach to corrective and
preventive action increases the likelihood that the basic cause of actual or potential quality problems
will be identified and lasting remedial action taken.
In addition, the Pharmaceutical Quality System should encourage the employees to make suggestions
for improvements by incorporating a system which makes it easy for employees to communicate
suggestions and which provides for timely review of these suggestions.
1.D.4.10 Control of non-conforming product
Product which does not conform to specification (OOS) and established processing requirements is
usually identified by inspection and/or testing, customer complaint or internal quality audit. A non-
conforming product should be recorded, clearly identified as non-conforming and physically segregated
(unless an alternative, equally effective procedure is available) to prevent unintended use until its
disposition (i.e. reworking, reprocessing, release on conditional status or disposal) can be agreed.
Relevant staff should be notified and an investigation performed to determine the extent and cause of
the nonconformity and to agree appropriate action.
The process for investigating and controlling non-conforming product should be described in written
procedures.
Responsibility for reviewing information relevant to, and authority to decide the
disposition of non-conforming product should be clearly documented.
Subsequent use of non-conforming material should be approved by the Quality Unit
after full review of the non-conformities or deviation, including results that are out of
specification, and the investigation.
The likely effect upon related batches of product should be assessed.
Any decision to reprocess returned non-conforming product should take into
consideration the fact that the product has been outside the control of the manufacturing
company.
Reworked product should be retested in accordance with documented procedures
incorporating appropriate controls agreed between production and the Quality Unit. Special
consideration should be given to the impurity profile of a reworked batch, including the use of
non-routine measurements if necessary. The release of reworked product has to be agreed
with the relevant authority.
Reprocessing and reworking should be documented and included in the batch records.
A new batch number should be assigned following reworking.
The nature of the non-conformities together with details of the associated investigation
and justification for disposition of the non-conforming product should be recorded.
If reprocessing becomes a regular occurrence, the adequacy of the original
manufacturing process should be re-evaluated.
A written, approved procedure should clarify the circumstances in which a recall should
be considered. This document should also indicate responsibilities and actions in the event of a
recall. The distribution system should permit prompt determination of the location of each batch.
In the event of a serious and potentially life-threatening situation, the (local and national)
authorities should be informed and their advice sought.
More information about handling of non-conforming product is given in the following chapters:
chapter 11.K Deviations

chapter 11.L Reworking
chapter 14.H Out-of-specification results
1.D.4.11 Measurement of customer satisfaction
To fully benefit the company, the Pharmaceutical Quality System should incorporate relevant, realistic
performance measures with emphasis on satisfying (internal and external) customer needs. Methods
for collecting information on customer satisfaction should be developed, and the results used as part of
the continual improvement process of the Pharmaceutical Quality System.
1.D.4.12 Measurement of employee satisfaction
A concisely documented Pharmaceutical Quality System, having the full visible support of senior
management, will lead to better understanding of employee roles, responsibilities, authorities, and
working interfaces. It will avoid confusion, and reduce the risk of omission and/or duplication. Less staff
time will be absorbed by "fire-fighting" and crisis management, allowing more time to be devoted to
improving operating efficiency.
Continually improving operations should result in measurable improvements in employee satisfaction

with their work and working conditions. Management should periodically survey employees to measure
their satisfaction as well as to identify opportunities to improve the Pharmaceutical Quality System.
Summary
This section shows how the specific GMP requirements of the pharmaceutical industry can be merged with the
general demands of the PQS. The four main processes of a PQS are "Management responsibility", "Resource
Management", "Manufacturing Operations" and "Evaluation Activities". All GMP requirements can be assigned
to one of these processes.
1.E Essentials of a PQS

What are the major characteristics of a process?
How can a process contribute to continual improvement?
What are the techniques to be used for describing and visualizing processes?
Why do we need Process Owners?
How can the performance of a process be measured?
1.E.1 Principles of a process
1.E.1.1 General aspects
A process approach is a powerful way of organizing and managing how work activities create value
and to enhance an organization's effectiveness and efficiency in achieving its defined objectives.
Organizations are often structured into a hierarchy of functional units. Organizations are usually
managed vertically, with responsibility for the intended outputs being divided among functional units.
The receiver of the work is not always visible to all involved. Consequently, problems that occur at the
interfaces are often given less priority than the short-term goals of the units. This leads to little or no
improvement, as actions are usually focused on the functions, rather than overall benefit to the
organization.
In contrast, the process approach introduces horizontal management, crossing the barriers between
different functional units and unifying their focus to the main goals of the organization. It also improves
management of process interfaces.
The benefits of a process approach can be summarized as follows:
Integration and alignment of processes to enable achievement of planned results.

Ability to focus effort on process effectiveness and efficiency.
Giving customers, and other interested parties, confidence about the consistent
performance of the organization.
Transparency of operations within the organization.
Lower costs and shorter cycle times, through the effective use of resources.
Improved, consistent and predictable results.
Providing opportunities for focused and prioritized improvement initiatives.
Encouraging the involvement of people and the clarification of their responsibilities.
1.E.1.2 Process characteristics
According to ISO 9000:2000, a process can be defined as a set of interrelated or interacting activities,
which transforms inputs into outputs. A process is thus a specific ordering of work activities across time
and place. These activities require the allocation of resources such as people and materials.
Figure 1.E-1 shows a generic process.
Figure 1.E-1 A generic process (numbering relates to descriptions in the text)
to enlarge, click
here!
The characteristics of a generic process can be broken down as follows:
1. Objective of the process: A process exists within an organization for a very specific reason. It
benefits the organization as a whole and contributes to satisfying business needs. Examples of
objectives are e.g. to organize change management, a transfer, ensure stability, handle complaints and
recalls.
2. Input from a provider: Every process requires something to start with. This can be an order,
incident or routine activity, etc.
3. Output to a receiver- what this process delivers: A process will typically produce one or more
outputs of value to the business. The output, either internal or external, may be a physical object, a
transformation or a result.
4. Activities within the process: Within a process different tasks need to be accomplished and
coordinated to achieve the defined results.
5. Interfaces to other processes: No process operates in isolation - they have interfaces to other
processes, internally and/or externally. These interfaces need to be carefully coordinated to optimize
the organization's output as a whole.
6. Information required from outside the process: Information is required to tailor or complete
activities in a process. Information, unlike resources, is not consumed in the process - rather it is used
as part of the transformation process. Information may come from external sources, from internal units
and may even be the product of other processes.
7. Resources needed to perform activities within the process: A resource is an input to a process
and is typically consumed during the processing.
8. Key Performance Indicators (KPIs) of the process: The value added by a process needs to be
measured by appropriate means. To this end, KPI(s) are identified and established for each and every
process.
The activities to be conducted within a process need to be carefully coordinated in order to avoid
disruptions and inefficiency (numbers relate to those inFigure 1.E-2.):
1. Gaps in responsibility need to be addressed in order to get the work done.

2. Overlaps in competencies have to be identified and remedied to avoid functions/people working
against each other, thereby reducing process performance.
3. Poorly defined interactions lead to parallel working and thus duplicating results
4. Poorly defined interfaces will give rise to activities that are surplus to the needs of that process
5. If numerous interfaces are ambiguous and results from one activity feed into the next, at some point
in the process it will be difficult to utilize the work produced in the preceding step.
Figure 1.E-2 Interfaces within a process (numbering relates to descriptions in the text)
to enlarge, click here!
The performance of a process is highly dependent on the optimal alignment of its constituent activities.
Every process defined within a Pharmaceutical Quality System is established with a view to performing
a specific task which will contribute to the overall output of a company. Thus, a company can only be
successful if each of its processes adds value to the business (Figure 1.E-3).
Figure 1.E-3 Added value created by a process
Basically two different process types can be distinguished:
Manufacturing processes (realization of the product) and

Business processes (procurement of materials, sourcing decisions)
Examples of manufacturing processes include individual production steps, e.g. operation of filling
lines, flow of a material, testing of samples, etc.
Business processes are activities which are not directly involved with production but which are
needed to coordinate all efforts related to production, either to ensure compliance with regulations or to
achieve the best possible organization of company activities. Typical examples are recall management,
change management, transfer of products or auditing.
A major advantage of the process approach is that it allows for better management and control of
interactions between processes and the vertical and horizontal interfaces within the organization.
Inputs and outputs may be tangible (such as equipment, materials or components) or intangible (such
as energy or information). Outputs can also be undesirable, such as waste or pollution.
Each process has a receiver (either internal or external to the organization), who is affected by the
process and who defines the required outputs according to his needs and expectations.
All processes should be aligned with the objectives of the organization and be designed to add value,
in relation to the scope and complexity of the organization.
Process effectiveness (the ability to achieve desired results) and efficiency (results vs. resources used)
can be assessed through the implementation of achievable key performance indicators - KPI(s).
The output from one business may feed into another process, either as a requested item or a trigger to
initiate new activities (for generic examples seeFigure 1.E-4 and Figure 1.E-5).
Figure 1.E-4 Example of a generic process sequence

Figure 1.E-5 Example of a process sequence and its interactions

1.E.1.3 Process implementation
The following implementation methodology can be applied to any type of process:
Identification of processes of the organization
Definition of the needs of the receiver (customer requirements)

Definition of the objectives of the organization
Determination of the processes in the organization
Determination of the sequence of the processes
Definition of process ownership
Definition of process documentation
Planning of a process
Definition of the activities within the process

Definition of the monitoring and measurement requirements
Definition of the resources needed
Verification of the process and its activities against its planned objectives
Implementation of the process
Implement the processes and their activities as planned. The organization may develop a project for
implementation that includes, but is not limited to:
communication,
awareness,
training,
change management,
management involvement,
applicable review activities.
Measurement of the process
Identification of process-related indicators

Performance of measurements, monitoring and controls as planned.
1.E.1.4 Process improvement
Once the planned process requirements are achieved, the organization should focus its efforts on
actions to improve process performance to higher levels, on a continual basis.
The PDCA methodology (Plan-Do-Check-Act, see Figure 1.E-6), also known as the Deming cycle, is
the tool that is most commonly used to define, implement and control corrective actions and
improvements. The methodology applies equally to high-level strategic processes as well as to simple
operational activities.
Figure 1.E-6 The PDCA methodology (Plan-Do-Check-Act)

Plan Establish the objectives and processes necessary to deliver results in
accordance with customer requirements and the organization's policies;
Do Implement the processes;
Check Monitor and measure processes and product against policies, objectives and
requirements for the product and report the results;
Act Take actions to continually improve process performance
When it is identified that items within or between activities in a process can be performed in a better or
more efficient way, these items are fed into the PDCA cycle (no. 1 of Figure 1.E-7). Here they undergo
a systematic evaluation in a continual improvement loop. Following the decision to revise the item, the
item is fed back into the process, thereby modifying conditions in the process and all going well,
increasing the value added.
Figure 1.E-7 shows a process being challenged with Deming (PDCA) cycle methodology, firstly
through Planning, and then sequentially, through the other steps of: "Do" - "Check" - "Act".
Figure 1.E-7 How PDCA methodology is applied to a process

1. Input of process into Deming cycle
2. Output of Deming cycle back into process
3. The step between "Check" and "Act" is key to the conversion of information
into knowledge
4. represents the learning step of the Deming cycle and thus knowledge
enrichment
5. The entire cycle is the so-called "continual improvement" loop
1.E.2 Process mapping
1.E.2.1 Reasons for mapping processes
It has been estimated that people working in organizations can waste 15-20 % of their time by re-doing
things that are wrong, chasing things without results, querying incomplete instructions or doing other
people's jobs.
Presumably all companies have organizational charts. While these are useful tools for communicating
reporting relationships, given the complexity of the tasks in hand, they can never fully reflect the actual
relationships and interactions within a company. Organizational charts do not answer the question of
what is required to deliver a given output, or what contribution a department makes to the whole or how
work is accomplished.
Process mapping gives a better understanding of the work to be done in the organization. Maps are
often used to show how work currently gets done and they serve to make the work more visible. The
very act of mapping involves the gathering and organizing of facts about the work, and paves the way
for improvements. Process maps aid understanding by abstracting the key elements of a process and
using visual charting symbols which mask unnecessary details.
A better understanding of the important characteristics of a process generates useful data from which
to derive findings, draw conclusions and formulate recommendations. Furthermore, process maps urge
us to systematically ask questions and adopt a viewpoint of business process improvement.
Process maps help to:
Orient new employees

Organize the work to be done by the organization
Evaluate or establish alternative ways to organize the tasks to be done
Clarify roles and contributions
Identify areas of improvement
Evaluate, establish and/or strengthen performance measures.
There are a variety of maps that can be used to visualize the work of an organization. In this chapter,
three different approaches are introduced which are complementary when used in combination:
Relationship maps
Flowcharts
Cross-functional process maps
Relationship maps (see Figure 1.E-8) show - as the name suggests - relationships or linkages
between parts of an organization. They illustrate the general landscape and reveal the coherence of
the overall framework of processes in a logical sequence. They are used to give a broad overview of
the situation and outline how major functions of the business interact with one another. A relationship
map can be drawn up for any level of the organization.
Figure 1.E-8
Example of a relationship map
Flow charts (Figure 1.E-9) are presumably the best known tool for illustrating work processes.
Flowcharting has long been used to define all aspects of tasks and work at the most detailed level -
that of the individual performing the task. They lay down operational activities and include decisions
and descriptions of responsibilities.
Figure 1.E-9 Example of a Flowchart
The correlation between a relationship map and a flowchart is shown in Figure 1.E-10.
Figure 1.E-10 Correlation between relationship map and flow chart

to enlarge,
click here!
Flow charts represent a small segment of the wide span relationship map and describe the actions in
this part of the relationship map in detail.
Cross-functional process maps show how an organization's major work processes are distributed
across several functions (Figure 1.E-11). This kind of map shows what goes on inside the "black box"
of the organization's functions and shows the sequence of steps that make up the work associated with
each process step. Whereas the relationship map does not generally show the steps that make up a
process, this is a key feature of the cross-functional map.
Figure 1.E-11 Example of a cross-functional map
Figure 1.E-12 gives a brief summary of the major elements of the different process maps that will be
discussed in detail in the next sections.
Figure 1.E-12 Comparison of major elements of the different process maps

Relationship Map Flow chart Cross-functional process map
Purpose Shows relationships within Shows tasks, sequence of tasks, Shows sequence of steps of a
the organization inputs, outputs and activities particular work process across the
organization
Focus Organization Process Detail Interfaces
Level of Low High Medium
detail
Key "black box", Shows everything in detail Shows who (function) performs the
elements Does not show processes Does not outline who performs steps
within the box the task Shows the sequence of activities
Shows linkages Shows how the work gets Shows linkage of input/output of a
Connects pieces of the accomplished process
organization to one another
1.E.2.2 Relationship maps
Relationship maps provide a framework of processes performed. They are the umbrella for the
processes to be carried out in detail and provide a "high-level" view. Relationship maps have to be
requested and supported by senior management. They involve interfaces beyond the organization
charts and reflect sequences of workflows performed.
Relationship maps help to
understand the work flows through functional boundaries

identify internal or external relationships
eliminate unnecessary tasks
clarify roles within processes
reduce delays and duplication
allocate resources where needed
The principle construct of process maps has to consist of two equally important tracks:
The main processes represent a series of areas that need to be passed in order to link
the input from the provider to the output to the receiver
Performing these series of activities assisted by supporting processes.
The following steps need to be followed when creating a relationship map:
Decision/agreement of senior management to establish a relationship map

Define scope and objective
Determine input (provider) and output (receiver)
Define activities towards objective (logical sequence of activities)
Define activities needed to support the process (additional processes needed to enable
the main process to achieve the objectives)
Draw relationship map
Determine Process Owner
Approve relationship map by senior management
Communicate relationship map to the organization.
Relationship maps show the parts of an organization which are "wired" together. It helps to identify
quickly:
connections and interfaces on a "high-level"

in- and output needed
involvement of organizational functions in the process.
In addition it is easy to identify "disconnects" in a process, e.g. missing linkages. Disconnects are
usually seen in cross-functional processes; the more functions a process crosses, the more likely is it
to find disconnects.
There are no instructions or guidance as to how to physically draw a process map. The following
examples (Figure 1.E-13, Figure 1.E-14, Figure 1.E-15) are intended to show the variety of possibilities.
Figure 1.E-13 Relationship map outlining major blocks of the process
to enlarge,
click here!
Figure 1.E-14 Relationship map showing sequence of interaction

to
enlarge,
click
here!
Figure 1.E-15 Relationship map providing details of interactions
to
enlarge,
click
here!
1.E.2.3 Flowcharts
A flowchart is a graphic representation of the sequence of steps that make up a process. It is a tool to
describe a detailed workflow of processes embedded in a process map or into another flowchart.
There are a number of benefits to using flowcharts:
Promote process understanding: People may have different ideas about how a
process works. Flowcharts can help gain understanding about the sequence of steps. A good
flowchart can replace pages of words.
Provide a training tool for employees: Because of the visual layout of the sequences
of process steps, flowcharts can be helpful in training employees to perform the process
according to agreed procedures.
Identify problem areas and opportunities for process improvement: Once the
process steps have been broken down and visualized, problem areas become more visible. It is
easy to spot opportunities for simplifying and refining processes by analyzing decision points,
redundant steps and rework loops.
There are key success factors when drawing up a flowchart:
Start with the overall picture: It is the best to start off with the macro level. After
depicting the big picture of the process, other diagrams can be developed with increased levels
of detail.
Observe the current process: In a first step the current process needs to be
described, observing it in actual operation.
Record process steps: Record all steps in detail as they occur. This will disclose all
parties involved and will facilitate the structuring of activities.
Arrange the sequence of the process steps: In the next step the sequence needs to
be described exactly as observed.
Flowcharts are able to visualize complex organizational activities. These complex structures are
subject to change over time in response to the changing environment and/or new laws and regulations.
Changes are often made in isolation, reactive and piecemeal, and are not necessarily best for the
company or the people conducting the work. The only way to control changes (and not to be controlled
by changes), is to clarify what actually happens and to decide whether this is the way it should be. How
a change might influence other processes must be assessed before the change becomes effective
(see chapter 1.D.4.3 Change management Change Management).
Flowchart building blocks

The use of symbols to represent what actually takes place in the work process is a pre-requisite of
flowcharting. It is not the number or variety of symbols that makes the flowchart useful, it is whether
enough symbols are used to help to recognize where waste, delays, rework, etc. occurs in a process.
The symbols commonly used (Figure 1.E-16) are laid down in ISO 5807. In practice, only a few of
them are normally enough to describe a process as a well-structured and easy-to-understand overview.
Where additional symbols are introduced they should add clarity to the workflow.
Figure 1.E-16 Basic symbols to use in a flowchart (according to ISO 5807)

Symbol for a step Description of symbol Explanation
Rounded First/Last step: when Represents an activity which occurs automatically. Such an
box: and why the process is activity will trigger or end any subsequent actions and
to enlarge, click here! going to start/end decisions.
Rectangle Represented by a verb Represents an activity which is controlled within the process
and a subject and which describes typically a step or action which is
box : taken. Normally an activity or an action has a go/no-go
to enlarge, click here! decision at the end. Thus these activities or actions can
themselves represent a sub-process. This also includes
creation or approval of records/documents.
Marked Refers to another Represents a set of activities and decisions which run
box: process several times or in several processes.
Waved box: Reference to a Represents an activity to issue a deliverable (if put in the
to enlarge, click here! document sequence) e.g. a report
Line Expresses interrelation Represents the flow of activity in the process. It can be a
connector of symbols, if line or a unidirectional or bidirectional arrow
to enlarge, click here! applicable to enlarge, click here!
Question for branching Represents a decision point in the process. Typically, the
statement in the symbol will require a `yes' or `no' response
Diamond:
and will branch to different parts of the flowchart
accordingly.
Interface and Represents a point at which the flow chart connects with
responsibilities: Link to another process/interfaces or resources (responsibilities).
Circle: resources or The name or reference for the other process should appear
to enlarge, click here! other/further processes within the symbol.
Small Connector if the flow Connects the outcome of several flows
chart has to be
circle: continued; use e.g. a
to enlarge, click here! letter to mark (A, B ...)
Rhomboid: Link to a data base or Represents a point at which the flow chart connects links to
to enlarge, click here! data collection databases or other interfaces.
Set up of a flowchart
Each sequence representing the process needs to have a start and an end (rounded boxes). It
provides a clear and simple visual representation of the steps involved. The technique breaks down a
process into its constituent steps (e.g. unit operations) in order to make the flow transparent. These
steps can either be activities, actions or decisions with feedback loops. Annotations can be made as
appropriate. It has been shown to be beneficial to number the sequences of steps as shown
in Figure 1.E-17 and Figure 1.E-18.
Figure 1.E-17 Principle view of a flow chart (part I)

Figure 1.E-18 Principle view of a flow chart (part II)
Flowcharting facilitates the understanding, explanation and systematic analysis of complex processes
and associated risks.
To accompany the flowchart, a separate table is usually created which describes the responsibilities
and interfaces. This table supports the flowchart and explains with brief wording the intention of the
symbols. As a model in Figure 1.E-19 and Figure 1.E-20 the interaction of the flowchart with the
coupled table is shown.
Figure 1.E-19 Example of the first part of a process flow

Figure 1.E-20 Example for description of the activity/decisions in a flow chart
Responsibility
Nr Input Activities Output
R A C I
01 Potential need for Idea to create a Consider purpose and stakeholders Any person, who X
a new document new document suggest a document
Secretary X
02 Idea Check with Yes: Consistency check with PMS Senior Management X
available stakeholders if (go to step xx) and decide on Author X
needed potential author
No: no extensive revision needed
(go to step yy)
Within the table - and this is its major purpose - a responsibility assignment matrix, also known
as RACI is integrated, describing the participation by various roles and/or functions in completing the
activity. It is especially helpful when activities have a cross-functional/departmental character.
RACI is an acronym derived from the four key responsibilities most typically used (see Figure 1.E-21).
Figure 1.E-21 Explanation of "RACI"

Responsible Person(s) responsible for carrying out an activity within a specified time and budget
(R)
Accountable Person who is ultimately accountable for the correct and thorough completion of the deliverable or
(A) task and the one to whom the "Responsible" person is accountable. In other words, an
Accountable person is the approver of the work that the "Responsible" person provides.
Only one person can have this activity in each step.
Consulted Those persons whose opinions are sought and with whom there is a two way communication.
(C)
Informed (I) Those (e.g. organizations, people) who need to be informed about decisions made, about a
finalized action or a result and with whom there is just one way communication.
For more complex processes it might be worthwhile to have an overview of responsibilities for the
sequence in the form of a summary matrix, as shown inFigure 1.E-22.
Figure 1.E-22 Example of a summary RACI matrix

Responsibilities
Nr Activities Senior Remarks
Person Author Secretary Sites
management
01 Idea to create a new document R - - I -
02 Check with stakeholders if needed - I A - -
Note that the RACI matrix is of one of many alternative ways of describing the responsibilities of
involved person(s) and/or function(s).
The flowchart shown in Figure 1.E-23 and the attached table (Figure 1.E-24) show how to set up a
flowchart using flowcharting as an example.
Figure 1.E-23 Steps to follow in setting up a flowchart and respective descriptions
Figure 1.E-24 Description of process to set up a flowchart and respective descriptions

Responsibility
Nr Input Activities Output
R A C I
01 Set up of the Process as part Request to establish a Senior X
process of the process flow chart by management management /
framework map team Management
communicated Process owner to form a team
matrix team consisting of Process owner X
departments and functions
involved in the process Matrix team X
Process owner to Heads of X
organise a kick off involved
departments
02 Kick off Determine Process is set up: Process owner X
organised scope, objective, Scope defined Matrix team X
provider & Objective agreed
receiver Provider identified Heads of X
Receiver involved
Adapt membership of the matrix team departments
03 Process set up List activities What to do? Process owner X
concluded performed Start with the activity Matrix team X
that triggers the process
Use a verb to start the
activity
description of the
activity
Focus on the main flow
of activities and decisions
All activities & decisions listed
04 All activities & Draw flow chart A flow chart is drawn: Follow the process Process owner X
decisions listed through to a conclusion as a final target Matrix team X
IT tool for point
drawing Activities & decisions ordered in a
sequence as per the current way of
executing
05 A flow chart is Describe each Determine details for each activity in the Process owner X
drawn activity flow chart: Matrix team X
Input/provider
Output/receiver Involved X
Think about end point departments /
of an activity functions
Responsibilities &
interfaces
Add cross-reference to requirements, laws
and norms, supporting information, other
processes and resources, as appropriate
06 Activities are Consider risks List of risks involved in the process which Process owner X
described can hinder reaching the objective (critical Matrix team X
success factors) e.g.
Receive the input
needed
Run the process and the
interfaces
Achieve the output in a
timely manner
07 Risks assessed Set up process Process flow and descriptions summarised Process owner X
description and documented Matrix team X
Document (e.g. sop) issued by the process Senior X
owner management /
Document approved by the head of the Management
department / management team team
Heads of X
involved
department /
functions
08 Details are Agreement Is consensus on the flow achieved? Process owner X
determined achievement Is the description consistent?: Matrix team X
Same level of details?
Is all implemented? Heads of X
What should be involved
considered for further departments /
improvement? functions
What is redundant?
What is missing?
If yes: Consensus and consistent
description of the process; approve the
description
If no: go to 02
09 Approve the Communicate Training performed Process owner X
description (e.g. process Ideas for improvements collected Involved X
sop) departments /
people
10 Potential Consider Decision to revisit the process flow for Process owner X
improvements optimisation continual improvement Senior X
communicated to management /
process owner Management
Process is not team
running smoothly
Involved X
departments /
people
Working with flowcharts
A flowchart will help to understand the process and uncover ways to improve it by taking into
consideration the following:
Determine who is involved in the process

Tracing back root causes
Identify ways to streamline the process
Determine how to implement changes to the process
Locate "cost-adding-only" steps
Providing training to the employees on how the process should work
To improve the process, the following aspects are to be discussed on the basis of the flowchart:
Examination of each process step

o Bottlenecks: These points in the process where it slows down may be caused
by redundant or unnecessary steps, rework, lack of capacity, etc.
o Weak links: These are steps where problems occur because of inadequate
training of employees, equipment that needs to be repaired or replaced, insufficient
documentation, etc.
o Poorly defined steps: Steps which are not well-defined may be interpreted and
performed in a different way by the persons involved, leading to process variation. To
"improvise" is a poorly defined step in the weak link cited above.
o Cost-adding-only steps: Such steps add no value to the output of the process
and should be marked for elimination.
Examination of the decision symbols: Data should be collected on how often there is
a "yes" or "no" answer at decision points (marked by a diamond shaped symbol;
compare Figure 1.E-16. If most decisions go one way rather than the other, it should be
considered to remove this particular decision point.
Examination of each rework loop: Processes with numerous checks generate rework
and waste. Examine the activities preceding the rework loop and identify those that need to be
improved. Look for ways to shorten or eliminate loops.
Examination of each activity symbol: Answer the question: does the step help to
build a key quality characteristic into the output of the process? If not, consider eliminating the
step.
Working with flowcharts requires a certain degree of experience. Therefore a number of pitfalls can
occur by creating and using flowcharts in daily business:
Those developing the flowchart may have drawn it to represent the process as it should
work and not as it is.
People may be reluctant to accept the obviously illogical parts of the process for fear
they will be held accountable and to explain why they allowed it to be this way.
Rework loops are either not seen or not documented because it is assumed that rework
is negligible and inevitable.
Persons drawing the flowchart are not familiar with the process.
Measures should been taken to avoid and correct these pitfalls.
1.E.2.4 Cross-functional process maps
When following a flowchart which describes a specific process, it is sometimes difficult to keep track of
who is responsible for each step. A useful technique for tracking this and for analyzing the number of
times a process is "handed over" to different functions / peoples is to break flowcharts into columns.
Cross-functional process maps are used to show the relationship between a business process and the
function (such as departments) responsible for that process.
Cross-functional process maps show the value-producing chains of the business. They depict the
pathways from input to output. Whereas relationship maps focus on the overall picture, cross-functional
process maps show in more detail how an organization uses processes to create value.
Cross-functional process maps can be projected either vertically (see Figure 1.E-25) or horizontally
(compare Figure 1.E-26).
A vertical layout places slightly emphasis on the functional units, while a horizontal layout gives greater
emphasis to the process.
Figure 1.E-25 Simple example of a vertical cross-functional process map

to enlarge, click
here!
Drafting cross-functional process maps uses similar techniques to those described in chapter 1.E.2.3
Flowcharts. Some simple rules need to be followed:
Each process needs an input and output (no. 1 in Figure 1.E-26)

The sequence of the steps needs to be reflected. Each box represents an activity as
defined in Figure 1.E-16 (no. 2 in Figure 1.E-26).
Functions are outlined that perform each step (no. 3 in Figure 1.E-26).
Figure 1.E-26 Simple example of a horizontal cross-functional process map
to enlarge, click
here!
Some other conventions can be used which represent the most common cases (Figure 1.E-
27 and Figure 1.E-28).
Figure 1.E-27 Use of diamonds in cross-functional process maps
to
enlarge,
click
here!
Whenever a dotted line is passed, the responsibility is handed over.
In Figure 1.E-28 an option for presenting tasks that are jointly performed is outlined.
Figure 1.E-28 Depiction of jointly-performed tasks in a cross-functional process map

There are a variety of other possibilities to visualize the process across departmental/functional
responsibilities. The techniques of flowcharting can be adapted. In practice, flowcharting and cross-
functional process mapping are used simultaneously and are combined into one graph.
Cross-functional process maps help to:
understand what steps are required to produce a particular output,

visualize the order in which the steps are performed,
address who (function / department) performs the step,
outline the interfaces between the functions / departments,
describe in which parts of the process someone is involved.
As cross-functional process maps are set up, inputs or outputs may be discovered that do not feed into
any other steps within the same function/department, or into steps within other functions/departments.
In addition, missing or implied steps, inputs or outputs can be identified. Each of these are a form of
disconnect that should be noted and resolved.
1.E.3 Responsibilities
Each process must have one defined process owner. The process owner is accountable for the
proper maintenance of the process, for ensuring that continual improvement is enabled and making
sure that the process and interfaces are agreed with all involved parties (e.g. functions, departments).
The process owner ensures that sufficient resources are allocated by the senior management and is in
charge of evaluating and communicating key results and Key Performance Indicators (KPI) to senior
management.
The process owner is responsible for defining the strategy of his/her process in the given framework
and for managing all operations associated with the process. Another area of responsibility is to
administer the description of the process. In an advisory role, the process owner identifies weak points
in the process and continuously improves and optimizes it, collecting and driving matters under his/her
responsibility towards improvement (e.g. CAPA).
In describing a process, it is important to provide a clear understanding of the contributors involved,

such as:
Who (department, function or person) is responsible for carrying out a qualitative

operation within a specified time and budget?
Who has accountability for basic decisions? Only one person can have this task in each
step.
Who has to be involved as advisor / consultant in helping to identify solutions for
problems and produce decisions? The solution should be achieved by consensus with the
person who has to take the decision.
Who must be informed about decisions made, about a finalized action or a result?
For more details see chapter 1.E.2.3 Flowcharts and specifically Figure 1.E-21.
The overall interactions within the process and between different processes are managed by the
process owner.
1.E.4 Key Performance Indicators (KPIs)
If a process is not measured it cannot be effectively managed, and if a process cannot be effectively
managed it cannot be improved. Thus, every process needs to be measured and at least one Key
Performance Indicator (KPI) per process has to be established.
It has been estimated that people working in organizations waste up to 15 - 20 % of their time by
redoing things that are wrong, chasing things without result, querying incomplete instructions and/or
doing other people's jobs.
In order to assess the performance of a process, KPI(s) are established. KPIs are intended to monitor
the success i.e. the performance of a process - and not individual performance! Alarm limits should be
established to address when an intervention is needed.
The environment for identifying KPIs is:
Having pre-defined processes

Having clear goals/performance requirements for the processes
Having a quantitative/qualitative measurement of the results and comparison with set
goals
Investigating variations and tweaking processes or resources to achieve short-term
goals
Normally the SMART technique (Specific, Measurable, Achievable, Relevant, Time-bound) is to be

applied when identifying indicators.
KPIs can be categorized as follows:
Quantitative indicators
presented as a number or other alphanumerical coding
Directional indicators
specifying whether a process is getting better or not
Actionable indicators
to alert an organization to consider changes.
Key Performance Indicators should be monitored with a view to adding value to the business and
process.
In the following examples, a number of possible (but by no means all-inclusive) indicators are shown.
KPIs may vary from company to company.
Management responsibility
Frequency of management review meetings actually held (versus scheduled)

Number of improvement initiatives generated (and implemented)
Quality system
Incidence of non-conformances
Relative categories of non-conformances
System improvement initiatives in progress/completed
Contract review
Customer satisfaction score

Delivery against agreed lead time
Design control
Project delays
Significant post-launch quality specification revisions
Quality-related cost overruns
Document control
Proportion of controlled documents beyond official review date

Delays/failure costs due to lost/out of date documentation
Relevant internal quality audit observation trends
Purchasing
Late delivery
Percentage deliveries with quality problems
Percentage of customer complaints traceable to purchased material/services
Change control
Overall effectiveness of change control procedure

Number of delays due to weaknesses in change control procedure
Identification and traceability
Impact upon complaint response time

Lost/misplaced material/product
Process control
Rejected/reworked/reprocessed/recalled product (incidence/cost)
Inspection and testing
Detected defects, leading to subsequent quality problems
Control of inspection, measuring and test equipment
Instances of measuring instrumentation overdue for calibration

Delays and retests due to equipment being out of calibration
Inspection and test status
Inadequate status identification

Number of quality failures which could have been avoided by adequate status
identification
Control of non-conforming product
Number of process deviations per batch

Number of reworks per month
Cost of rejects per month
Corrective and preventive action
Number of preventive actions ongoing/completed

number of corrective actions ongoing/completed
Customer satisfaction
Number of customer complaints
Customer complaint turnaround time
Handling, storage, packaging, preservation and delivery
Damage to product during handling/storage in-house

Instances of transit damage
Quality records
Average time to locate archived records

Number of records lost/misplaced
Records retained beyond official destruction date
Internal quality audits
Percentage of audits performed on schedule

Average number of major/critical observations per area audited
Percentage of actions completed within agreed timeframe
Number of observations by external auditors
Training
Percentage of staff with current training need identified/outstanding

Percentage of training records available/up to date
Statistical techniques
Percentage of statistically-based sampling plans

Instances of statistically-based experimental investigation design
Number of trainings in application of statistical techniques
Hygiene
product contamination
Number of customer complaints of foreign matter/microbial contamination
Number of cleaning process failures
Facilities, utilities, engineering
Instances of equipment breakdown

Monitoring trends for quality of air, water, etc.
Instances of security breaches
Incidences of cross contamination
Reprocessing due to inadequate equipment performance and/or environmental
conditions
Validation
Proportion of quality critical processes validated (or in need of validation)

Proportion of quality critical analytical methods validated (or in need of validation).
Summary
The introduction of a process orientated approach leads away from the classical departmental behaviour,
but does not replace these. It must be understood in a company that each activity should add value to the
business. Through the definition of processes an alignment of all activities can be achieved and gaps,
especially at interfaces between processes, identified. Thus overall efficiency of the organization can be
raised. Processes need to be controlled by appointed Process Owners and their efficiency measured by
Key Performance Indicators (KPIs).
There are a number of techniques to be applied for describing processes of which the most common are
captured in this chapter. Different techniques are used to address various situations in an organization.
1.F Practical implementation of a PQS

What are the different phases during an implementation of a PQS?
What organizational aspects need to be covered?
What kind of documents are needed and how are they developed?
1.F.1 Assistance for implementation
The implementation of a Pharmaceutical Quality System should be seen as a top-down approach. A

very important success factor in this process is the visible commitment and full support of senior
management.
The implementation of a PQS takes place in four different phases
Status quo analysis

"To-be" analysis (identification of requirements)
Gap analysis (Variance comparison)
Implementation
The first three phases can be considered as the preparation of the implementation phase. Typically,
too many resources are used for the analysis in relation to the implementation. 25 % of the total
resources should be sufficient for the first three phases. The speed of implementation of the PQS
correlates with the size of the organization but not necessarily with the number of processes and their
related support and sub-processes.
The implementation of a PQS is the most resource-intensive phase of the whole project and will cost
approximately 75 % of the total resources. For the Project Leader and the facilitators in the different
departments, this is a full time job throughout this phase. It will be highly beneficial to have these key
persons focused only on implementation work.
1.F.1.1 Status quo analysis
During this analysis the main focus is set on the review of documents (e.g. policies, directives, SOPs,
guidelines, master production instructions) as well as the corresponding records. Other effective tools
to analyze processes are interviews with the employees involved in these processes and physical
audits in the different departments. All current activities of the company are of interest at this stage.
Tools like VAT Analysis (value added time analysis), integrated resource planning or flow charting are
helpful to prioritize the different activities and the extent of the corresponding process analysis.
1.F.1.2 To-be analysis (identification of requirements)
Additionally, the regulatory environment (i.e. local laws, international guidelines like ICH etc.) has to be
considered. The outcome of this to-be analysis should be a description of the proposed structure of the
Pharmaceutical Quality System.
1.F.1.3 Variance comparison (gap analysis)
The comparison between the current activities and the proposed PQS reflects the main areas for
adaptations. More emphasis should be placed on planning the closure of major gaps than in
comprehensive identification of minor gaps.
Since the management of the implementation phase is the most resource-intensive step, careful
planning in this phase of the project will enable a smooth and successful implementation and will lead
to savings in resources.
1.F.1.4 Implementation phase
It is advisable to work out a detailed project plan (see Figure 1.F-1) with appropriate milestones to
follow and control the implementation.
Figure 1.F-1 Example of a project set up
Prioritization Variance comparison shows different areas for improvement but not all of them are
equally critical in respect to product quality and the effectiveness of the PQS. The provisions described
in ICH Q9 Quality Risk Management can be used to prioritize the changes to be made (see chapter
E.9).
Implementation plan Based on the prioritization, a road map is established which clearly addresses
responsibilities, timelines, milestones and resources. All individual activities as proposed before should
finally be fed into the PQS. Criteria for the kick-off of the PQS have to be defined. The operational
phase of a PQS may start before all gaps are closed. Those gaps still open are included in the
continual improvement process. It is important to address how the implementation is controlled, e.g. by
Change Management. The road map needs to be signed off by senior management to make available
necessary resources.
Diversification of the implementation plan into projects Activities that have been prioritized on the
top level should be described in detail and interfaces to other processes identified. These activities are
then distributed into projects and responsibilities and timelines are assigned. It should be defined how
the effectiveness and efficiency of the PQS will be measured, e.g. by implementing KPIs. At this stage,
it is essential to train the project team members and employees involved.
Management of implementation The project leader is committed to monitor costs and milestones.
The progress of implementation can be monitored by audits and measuring KPIs. The status of
implementation should be reported to senior management.
Documentation It is recommended to document the transition from existing to new design. For this
purpose, all necessary documentation for the new system has to be prepared and issued. Training
performed on all levels needs to be documented.
Operate the new system When the predefined criteria are fulfilled, senior management can declare
the operational phase of the Pharmaceutical Quality System by signing off the Quality Manual.
1.F.2 Organizational aspects
A proper organization of the project is key for the success of the implementation of a PQS. Figure 1.F-
2 shows a generic organization chart that may be applied in one or the other way, just as the structures
of the company allow.
Figure 1.F-2 Possible organization of a PQS project
Figure 1.F-2 shows the key functions that are involved in the project:
Steering committee This committee should be set up by senior management persons

who direct the organization and provide the resources. They approve the scope and
presumably also the key documents of the PQS.
Project leader The project leader is responsible for all organizational and coordination
matters during the project. He/she also assumes responsibility for the content and structure of
the PQS, ensuring that regulatory requirements are aligned within the PQS.
Process owners The Process Owner designs the process for which he/she is named
as responsible person, in close collaboration with the authors of document describing the
process and the experts. He/she takes the final decisions regarding the process assigned and
resolves disruptions with other processes involved.
Oversight team The oversight team takes responsibilities in terms of content of the
PQS. In addition it could also cover technical aspects, such as which IT system is to be used
and how it is adapted best to the PQS. It should be ensured that in the oversight team, the
interests of functions and manufacturing sites are represented.
Implementation coordination After the PQS documents have been approved, they
need to be implemented at the manufacturing sites and distribution affiliates of a company. The
coordinator ensures that implementation timelines are met, gap analyses at the sites and
affiliates have been conducted and resolved according to an agreed schedule.
Authors and experts The author(s) and experts generate the technical content of a
document in collaboration with the respective process owner. They also assist in developing
training material for the training team.
Training team The training team compiles the training material for the various
documents together with the authors and experts. The material should be provided before the
respective documents become effective: they can be compiled by eLearning tools,
presentations or at the location itself in person - just as the needs require the involvement.
Manufacturing sites and distribution affiliates These are the areas where the
documents are used, especially when they are GMP relevant.
Headquarters functions Many processes also affect functions within headquarters.
For that reason a proper implementation of the documents of the PQS needs to be made.
It should be mentioned that this organization chart outlines the different roles / functions involved in the
project. It does not necessarily mean that for each role, different persons need to be employed. The
smaller a company is, the more it will be the case that the execution of several functions is combined
and done by the same person.
1.F.3 Process of developing documents
The development and implementation of documents created in the scope of the Pharmaceutical
Quality System normally runs through the following steps:
Recruiting the stakeholders of the process In case a new process is established or

revised the persons involved need to be nominated. Senior management takes the
responsibility of nominating the process owner, while the process owner recruits the necessary
author(s) and expert(s), if applicable, for creating the relevant documents of the process. In
case of a revision of documents the activity is limited to confirm the involved persons, especially
author(s).
Drafting the relevant documents The author(s) and expert(s), if applicable, draft the
necessary document(s) for the process in close cooperation with the process owner.
Consolidation phase of the document(s) The draft document(s) are distributed for
review among the functions, manufacturing and distribution affiliates concerned. The purpose is
not that the areas rewrite or dilute the requirements, but to check for plausibility and
correctness. Sometimes, local legal aspects need to be considered. The author(s) consolidate
the document(s) on the basis of the comments provided by the areas. Sometimes it is
necessary to circulate another draft, especially when many and/or major changes have been
made to the initial draft.
Approval of the document(s) After the document(s) have been agreed and accepted
by all involved parties, they need to be approved by the relevant persons (e.g. process owner,
senior management)
Gap analysis at the areas of applicability The functions and/or areas affected by the
document(s) need to carefully check if they comply fully with the requirements laid down in the
document(s) and identify all points where actions or activities are required. Some actions
require capital investment and by nature will take longer to fulfill.
Implementation of the requirements as laid down in the document(s) Execution of
the implementation schedule resulting from the gap analysis.
Figure 1.F-3 shows the basic steps within the process of developing documents.
Figure 1.F-3 Basic steps in the process of developing documents within the scope of a PQS
1.F.4 Document hierarchy
It is absolutely necessary to define the document types within the PQS in order to have a clear
understanding about their applicability. Figure 1.F-4 shows a possible document hierarchy structure.
Figure 1.F-4 Example of a document hierarchy
Policy A policy describes the declared intention and commitment by senior

management to follow and comply with given internal and external standards. Many companies
are flooded with policies, which unfortunately distracts from the original purpose of senior man-
agement's commitment towards the activities and requirements that need to be initiated and
fulfilled. From the language meaning of a "policy", a company only needs one (1) policy.
Directive A directive is an executive instruction or set of instructions, formu-lated within
the scope of the quality policy, which must be followed in order to comply with or to achieve a
given external and/or in-ternal standard. A directive describes "what to do" requirements and
serves as an umbrella document for guidelines. The fact that directives concentrate on the
"what to do" requirements makes them short and concise documents.
Guideline Guidelines support or complete a particular directive and provide tools,
possible suggestions or recommendations which assist, faci-litate or enable a given standard to
be achieved. Whilst there is a degree of flexibility permitted in the application of a guideline,
alternative measures or approaches must be shown to be at least equivalent to those described
in the guideline. Guidelines describe "how to do" requirements and thus are much more
comprehensive than directives.
Standard Operating Procedures (SOPs) An SOP is a written document that
prescribes the detailed methods and action steps to be followed in order to successfully
accomplish a particular task, operation or procedure. The vast majority of documents within a
PQS are presumably SOPs when considering all documents in the plants for producing the
drug (medicinal) product.
Supporting documents This type of document is linked to or referred to in another
docu-ment (e.g. guideline and/or standard operating procedure) for the purpose of providing
specific information (e.g. lists of equipment, limits of temperature for transportation, checklists).
Records Records are documents containing and combining information such as text,
graphics, data (in hand-written and/or electronic form), audio or pictorial and in any combination
thereof. A record usually refers to a respective SOP and confirms prescribed methods have
been followed. A typical record is a "Batch record".
Summary
Before implementing a PQS a detailed analysis of the situation of the organization needs to be conducted.
The implementation of a PQS requires the set up of a project organization and should cover all involved
parties. A good documentation is key for a PQS and thus the development of documents should be
defined in detail as well as the different kinds of documents to be used within the scope of a PQS
2 Personnel
2.A Place of work and job descriptions
2.B Requirements of the personnel
2.B.1 Qualification requirements
2.B.2 Health requirements
2.C Training
2.C.1 Purpose of training
2.C.2 Responsibility for training
2.C.3 Requirements profiles/learning objectives
2.C.4 Training contents and target groups
2.C.5 Training planning
2.C.6 Carrying out
2.C.6.1 External factors
2.C.6.2 Qualification of the trainer
2.C.6.3 Training methods
2.C.7 Reviewing the training and the training system
2.C.8 Documentation
2.D Function owners subject to public law

2.D.1 Qualified Person (QP)
2.D.1.1 Requirements of the Qualified Person in accordance with European law
2.D.1.2 Area of responsibility of the Qualified Person in accordance with European Law
2.D.1.3 Organisational appointment/substitution regulations
2.D.2 Head of Production
2.D.2.1 Individual requirements for Head of Production
2.D.2.2 Areas of Responsibility of the Head of Production
2.D.3 Head of Quality Control
2.D.3.1 Individual Requirements for the Head of Quality Control
2.D.3.2 Areas of Responsibility of the Head of Quality Control
2.D.4 Qualified Person in Accordance with

Article 103 of Guideline 2001/83/EC
2.D.4.1 Individual Requirements for the Qualified Person in Accordance

with Article 103
2.D.4.2 Areas of Responsibility of the Qualified Person in Accordance

with Article 103 of Directive 2001/83/EC
2.D.5 Scientific Service in Charge of Information
2.D.5.1 Individual Requirements for the Scientific Service in Charge of Information
2.D.5.2 Areas of Responsibility of the Scientific Service in Charge of Information
2.D.6 Medical sales representatives
2.D.6.1 Individual requirements for medical sales representatives
2.D.6.2 Areas of responsibility of the medical sales representative

2.A Place of work and job descriptions

What must be included in a job description?
The tasks of staff in management or responsible positions, including the Qualified Person(s), should be
recorded in writing in descriptions of the place of work. The requirements of descriptions of the place of
work are established uniformly for all of Europe in Article 7(2) of Directive 2003/94/EC. The hierarchical
relationships between places of work must be described in an organisational chart. Organisational
charts and descriptions of places of work must be approved in accordance with internal procedures.
As well as tasks, staff must also be assigned sufficient authorities to be able to fulfil their responsibility.
In addition to this, the EU GMP Guideline expects gaps or unjustified overlaps in the definition of fields
of responsibility to be avoided.
By nature, the place of work is locally contained and should fulfil an exclusive number of functions. The
description of the place of work defines the responsibilities of an employee in terms of the tasks and
responsibilities given to him at a place of work assigned to him. It should be available in written form
and must be adapted to changing operating circumstances as required.
In many plants, the managing staff in particular are responsible for several places of work, e.g. one
employee might simultaneously be the head of quality control and the security manager, or he might be
the managing director and head of production or might perform the functions of head of warehousing
and head of sales in a combination of functions.
A job description summarises the tasks of an employee for a particular job. As the job holder, an
employee can perform several functions at different locations. The job descriptions for the staff in
management positions, in particular those of the public law functionaries, must be formulated in detail
and authorised by the board of management. The job descriptions of other staff can be recorded in the
form of group job descriptions.
The following diagram (see Figure 2.A-1) shows the contents of a job description:
Figure 2.A-1 Contents of a job description

Company name/company logo
Job description valid from: Page x of y
Name of the job

E.g. "Head of Research and Development Department" or "Head of Production"
Name of the employee and internal abbreviation, if used

E.g.: "Hans Meier (HME)"
Address
Address of the job, or personnel number, telephone
Name of department
This is where the relevant plant unit assignment should be specified, according to the position within the
company organisational chart, e.g. "Liquids manufacturing department II" or "Quality control department,
microbiology sub-department".
Deputy of the job holder

The deputy stands in for the job holder when they are on vacation or absent due to illness or for business-related
reasons, such as training or business trips. If several deputies are named, there must be a clear definition of which
of these deputies is responsible for which areas/functions, or in which order the deputies should assume their
role.
Superior
Here, a distinction should be made between personnel supervision and technical supervision. Personnel
supervision and technical supervision can be undertaken as one job or by several superiors.
Personnel supervision, usually the personnel department, regulates all queries associated with the job holder's
employment relationship, such as salary, vacation requests or internal relocation applications and, to this extent,
has authority over the job holder.
Technical supervision monitors that the job holder is executing his tasks in a technically correct manner. In
hierarchically organised plants, technical supervision is undertaken by the direct superior in the line management.
For drugs law functionaries, such as the head of production, the head of quality control and the head of sales,
please note that they are not bound by instructions in the context of their public law tasks.
Authority of the job holder to instruct

The authority of the job holder over staff can be taken from the hierarchy of the company organisational chart. In
this case, the job holder has authority over the staff on the line below him. However, interdepartmental
authorities are also possible, e.g. the authority of the head of production to instruct warehouse staff in terms of
drugs law, if the warehouse is not under the control of the production department, but the sales or administration
department, for example.Authorities to instruct in matrix or team organisations, as well as for particular projects,
must also be specified here.
Authorisations
These include:
Authority to sign, e.g. "signed on behalf of second person" or "signed ppa"
Power of disposal over materials and funds, also budget responsibility
Requirements profile
Description of the expected, personal requirements (e.g. education) and the minimum qualification (professional,
personal, social competence), to be fulfilled for this job.
Job targets
The targets to be achieved by the job holder, e.g.: "as head of production, is responsible for the proper production
of the drugs in compliance with the pertinent legal provisions and guarantees a cost-effective production
workflow." A job target is the description of a verifiable status, which can be deduced as a result of the decisions
expected of the job holder.
Detailed description of the tasks/activities

Here, there should be a description of the tasks, in particular those that are of significant importance for the
organisation and are to be continuously fulfilled. It should actually be possible to evaluate the tasks shown. In the
detailed description of the tasks, a distinction should be made between the job holder's responsibility to execute,
cooperate and inform.
The responsibility to execute exists for original tasks of the job holder, such as monitoring of proper storage by
the head of production, assessment of drugs risks by the drug safety manager or validation of analytical methods
by the head of quality control. In these cases, the job holder is personally responsible for achieving the targets.
The responsibility to cooperate relates to tasks in which the job holder should provide assistance to others, e.g.
the cooperation of the head of production in production planning, the cooperation of the head of quality control
in the auditing of contractors or the cooperation of the head of engineering in the qualification of machines. In
these cases, the job holder fulfils a service function by helping other staff to achieve their targets.
The responsibility to inform includes the comprehensive and timely transfer of information that accrues in the
job holder's task area, and is which is required by others to fulfil their tasks.
In this sense, for example, the head of quality control determines the personnel and material costs per analysis for
the administration department's budget planning, or the head of warehousing informs the sales department of the
goods stock, or regulatory affairs department informs the head of production of production related contents of the
registration dossier.
If possible, the tasks/activities should also be quantified, e.g. as "frequent" with 10% activity scope, "significant"
with > 25%, "predominant" with > 50%, and "complete" with > 90%.
Special tasks
Special tasks can be short-term tasks in excess of the employee's regular obligations, e.g. carrying out activities
within projects or performing special tasks on the instructions of the superior.
Personal obligations
This could be, e.g.:
regular undertaking of the health check by the company doctor, incl. reporting of infection
diseases
participation in further training measures in the context of the in-house training plan
provision of own car for business trips
Reviewed by/on
The accuracy and completeness of the job description should be reviewed by the superior
Approved by/on
The job description for management staff should be authorised by the board of management. For all other
employees, approval can be granted by the technical- or personnel supervision.
Acceptance of the job holder/on

Of course, the job holder must also document his acceptance of the job description by means of a signature.
Usually, the job holder receives a copy of this.
Job descriptions are an important requirement for the introduction and maintenance of a
pharmaceutical quality assurance system. The quality of drugs depends crucially on the quality of the
organisation and the management. Each employee must know which targets he is expected to achieve,
which tasks and authorities he has and for what he is responsible.
A good job description therefore contains clearly defined competencies, tasks and targets of the
individual jobs. The job description is not a bureaucratic formalism and should in no way inhibit the
employees' independent initiative. Nor does the definition of tasks and competencies exclude the
possibility of collaboration within the team, even across departmental boundaries. Rather, the job
description should create clear fields of action and responsibility and thus increase the employees'
motivation and willingness to work.
From his job description, the job holder must be able to recognise his place in the overall organisation.
He must be able to delimit his responsibilities from other areas. He and his superiors must have a
consistent concept of the type and scope of the tasks assigned to him.
A job description forms a good basis for future personnel recruitment measures or personnel
deployment planning. For the employees, the job description allows for a current determination of their
position in terms of their personal career plan. For all specialised superiors, job descriptions are the
basis for defining learning objectives for training course planning and execution.
In order for a job description to retain its practical orientation, it should be composed by the current job
holder and reviewed by their superior. The job holder is usually able to describe his tasks in the most
detail. In addition, this procedure requires the superior and employee to communicate with each other
from the outset and to agree on the tasks and targets of the job. Of course, the superior also reserves
the right to explicitly record unpopular tasks in the job description. On request by the employee, the
personnel council or works council can be involved in compiling the description of the place of work.
Summary
Job descriptions define the tasks, competencies and responsibilities of an employee. They must be available in
written and up-to-date form, and must be approved.
2.B Requirements of the personnel

What accounts for the "qualification" of staff?
What restrictions exist in terms of the deployment of personnel?
How must the employees' health be monitored?
What tasks can be performed by the company doctor?
2.B.1 Qualification requirements
Personnel with sufficient technical qualification must be available. Qualification means the theoretical
knowledge, practical skills and professional and business experience of the employee. The legislator
has left the definition of "sufficient" to the entrepreneur, who makes specific requirements in individual
cases. These result from the type and scope of the activities carried out in the plant.
Figure 2.B-1 Employee qualification features

Technical
Methods competence Ability to act Social competence
competence
Subject-related and The ability to procure, The ability to solve or Knowledge/abilities in the
multidisciplinary structure and process process problems and tasks fields of communication,
knowledge information, and to correctly independently, responsibly, cooperation, conflict
Professional interpret the results of professionally and properly. management, empathy, team
experience processing procedures and The ability to work in work
present them in a suitable professional working areas in Management skills,
form. The ability to apply the prescribed manner knowledge/abilities in the
problem-solving techniques fields of awareness of
responsibility, management,
ability to assert oneself,
initiative and ability to
motivate
Qualification is not only expressed in the employee's technical knowledge. In addition to the
requirements related to the place of work, management staff in particular are also expected to
demonstrate social skills, as well as the ability to manage staff. Figure 2.B-1 gives an overview of the
different qualification characteristics.
Personnel must be employed only "on the basis of their education and knowledge". In addition, the
personnel are to be regularly instructed "on how to handle drugs and starting materials with due care".
This includes instruction in sanitation, for example.
Chapter 2.1 of the EU GMP Guideline requires the manufacturer to have employees with the required
qualification and practical experience. The training obligation, according to chapter 2.8, not only
concerns the staff employed in manufacturing and quality control, but rather it concerns all employees
whose activities could influence the product quality, such as maintenance and cleaning staff. Particular
attention must be paid to the newly appointed staff (chapter 2.9), who are to be given theoretical and
practical instruction in the principles of Good Manufacturing Practice (GMP) and trained according to
the tasks assigned to them. Staff who work in special areas or who handle highly active, toxic,
infectious or sensitising materials, are to be given special training (chapter. 2.10). In addition, the
concept of quality assurance and all measures that can improve its understanding and application,
must be discussed in detail.
§ 211.25 of the USA's Code of Federal Regulations (CFR) also requires the persons responsible for
the training to have the required level of qualification, and § 211.34 requires the same of the
consultants.
2.B.2 Health requirements
In order to preserve the staff's health status, superiors and the board of management must set up and
monitor a health program throughout the plant. The procedure for medical monitoring of staff should be
set out in writing in compliance with the criteria specified in Figure 2.B-2.
Figure 2.B-2 Health monitoring of staff
Regulation content for monitoring the health of staff
Responsibilities for examinations on starting a new job and repeat examinations
Type and scope of the examinations
Requirements (e.g. laboratory parameters, sight/hearing test, body functions)
Disqualification criteria for certain areas
Reporting procedure in case of illness and trips abroad
Measures in case of determining infectious disease in the employee
Health instructions
Risk analyses
Documentation
It must be ensured that all persons involved in the production of drugs are subject to a medical
examination before first taking up their activity (cf. Figure 2.B-3) and later, to a repeat examination, if
required (cf. Figure 2.B-4). The medical examination has two functions:
It is intended to protect the staff from the effects of the product and thus represents an important
measure in medical occupational health and safety. The respective employer's liability insurance
association guidelines provide for special examinations in defined frequencies for certain substances
(e.g. carcinogenic, radioactive or infectious).
It is also intended to protect the product from the effects of the staff. This concerns, in particular, staff
who come into contact with the open product or with product contact surfaces (facilities, equipment).
The aim is to prevent microbiological contamination of the drug through infectious staff.
Figure 2.B-3 Scope of medical examination on starting a new job

Scope of medical examination on starting a new job
Medical history (previous illnesses, family disposition, drugs)
Physical examination (in particular skin, mouth/throat, ears, nose)
Blood serological parameters
Urinary status
Stool sample (pathogenic organisms)
Sight test
Hearing test
Figure 2.B-4 Reason for repeat examinations
Reason for repeat examinations
Relocation of the employee to areas with a higher cleanliness grade:
e.g. from non-sterile area to sterile area or from packaging to formulation
Changes in handling of dangerous substances and preparations
Return after stay abroad in countries with risk of infection
Diseases of the ENT tract
Skin diseases
Diarrhoea
The employer must provide the employees with adequate and appropriate instruction on occupational
health and safety protection during their working hours. This instruction should include directions and
explanations which are explicitly aimed at the place of work or task area of the employees. Instruction
must take place before an employee begins his activity, upon starting the new job, if his task area
changes, if new materials are introduced or if a new technology is introduced. It must be adapted to the
development of risk and repeated regularly, if necessary (cf. § 12 Labour Protection Law).
The employer must enable the employee, at his request, to have a regular medical examination at
work depending on the risks for his occupational health and safety unless damage to health is not likely,
based on the assessment of the work conditions and the protection measures taken (§ 11 Labour
Protection Law).
The examinations should be performed by an experienced occupational medic (company doctor or

external contract doctor).
In accordance with § 3 of the Labour Protection Law, the employer is obligated to meet the necessary
occupational health and safety measures, taking into account the circumstances which influence the
occupational health and safety of employees. The employer must check the effectiveness of the
measures and, if necessary, adapt them to changing circumstances. The employer must aim to
achieve an improvement in health and safety protection for employees.
The employer must not transfer costs for measures in accordance with the Labour Protection Law to
the employee.
The employer must determine which occupational health and safety measures are necessary based on
an assessment of the risk associated with the employee's work. The employer must perform the
assessment according to the type of activity. In the case of similar working conditions, the assessment
of one place of work or one activity is sufficient. In particular, a risk can occur through the design and
set-up of the workstations and place of work, through physical, chemical and biological effects, through
the design, selection and use of work tools, in particular of work substances, machines, equipment and
facilities as well as handling them, through the design of work and production procedures, operational
cycles and working time and their interaction as well as through insufficient qualification and instruction
of the employees.
When transferring tasks to employees, the employer must take into account, depending on the type of
activity, if the employees are able to comply with the provisions and measures for occupational health
and safety.
Occupational medical check-ups are an important source of awareness of operational health protection,
but must under no circumstances be judged as the only source of information. Findings from physical
examinations might fail to attract attention in the event of numerous exposures/expositions. In addition,
the amount of information obtained from the doctor/patient meeting can be low if the employee is
defensive due to various feasible motives. Therefore, it cannot generally be assumed that the company
doctor will recognise the current, individual stress situation based on findings and discussions from
occupational medical check-ups. It can in no way be concluded from findings and discussions that are
not particularly striking, that the employee is with certainty healthy from an occupational medicine
perspective, or is not subject to any risk at the place of work.
Guaranteeing effective health protection of the staff is beyond the scope of check-ups alone. It requires
timely and comprehensive cooperation of the company doctor even in the planning and design phases
of the plant. The importance of occupational medicine advice in advance of planning and investment
processes is extraordinarily high and generally acknowledged. The company doctor can be involved in
the determination and assessment of risks at the place of work. He can suggest protective and design
measures. He can be involved in sanitation training courses and in the promotion of health within the
plant. He can cooperate in the improvement of occupational health and safety within the operational
organization.
Summary
The personnel must demonstrate the required knowledge and capabilities to fulfil their tasks and must only be
employed in a pharmaceutical plant in accordance with this knowledge. To ensure medicinal product safety and
to protect the staff, regular medical examinations are required. The plant should ensure medical occupational
health and safety in close collaboration with a company doctor.
2.C Training

Why is training necessary?
How should training be planned and organised?
What is to be taught?
What training methods are there?
What makes a good trainer?
How can you check the success of training?
2.C.1 Purpose of training
The knowledge required within a profession is redoubling increasingly rapidly; the "half-life" of what
was learnt during vocational training is ever shorter. If companies want to guarantee the quality of their
products, the "human factor" is a crucial variable. Staff must be adequately prepared for the
continuously increasing requirements in their professional environment. Only in this way can the
innovativeness of a company as a whole be guaranteed. To this end, training is a crucial staff
development measure. Training is intended to maintain the employees' skill features and adapt them to
changed conditions (further training). In principle, it is based on an existing basic vocational training
(e.g. pharmacologist, master pharmacist, engineer, pharmacist, etc.).
In accordance with Article 7 No. 4 of Directive 2003/94, training courses should in principle be
executed at the time when the employee first starts their job and then continuously thereafter.
Training should be planned in the form of approved training programs and must be periodically
assessed and recorded. Training of unskilled temporary staff must be given particular attention. Here,
training has the purpose of educating the temporary staff, i.e. of producing a still lacking qualification.
Professional training (e.g. to become a specialist pharmacist) goes beyond internal training and
usually leads to a higher professional qualification.
2.C.2 Responsibility for training
Training is a management task. The management of the plant is not only responsible for providing the
required personnel and materials required for training and for releasing the employees from work for
training purposes, but it should also use corresponding social and organisational measures to ensure
that the employee can develop fully in accordance with his qualification.
The strategic organisation of training includes the establishment of training guidelines in corresponding
process instructions, i.e. that the crucial factors for the quality of the training are defined. This includes
the selection of trainers, coordination of training activities and checking the training system, e.g.
through self-inspections. This is a typical task of the quality assurance department, with the training
manager being involved, if available.
The training manager develops the training plan, ensures proper execution of the training events and
their documentation and is involved in reviewing the level of success. The head of production and the
head of quality control are responsible for monitoring the qualification of their staff. They stipulate the
necessary technical content of the training, in collaboration with the foremen, and release the
employees for the training dates. The respective superiors review the success of the training on-site
and are involved in the practical education of their staff.
Figure 2.C-1 Concept of qualification-based training

to enlarge,
click here!
2.C.3 Requirements profiles/learning objectives
Efficient training requires that the plant has compiled requirements profiles for the employees of the
individual areas. A requirements profile is a detailed description of the features that are required in
terms of the knowledge, capabilities and practical skills required to perform the transferred tasks.
Requirements profiles are usually derived from the employee's job description or the description of
their place of work. (chapter 2.A Place of work and job descriptions).
As both the plant requirements and the general scientific, technical and legal requirements change,
requirements profiles must be adapted as required.
An employee can only fulfil his tasks in accordance with GMP if he fulfils his requirements profile.
In each case, there will be a gap of varying width between the theoretical requirements profile and the
employee's actual qualification. This gap must be closed through training. To this end, the knowledge
and capabilities that the employee still lacks must be determined, so that he can fulfil his requirements
profile. In this way, learning objectives are set, which must be achieved during the training. Learning
objectives are usually the acquisition of knowledge and practical skills.
2.C.4 Training contents and target groups
The obligation to undergo training extends to all employees whose activity affects the product quality or
the safety of quality-related procedures. This also includes the persons who are not actively involved in
the manufacture and quality control of drugs, but who have an indirect responsibility for the quality,
such as, employees from the registration department, the research & development department, the
management (including the board of management) or the engineering division.
As the employees must be employed based only on their knowledge and capabilities, the training
contents must be oriented to the individual requirements of the place of work. Workplace-related
training must be carried out regularly, at least once a year. In addition, training contents that are to be
applied throughout the plant should be communicated.
Figure 2.C-2 gives an overview of the relevant subjects.
Figure 2.C-2 Training subjects/content

Training subject Content (selection)
Company Legal form, company history, product range, business data, working time regulations,
introduction employee representation, canteen, introduction of the departments' head
GMP GMP Guideline, Drug Law, pharma business regulation, Product Liability Law, finished
principles/laws pack regulation
Quality assurance Quality term, quality policy, structure of the QA manual, set-up and workflow
concept organisation, continuous improvement process (CIP)
Documentation SOP administration, document hierarchies, forms, document handling, approval procedure,
archiving, GMP-compliant recording
Sanitation Cleanliness zones, cleaning/disinfecting procedure,
air lock procedures, handling of open products, personal hygiene, reporting procedure in
case of illness
EDP Training in relevant software, authorised access/password assignment, data backup/data
security
Labelling Labelling of rooms and storage positions, labelling of the operating, cleaning and
maintenance status, handling of rejected material, status labelling on containers
Changes Grading, execution and documentation, causes of deviations, reporting procedure
and deviations
Safety at work Protective clothing, noise/dust guard, heavy loads handling, monitor workstations, health
check-ups
2.C.5 Training planning
The need to train different employee groups in different subjects and in different frequencies, requires
accurate planning. Usually, plants have appointed training managers to perform this task. The training
manager knows the plant and the composition of the staff. He determines the need for training, i.e. the
learning objectives (cf. Figure 2.C-1) in close collaboration with the heads of the different areas (e.g.
head of production and head of quality control) and then executes rough planning (definition of the
training subjects and frequencies) and then based on this, compiles a detailed plan (definition of the
training dates and rooms, selection of the training groups and trainers) for the necessary training
events. He monitors compliance with the dates and ensures the smooth running of the events.
Planning and organisation of training events can also be undertaken using electronic training
databases. When deciding on the purchase and use of such programs, the internal function
requirements should be defined in advance.
These might include:
Possibility of employee-based scheduling

Subject-based display of the training events in the overview
Organisation of training through the formation of training groups
Target/actual comparison of the training requirements for each employee
Possibility of separate recording and planning of additional training
Possibility of compiling pertinent paper printouts
If the training is planned exclusively by electronic means, in particular the target/actual comparison of
training requirements for each employee, then the computer-assisted system is GMP-relevant and
must be checked for suitability before being implemented.
2.C.6 Carrying out
The effectiveness of each training course depends on various factors which, if not taken into account,
could endanger the success of the training.
2.C.6.1 External factors
The size of the training room should be appropriate to the number of participants. The temperature,
lighting and background noise of the room must not affect the participants' ability to concentrate. For
the presentation of OHP slides, videos or slides, it should be possible to darken the room. Comfortable
seating and a writing surface are actually taken for granted, but time and again we find training rooms
with stools and no tables. Equipment, such as slide projectors or video recorders, should be checked
before the training to ensure it is in working order. Sufficient resources, such as flip charts, pointers,
chalk, etc. must be provided, so that there are no undesired interruptions or delays during the training.
A sufficient number of participant handouts and writing utensils distributed at the start of the training
ensures that the participants can concentrate fully on the trainer and their attention is not compromised
through the need to write at the same time.
2.C.6.2 Qualification of the trainer
The trainer should be an expert in the training subject. He should know the plant and the composition
of the group to be trained (previous knowledge, work focuses). External trainers and consultants must
be informed accordingly well.
Adults learn independently and according to their own pattern. The trainer should therefore have the
didactic ability to support the individual participant in his learning process, encourage him to extend his
knowledge independently and not try to force his learning concept on the participants. For this reason,
the question of the trainer's or teacher's qualification must not be taken lightly, as otherwise the training
event can easily turn into an aloof self-projection of the trainer, which is of benefit neither to the plant
nor to the participants (cf. Figure 2.C-3).
In order to enable a uniform teaching level, the group to be trained should be composed of people with
the same level of education and experience.
Figure 2.C-3 Requirements of a good trainer

What makes a good trainer?
Extensive technical knowledge and experience
Didactic ability, in particular in terms of adult education
Preparation of the training in line with the target group
Clear, comprehensible structure of the presentation
Sensible and experienced use of media
Ability to motivate, humour, creativity
Self-critical control of learning objectives
2.C.6.3 Training methods
There are numerous ways of carrying out training courses. Each method, if used predominantly or
exclusively, is not effective enough. It is often forgotten that for people who completed their studies
decades ago, a training course represents an unfamiliar strain, which leads to quick mental exhaustion.
This is why corresponding rest breaks are necessary. The trainer must therefore bring knowledge and
a grasp of methodology and teaching tempo.
Lesson
The classical lesson form - a teacher speaks, the participants ("pupils") listen - is appropriate in
principle, if dealing with the communication of subject matter. The teacher can adjust to the listeners in
terms of language, gestures and with the available teaching resources (e.g. blackboard, flipcharts,
overhead projector) and adapt the lesson tempo accordingly. The extent to which the participants can
influence the training course through their own questions or contributions also depends on the teacher.
Working groups
Working groups are generally used to obtain more in-depth knowledge and require previous knowledge.
The advantage of working groups is that each individual participant is more intensively involved in the
lesson, in comparison with other methods. The group is intended to fulfil the task jointly, e.g. using a
case study, which is very close to the reality of the working world. The group members can contribute
their personal knowledge and experiences and thus teach each other mutually. The inhibition to ask
questions is significantly lower in working groups than in the classical lesson style. Working groups in
which individual participants dominate the group work due to their headstart in knowledge or
experience are problematic. In any case, the results of the working group must be summarised and
evaluated by the teacher.
Role plays
Role plays are particularly suitable for investigating personal behaviour and learning new behavioural
patterns. The employees' social competence is encouraged through the associated improvement of the
ability to communicate and work in a team.
Slides, films, videos, CD-ROM
All audio-visual techniques have the advantage that they make the subject matter "more visible" in the
true sense of the word, and thus also more easily accessible. The tempo, in which the subject matter is
communicated is fixed, which can sometimes mean that individual participants cannot always follow
the presentation. Therefore, such presentations should always be accompanied by an introduction and
conclusion of the learning objective.
Written learning programs
Learning programs in the form of text books allow knowledge to be communicated through
independent study. The user can determine the learning tempo individually and review his success
himself through corresponding tests. The suitability of this program depends greatly on how exactly it is
tailored to the specific requirements of the employee.
E-Learning
A series of computer-assisted, interactive learning programs is now available on the market. These
software packages often contain small video units combined with text or audio teaching contents, allow
knowledge to be tested via multiple choice tests or case studies, and thus enable online success
monitoring. Learning should be particularly memorable due to the fact that several senses are
addressed by this medium. If necessary, adaptation to the respective plant is possible through editor
programs.
The advantages for the company through the use of E-Learning are:
Reduction of the training costs and time off

Consistent quality of the training measure
Prevention of scheduling or personal bottlenecks
Methodical enrichment
The advantages for the user are:
Self-determined learning (place, time, tempo, learning path)

Self-checking instead of external checking (no worry about gaps in knowledge)
Consultation and repeating as required
High motivation through interaction and multimedia
Careful group analysis is crucial in selecting and using this medium. The software can only be used
effectively if it is tailored to the needs of the plant.
The conditions for saving personal data in the context of software usage should be agreed with the
Works Council (cf. chapter 2.C.7 Reviewing the training and the training system)
On-the-job-training (OJT)
On-the-job training is usually assigned to the foremen. The employee to be instructed should learn how
to carry out and document his tasks based on the relevant (standard) operating procedures. The
method is carried out according to the following principle: "Explain, demonstrate, copy, correct".
The foremen often consider the task of teaching to be inconvenient additional work. It is therefore all
the more important that the foremen not only develop a quality awareness for the product, but also for
the level of education of the employees, and are accordingly trained in the technique of teaching.
Ultimately, it is they who should first notice training deficits and the need for additional training.
External training
External training events are a good opportunity to find out about the latest knowledge and state of
technology and offer the possibility of exchanging information with other companies.
A distinction can usually be made between seminars and conferences:
At seminars, a subject is presented to a defined target group by means of different presentations and
sometimes also through working groups, podium discussions or round-table discussions. When
choosing these seminars, it is crucial that the employee first checks whether or not he belongs to the
target group being addressed, as otherwise his own field of work may not be dealt with in sufficient
detail. The trainers, who's names can usually be taken from the advance notification of the seminar,
can also give information on how in-depth or practical the communication of the subject is anticipated
to be. If the focus of seminars is on working groups or role plays, you should definitely ask the seminar
provider the maximum size of the groups beforehand. The learning effect in working groups and role
plays is highly dependent on the extent to which the individual can participate. Working groups and role
plays with more than eight participants usually offer the individual group members too little active
participation.
Conferences usually aim to present the latest knowledge on a certain subject. A conference should
therefore be considered less as a training event and more as an information event. At a conference,
you should expect to find out about the latest information on a specific subject from experienced
specialists. When selecting this type of event, the same principles apply as for seminars (target group,
trainers) and also the question of whether or not the conference subject is relevant for your own plant.
2.C.7 Reviewing the training and the training system
Article 7(4) of Directive 2003/94/EC demands that the effectiveness of the training be reviewed.
Chapter 2, No. 9 of the EU GMP Guideline assumes that the implementation of the training is
periodically assessed in practice. Accordingly, the plant must review the qualification of its staff. At the
fore of this review is the review of the level of success, which is carried out immediately after or within
a specific time interval after the training. This should prove that the training carried out was suitable to
achieve the intended learning objectives or to ascertain a potential need for additional training.
If personal data is saved during the review of success (i.e. individual information on personal or
business relationships of those concerned), prior consent of those concerned must be obtained (§ 4 (1)
of the Federal Data Protection Act).
The plant is authorised to execute personal reviews of success. Before executing personal reviews of
success, however, the Works Council must be involved and its approval must be obtained. If aspects
of data protection law were taken into account, the Works Council can usually not refuse its consent,
as the plant is legally obligated to ascertain the qualification of its staff. The Works Council is explicitly
obligated to promote professional training.
The effectiveness of the training event as a whole can be determined via anonymous reviews of
success, but an ascertainment of the individual need for additional training is not possible in this way.
In practice, various direct and indirect methods have prevailed:
The classical knowledge survey as a written question/answer test or multiple choice test
The online survey and evaluation in software training programs
Oral testing by the teacher or superior
The observation of behaviour at the place of work by superiors
The review of documents compiled by the employee for conformity with the
requirements taught
The evaluation of employee-dependent error statistics
In addition to selecting the method used to review success, the timing of the review of success is also
crucial. A survey test carried out shortly after a training course can check if the training objective,
namely the communication of the teaching content, was achieved. However, the result does not
guarantee that the employee will still remember the teaching content after three months have passed.
It doesn't take long to store facts in your short-term memory, but it takes quite a bit longer to also keep
them in your long-term memory. Anyone who has already learnt a poem by heart has had this
experience. Reviews of success should therefore also be carried out after a certain time delay and not
directly after the training
A review should also be carried out to check if the employee has only remembered the knowledge as a
collection of facts, or if he is able to apply the knowledge, i.e. independently draw conclusions from the
newly acquired knowledge, make decisions and transfer the knowledge to the plant. A review of
success should therefore not only check the technical competence, but also the method and handling
competence (cf. Figure 2.B-1).
In addition to assessing the individual employee, the training system as a whole should also be
reviewed (cf. Figure 2.C-4).
Figure 2.C-4 Quality assurance of the training system
to
enlarg
e,
click
here!
To assess the effectiveness of the training system, the checklist in Figure 2.C-5 can be used.
Figure 2.C-5 Checklist for reviewing the training system

Checklist for reviewing the training system
1. Requirements profiles
Have requirements profiles been compiled and approved?
By whom and how are they checked for plausibility and for how up-to-date they are?
2. Learning objectives
Are workplace-related learning objectives defined for employees?
By whom and how is the achievement of learning objectives reviewed?
Is there a subject catalogue for basic training of new
employees, tradesmen and visitors?
3. Planning
Have training dates, venues, target groups and training subjects been defined?
By whom and how is compliance with the training plan reviewed?
4. Carrying out
Are suitable rooms and media available for training courses
How is it ensured that the trainers are sufficiently qualified?
Is every training course documented in a traceable manner?
5. Review of success
By whom and how is the success of the training reviewed?
Is a need for additional training recognised and consistently pursued?
2.C.8 Documentation
All training activities are to be documented in a traceable manner. Documentation can be made in
paper form or via EDP. Records of the key aspects mentioned in Figure 2.C-6 should be available.
An evaluation of the training documentation should be possible under the following criteria:
Which (additional) training was carried our per employee in a defined period of time?
When were training courses held for specific subjects?
What training subjects were taught in a specific period of time?
How was the effectiveness of the training measures reviewed?
Figure 2.C-6 Contents of the training documentation

Key aspect Documentation contents
Job description of the training Tasks, deputisation regulations, authorities
manager
Training plan Subjects, times, training groups
Training execution Venue and duration, training contents, list of participants, trainer, reference to
resources and materials
Evaluation Success checks, self-inspection of the training system
Summary
Regular training of employees is a significant requirement for employees being able to complete their tasks in
accordance with GMP.
Training events must be planned carefully, be executed in a methodic manner, and be reviewed in terms of their
success.
2.D Function owners subject to public law

What prerequisites have to be met by the function owners subject to public law?
What tasks/responsibilities do they have?
Function owners subject to public law include:
Qualified Person (chapter 2.D.1 Qualified Person (QP)))

Head of Production (chapter 2.D.2 Head of Production)
Head of Quality Control (chapter 2.D.3 Head of Quality Control)
Qualified Person in accordance with Article 103 of Directive 2001/83/EC (chapter 2.D.4
Qualified Person in Accordance with Article 103 of Guideline 2001/83/EC)
Scientific service in charge of information (chapter 2.D.5 Scientific Service in Charge of
Information)
Medical sales representatives (chapter 2.D.6 Medical sales representatives)
2.D.1 Qualified Person (QP)
2.D.1.1 Requirements of the Qualified Person in accordance

with European law
For Europe, the qualification requirements for the Qualified Person are defined in Article 49 of Directive
2001/83/EC (Figure 2.D-1).
Figure 2.D-1 EU qualification requirements for the Qualified Person

Qualification requirements in accordance with Article 49 of Directive 2001/83/EC
The Qualified Person must hold a degree, certificate or other form of evidence that he or she has completed an
academic course of training or its equivalent in one of the member states in question, lasting at least four years
and including theoretical and practical instruction in one of the following scientific subject areas: pharmacy,
medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology, biology.
A minimum course duration of three and a half years may, however, be permissible if it is followed by
at least one years' theoretical and practical training that includes a placement in a pharmacy lasting at
least six months, involving contact with the public and culminating in a university-level exam.
If a member state offers two academic courses or training courses that it acknowledges as equal to
academic courses, of which one lasts four years and the other three, it is to be assumed that the
degree, certificate or other evidence of completion of the academic or equivalent training lasting three
years meets the requirements for duration specified in subclause 2, providing that the degrees,
certificates, or other proof of course completion are recognised as equal by this state.
The training course contains theoretical and practical instruction in the following basic subject areas,
as a minimum:
Experimental physics
General and inorganic chemistry
Organic chemistry
Analytical chemistry
Pharmaceutical chemistry, including drug product analysis
General and applied (medical) biochemistry
Physiology
Microbiology
Pharmacology
Pharmaceutical technology
Toxicology
Pharmaceutical biology (study of the composition and effects of natural active
substances of plant-based or animal origin)
Instruction in these subjects must be balanced in such a way that it enables the student in question to
fill his or her obligations as stipulated in Article 51 of this Directive.
If certain degrees, certificates or other evidence of completion of a training course in accordance with
subclause 1 do not meet the criteria stated in this clause, the responsible offices in the member state
must be satisfied that the individual in question has demonstrated sufficient knowledge in the relevant
subject areas.
The Qualified Person must have been employed for at least two years in one or more organisations
with manufacturing authorisation, working in the area of qualitative analysis of drug products and
quantitative analysis of their active ingredients, as well as the trials and tests that are necessary to
establish the quality of the drug product. The amount of practical experience required may be reduced
by one year if the individual has completed an academic training course lasting at least five years, and
by one and a half years if the course lasted a minimum of six years.
In order to obtain a manufacturing authorisation for approving pharmaceutical products for placement
on the market, a Head of Production and Head of Quality Control must be appointed in addition to the
Qualified Person, and suitable premises and facilities must be demonstrated. The Head of
Productionand the Head of Quality Control must be independent from one another (see EU-GMP
Guideline, chapter 2.3, see chapter C EU GMP Guide). The assessment of the Head of Manufacturing
or Quality Control's specialist qualifications and practical experience carried out by the authorities
responsible as part of the manufacturing or import licence issuing process will therefore be performed
on a case-by-case basis.
2.D.1.2 Area of responsibility of the Qualified Person in accordance

with European Law
For Europe, the duties of the Qualified Person are defined in Article 51 of Directive 2001/83/EC
(see Figure 2.D-2). Correspondingly, they are also described in the EU-GMP Guideline, Chapter 2,
No. 4.
Figure 2.D-2 Duties of the Qualified Person in accordance with Article 51 of Directive 2001/83/EC
Duties of the Qualified Person in Accordance with
Article 51 of Directive2001/83/EC
1. Ensuring that, for drug products manufactured in the member state in question, each batch of drug product is
manufactured and tested in accordance with the laws applicable in this member state and the requirements upon
which approval for placing on the market is based.
2. Ensuring that, in the case of drug products imported from third countries irrespective of whether they were
manufactured in the EC, every batch of drug product has undergone a complete qualitative analysis, quantitative
analysis of at least all active ingredients and any other trials and tests that are necessary to guarantee the quality
of the drug product in accordance with the requirements upon which approval for placing on the market is based.
3. Batches of drug products checked in this manner in a member state are exempt from the checks stipulated
upon import to another member state if inspection reports signed by the Qualified Person are enclosed.
4. If, in the case of drug products that have been imported from a third country, appropriate agreements have
been made between the EC and the country of export that guarantee that the manufacturer of the drug product has
followed instructions during manufacturing that, as a minimum, correspond to the instructions specified by the
EC, and that the checks described in 2. have been carried out in the country of export, the Qualified Person is no
longer required to carry out these tasks.
5. In all cases, but in particular as soon as the drug products are put into circulation, the Qualified Person must
certify in a record or equivalent document intended for the purpose that each production batch complies with the
provisions of this article; individual operations must be entered consecutively in the designated record or
equivalent document; these records or documents must be available to the agent or responsible authorities within
a time period designated by the law of the member state in question, but not less than five years.
Release for placement on the market
Before the Qualified Person can issue a release for placement on the market, he or she must either
ascertain personally or receive confirmation from other sufficiently qualified and suitable persons that
the manufacturer is in a position to manufacture and perform tests in conformity with good
manufacturing practice and in accordance with manufacturing and testing procedure. Auditing of third
parties is an important routine task to be performed by the Qualified Person (see EU-GMP
Guideline, chapter C.6.16 Annex 16 Certification by a Qualified Person and Batch Release). Other
persons can also carry out audits on site, in particular persons who have the specialist knowledge
outlined in Article 48 of Directive 2001/83/EC or Article 52 of Directive 2001/82/EC. Such persons are
considered suitable if they do not have financial or other interests that could influence their neutrality.
Written process instructions are required for release just as for other manufacturing or testing
procedures. This is stipulated in Section 4.24, Part I (chapter C.4 Part I Basic Requirements for
Medicinal Products) and Section 11.11, Part II (chapter C.5 Part II Basic Requirements for Active
Substances used as Starting Materials) of the EU-GMP Guideline. In Section 8.4., it is clearly stated in
Appendix 16 to the EU-GMP Guideline that the Qualified Person must have sufficient knowledge of the
product and procedures in accordance with Article 48 of Directive 2001/83/EC in order to carry out his
or her duties.
It is customary for manufacturing or quality control to be carried out in several levels, and at different
locations or different manufacturers if necessary. The complete manufacturing process, with the
exception of release, can also be carried out in other units and institutions. The Qualified Person can
take into account releases issued by a Qualified Person in accordance with Article 48 of Directive
2001/83/EC or Article 52 of Directive 2001/82/EC in other European member states. However, the
Qualified Person remains personally responsible overall for approving placement of the batch on the
market (Directive 2001/83/EC, Article 51 para. 3).
List of released products: The Qualified Person in accordance with Article 51 of Directive 2001/83/EC
must certify in a consecutive record or a comparable document intended for this purpose that the
instructions in Article 51 of Directive 2001/83/EC have been followed for every batch of a drug product
before the batch is put into circulation. If subsequent batches are recalled, this must be noted in the
record or comparable document.
Release of test preparations
The release of test preparations is based on the German GCP regulation. Manufacturing and test
procedures as well as the manufacture and testing of every batch must, for instance, conform to
documentation submitted for the approval of clinical investigations. For this purpose, in particular the
Qualified Person responsible for the release of test preparations must maintain close contact with the
sponsor of the clinical investigations. As with other drug products, test preparations may be approved
only if they are manufactured in accordance with regulations. All findings gathered during
manufacturing and testing, such as production conditions, the results of in-process control, review of
manufacturing documentation and conformity of products with their specifications, including their outer
packaging, must, therefore, be taken into account for the release decision (Article 11 para. 3 of
Directive 2003/94/EC). In some circumstances, further criteria are listed, in particular under point 40 in
Appendix 13 of the EU-GMP Guideline (chapter C.6.13 Annex 13 Investigational Medicinal Products),
which should form the basis for the release decision.
Retention samples
The Qualified Person responsible for release must ensure that a sufficient quantity of retention
samples from every batch of finished medicinal product is retained for at least one year beyond the
expiration date for the purposes of any analytical follow-up testing that may be necessary and for proof
of labelling, including the package insert (point 3 in chapter C.6.19 Annex 19 Reference and Retention
Samples). The Qualified Person must also ensure that retention samples of every batch of starting
materials used for drug product manufacturing are retained for at least two years after a drug product
manufactured using these starting materials is released, unless a shorter retention period is specified
in the submission file for marketing authorisation. If information is provided in accordance with § 5 of
the German GCP regulation in accompanying documentation, the specimens of these accompanying
documents must also be retained for each batch.
In accordance with Chapter 1.5 of Part I of the EU-GMP Guideline, the Qualified Person should also
ensure that the Product Quality Review (PQR) is compiled correctly and in good time. The PQR is a
product-based instrument for assessing the conformity of existing processes and suitability of
established specifications with regard to both raw materials and finished products. This assessment
serves, on the one hand, to correct errors and, on the other, to enable continual improvement. Another
important element of this assessment is the evaluation of the continuous stability studies in accordance
with Chapter 6.23 ff. of Part I of the EU-GMP Guideline, which must be made available to the Qualified
Person as per Chapter 6.31. For the Qualified Person, this documentation therefore represents an
important basis for assessing GMP conformity of the quality assurance system on which the drug
product manufacturing process is based.
More specific requirements for the Qualified Person's duties can be found in Appendix 16 of the EU-
GMP Guideline (see Figure 2.D-3). This appendix deals in particular with the duties of the Qualified
Person if a batch release is performed for drug products with different production and control levels
that have passed within, partly outside, or entirely outside the European Union (EU) and European
Economic Area (EEA). Cases are also listed in which an intermediate product or bulk material is split
up between more than one finished product batch.
Figure 2.D-3 Routine duties of the Qualified Person in accordance with Appendix 16 of the EU-GMP Guideline
Routine duties of the Qualified Person in accordance with Appendix 16,
EU-GMP Guideline
1. Ensuring that:
o Batch and manufacturing meet approval for placing on the market (including the
import licence where necessary).
o Manufacturing was carried out in compliance with the EU good manufacturing
practice or, in the case of batches imported from a third country, standards recognised as
equal.
o The most important manufacturing and testing procedures are validated, and the
current production conditions and batch production records have been taken into
consideration.
o All discrepancies or planned changes in production or quality control have been
approved by the responsible person, in conformity with an established system.
o All changes that require modifications to the marketing and manufacturing
authorisation have been reported to the relevant authorities and authorised by them.
o All necessary inspections and tests have been carried out, including all additional
sampling, checks and inspections necessitated by discrepancies or planned changes.
o The necessary documentation regarding production and quality control is complete
and has been approved by the staff.
o All audits have been carried out as specified by the quality assurance system.
o All factors known to the Qualified Person and relevant to batch quality have been
taken into account.
2. The Qualified Person should always update his or her knowledge and experience of technical and scientific
progress and changes in the quality control procedures in as far as these are relevant to the products to be
certificated by him or her.
3. If the Qualified Person has to certificate a product with which he or she is not yet familiar, whether as a result
of new product line being introduced or a job change, he or she must first familiarise him or herself thoroughly
with this product in order to be able to complete the task.
4. In line with the relevant national regulations, the Qualified Person may be urged to inform the authorities of
changes and may have to reapply for marketing authorisation.
If clinical samples are imported from third countries, the importers are subject to certain obligations.
In accordance with Article 13, para. 3 of Directive 2001/20/EC, this responsibility is assigned to the
Qualified Person acting on behalf of the importer. The Qualified Person acting for an importer must
ensure that drug product manufacturing or testing in third countries is at least equivalent to the
standards stipulated by the EU for good manufacturing practice and that each batch complies with the
approval documents for clinical trial, in particular the drug product specifications. As stated under
No. 40 in chapter C.6.13 Annex 13 Investigational Medicinal Products of the EU-GMP Guideline et al.,
the Qualified Person will have to satisfy him or herself of this by performing anaudit to establish
whether manufacturing has been carried out correctly (see Figure 2.D-4).
Figure 2.D-4 Batch assessment of clinical samples by the Qualified Person in accordance with Appendix 13 of
the EU-GMP Guideline (chapter C.6.13 Annex 13 Investigational Medicinal Products)
Batch Assessment of Clinical Samples in Accordance with Appendix 13,
EU-GMP Guideline
Assessment of batch records, including control reports, test reports of in-process
controls and release reports, checks for discrepancies or changes
Inspection of manufacturing conditions
Establishing the validation status for production facilities, manufacturing processes
and methods
Investigation of completed packages
Assessment of the results of all analyses or tests carried out after import
Assessment of reports on stability
Verification of storage and shipping conditions
Assessment of audit reports concerning the manufacturer's quality assurance system
Inspection of the manufacturer's manufacturing authorisation for clinical samples or
reference samples
Consideration of relevant legal requirements for marketing authorisation, GMP
standards to be implemented and each official confirmation of compliance with GMP
provisions
Consideration of all further factors relevant to batch quality
While the manufacturing process for test preparations (as with other drug products) within European
Union member states and states contracting with the European Economic Area must meet the
standards for good manufacturing practice specified by the EC (Article 13 para. 3 fig. a of Directive
2001/20/EC), manufacturing processes in a third country must be carried out in accordance with
standards that are at least equivalent to those of the EU. In addition, the importer must make sure that
the manufacturer is authorised to manufacture and test test preparations. A test preparation must also
be released by the Qualified Person if it is listed under Article 13 paragraph 3 fig. c of Directive
2001/20/EC as comparator drugs to be used in a clinical investigation (Figure 2.D-4).
2.D.1.3 Organisational appointment/substitution regulations
As described in the previous chapters, the Qualified Person has various tasks, which span the entire
pharmaceutical quality assurance system. In addition to batch-related document checking at the
operative level, he or she fulfils duties that extend far into the strategic area of the business and
thereby pertain to classic quality assurance or quality management functions. The appointment of the
Qualified Person in the business organisation must allow for this extensive range of responsibilities.
As the person responsible subject to public law, the Qualified Person must forge for him or herself a
position that is largely independent of the classic structure and process-oriented organisation, since the
Qualified Person is not bound by instructions within the context of fulfilling his or her tasks. Ideally,
therefore, the Qualified Person is integrated in the quality assurance department, usually in a dual role
with the management of this department. A staff position in the upper echelons of the organisational
hierarchy would also be possible.
The various duties to be fulfilled by the Qualified Person should be described in a job description in
accordance with Article 7 of Directive 2003/94/EC.Figure 2.D-5 shows a sample job description for a
Qualified Person (for general requirements for job descriptions, see chapter 2.A Place of work and job
descriptions).
Figure 2.D-5 Sample job description for the Qualified Person

Sample GmbH, Modeltown
Job description Posting date: 06.09.2005 Page 1 of 4

Description of position
Qualified Person in accordance with Article 48 of Directive 2001/83/EC, lyophisilate area
Name of current job holder (internal identifier)
Dr. Susanne Meier (10-123)
Company address
Sunny Street 4
23456 Modeltown
Tel.: 04991-87654, fax: 04991-87655, e-mail: smeier@sample.de
Department code
Quality Assurance (QA)
Deputy for job holder
Dr. Klaus Müller, Qualified Person for "Solida"
Supervisor
For all personnel matters such as salary, holiday allowance or internal transfer applications, the position holder
reports to the personnel department. On technical and organisational matters, the position holder reports to the
Quality Assurance department.
In the context of the Qualified Person's position relating to public law, the position holder acts without
instruction and reports directly to company management.
Authority of the position holder
The position holder is authorised to issue instructions to:
The secretariat of the QA department on matters of correspondence
The Head of the Quality Control on matters of retention sample storage, the Product
Quality Review and follow-up stability studies
Authorisations
When acting in the function of Qualified Person, the position holder signs all external correspondence on his or
her own authority by adding "Qualified Person for lyophilisate" under his or her signature, and all other written
communications with the prefix "By proxy" before the signature.
Job specifications
Expert knowledge
Very good knowledge and experience in pharmaceutical manufacturing and quality
control of aseptic dosage forms, in particular in the area of freeze drying
Good knowledge of current EU and FDA GMP regulations
Project management experience
Reliability
Leadership skills
Decision-making abilities and assertiveness
Pronounced sense of responsibility
Business mindset
Teamwork and organisation skills
Ability to work under pressure and flexibility
Very good written and spoken English
This is a full-time position and presupposes that the position holder will fulfil the necessary working hours.
Position objectives
As the Qualified Person, the position holder is responsible for both batch release and the control and release of
manufacturing and test documentation. He or she is involved in the monitoring and continual further
development of the QA system, including monitoring critical quality parameters as necessary in this context. He
or she is responsible for coordinating, preparing, executing and postprocessing inspections by national and
international authorities, as well as supplier audits. The Qualified Person is also responsible for organising GMP
training (planning, execution, control of success).
Detailed description of duties/functions
R = responsibility for execution/makes the decision
S = shared responsibility
I = remains informed
Responsibility for executing a duty always includes the obligation to inform all affected posts.
Duty R S I
Checking and approving GMP-relevant SOPs X X

Checking manufacturing and test procedures and records X X
Making changes to marketing authorisation content X X
Qualifying equipment used for manufacturing and quality control X
Validating manufacturing, cleaning and test procedures X
Process and plant-specific monitoring of GMP-critical parameters X X
Inspecting discrepancies X X
Batch release for placement on the market X
Making entries in the list of released products X
Organising self-inspections X
Organising inspection by the authorities and supplier audits X
Monitoring the storage of retention samples X
Compiling and evaluating the Product Quality Review X
Evaluating the results of the continuous stability studies X
Change control procedures X X
GMP training X
Handling complaints and recalls X X
Resource planning with regard to budget and personnel in the "parenterals" area X X
Production planning and control in the "parenterals" area X
Qualifying new suppliers and contract acceptors, reauditing existing contract acceptors X
Checking customs and legal prerequisites relating to drug products when raw materials, X
packaging material and drug products are imported or exported
Other duties
Participation in the company "Global Quality System" project
Personal undertakings
Willingness to make domestic and foreign business trips lasting several days
Sole responsibility for arranging own further training
Annual medical exam by the company medical officer
Reviewed by/on Dr. Manfred Keller (Head of QA), 05. 09. 2005
Approved by/on Sally Sample (Managing Director), 06. 09. 2005
Position holder informed on Dr. Susanne Meier, 06.09.2005
Figure 2.D-6 The position of the Qualified Person
The position of the Qualified Person
He or she can be deputised only by other Qualified Persons.
He or she may also be Head of Production or Head of Quality Control (not
recommended).
He or she is not involved in the operational business of manufacturing or quality
control but has a supervisory position (recommended).
A job description is required (if there is to be more than one Qualified Person, this
must include division of responsibilities).
In the event that more than one Qualified Person is involved in a drug product manufacturing process,
all Qualified Persons must agree that the QA system on which the process is based complies with
GMP. In particular, if more than one Qualified Person is appointed, it is essential for individual
responsibilities to be divided clearly by means of job descriptions.
As well as defining responsibilities in the job description for a Qualified Person, top company
management must also ensure (by means of instructions, for example) that all company divisions
support the Qualified Person in the execution of his or her role: "The holder of a manufacturing
authorization shall at least be obliged: ... e) to enable the Qualified Person referred to in Article 48 to
carry out his duties, for example by placing at his disposal all the necessary facilities" (Article 46 of
Directive 2001/83/EC).
This applies especially to the provision, in full measure and in good time, of information and documents
to be assessed by the Qualified Person.
To ensure that the Qualified Person can carry out his or her duties as objectively as possible, many
supervisory authorities expect him or her not to be directly involved with drug product manufacturing
and quality control. On account of the type of role he or she fulfils, the Qualified Person has a quasi
supervisory function, as a result of which carrying out any other function, in particular in a supervised
operational area, could be considered subject to a "ban on self-contracting". It is, ultimately, a serious
conflict of interest for the Qualified Person if, in a dual role as Head of Production, he or she is
responsible for selecting starting materials and for the manufacturing procedure and also, as Qualified
Person, has to issue the release for the overall process.
2.D.2 Head of Production
2.D.2.1 Individual requirements for Head of Production
The requirements for qualifications and practical experience are based on the type of drug product to
be manufactured and must be defined in-house. It is important to bear in mind that the fundamental
requirement for sufficient Qualified Personnel is already included in Article 7 of Directive 2003/94/EC.
This is all the more important for the Head of Production, since he or she has a guarantor function for
ensuring that drug products and substances are manufactured and stored in line with modern scientific
and technological standards (Figure 2.D-7).
Figure 2.D-7 Requirements for the Head of Production

Requirements for the Head of Production
Adequate specialist qualifications and practical experience
Job description required (if there is to be more than one head of production, this
must include division of responsibilities)
The areas subordinate to the Head of Production act as a benchmark for the qualification requirements
for this position. The most important areas include the following:
Type and volume of the products manufactured

Company experience with the processes to be applied
Complexity of the manufacturing facilities used
Number and qualifications of persons to be supervised
2.D.2.2 Areas of Responsibility of the Head of Production

Figure 2.D-8 Areas of responsibility of the Head of Production in accordance with the EU-GMP Guideline
Areas of responsibility of the Head of Production in accordance with the EU-GMP Guideline
Ensuring that products are manufactured and stored in compliance with specifications
Approving manufacturing instructions and ensuring that these are followed
Supervising maintenance, premises and manufacturing equipment
Ensuring that the necessary validations for manufacturing procedures are carried out
Ensuring that production staff receive the necessary initial and ongoing training
Cleaning premises and equipment in the manufacturing area
Qualifying premises and equipment in the manufacturing area
Validating cleaning processes
Ensuring that batch production records are reviewed and signed before they are
passed on to the Quality Control department
Participating in audits (suppliers, subcontractors)
Helping process complaints
Compiling relevant operating instructions
Maintaining specifications
Selecting containers for starting materials and bulk material
Change control
Participation in the compilation and adaptation of submission files for marketing
authorisation
Participation in environmental monitoring
Participation in self-inspections
The main task of the Head of Production is to ensure that manufacturing operations are carried out in
line with the written instructions and operating procedures (manufacturing instructions) that have been
drawn up previously. Manufacturing must conform to good manufacturing practice as well as accepted
pharmaceutical regulations (Article 46 f of Directive 2001/83/EC) (see Figure 2.D-8).
The Head of Production's scope of responsibilities and duties must be defined in writing in job
specifications in accordance with Article 7 of Directive 2003/94/EC (see Chapter 2.A Place of work and
job descriptions). Figure 2.D-9 gives a sample job description for the Head of Production.
If the holder of the manufacturing authorisation has appointed more than one Head of Production, the
individual areas of responsibility must be clearly defined and distinguished from one another. If such a
distinction is not made, all persons have equal responsibility for the entire manufacturing facility.
The holder of the manufacturing authorisation must help the Head of Production carry out his or her
duties by making the necessary organisational, personnel and material arrangements to enable the
Head of Production to fulfil his or her role in full.
The Head of Production and the Head of Quality Control must be independent from one another.
(Article 11 of Directive 2003/94/EC) (Figure 2.D-9).
Figure 2.D-9 Sample job description for the Head of Production (cont.)

Description of position : Head of Production
Harry Neumann (20-023)
Company address
Sunny Street 4
23456 Modeltown
Tel.: 04991-87652, fax: 04991-87652, e-mail: hneumann@sample.de
Department code
Dept. Production, "Solid Dosage Forms" subdivision
Deputy for job holder
Dr. Gert Klawitter, "Liquida" subdivision
Supervisor
reports to the personnel department.
On technical and organisational matters, the position holder reports to the head of the Production department.
In the context of the Head of Production's position relating to public law, the position holder acts without
The position holder is authorised to issue instructions to staff in the "Solid Dosage Forms" subdivison as well as
warehouse and engineering staff.
Authorisations
The position holder signs external correspondence with the prefix "By proxy".
Job specifications
Very good knowledge and several years' experience in pharmaceutical production of
solid dosage forms incl. relevant in-process controls
Basic business knowledge
Reliability
Leadership skills
Business mindset
Position objectives
To ensure that the drug products (in this case, solid dosage forms) are manufactured and stored properly in
accordance with regulations under drug product laws as well as EU and USA GMP regulations.
Duty R S I
Checking, approving and regularly updating manufacturing instructions as well as the X

necessary operating instructions
Checking and signing batch production records X
Qualifying suppliers of starting and packaging materials X X
Ensuring that the hygiene status in the area of solid dosage forms complies with GMP, X
including carrying out environmental monitoring
Monitoring maintenance, qualification and calibration of the premises and facilities in the area X
of solid dosage forms
Validating the manufacturing and cleaning processes in the area of solid dosage forms X
Monitoring to ensure that all personnel in the area of solid dosage forms take part in regular X
training measures
Monitoring storage conditions for starting materials, packaging materials, intermediate X
products, bulk materials and finished goods as well as defective products in the area of solid
dosage forms
Clarifying discrepancies in the area of manufacturing solid dosage forms including operating X
an error prevention system
Change control X X
Fulfilling obligations in accordance with Article 46 c of Directive 2001/83/EC to report X
significant changes in terms of premises and facilities in the area of solid dosage forms to the
relevant authorities.
Further developing manufacturing technology in the area of solid dosage forms X
Production planning and control X X
Budget and personnel planning X X
Self-inspections, customer audits and inspections by the authorities X X
Providing customer service in the area of solid dosage forms X X
Reviewed by/on
Dr. Stefan Bach, head of Production department/03. 07. 2006
Approved by/on
Sally Sample (Managing Director), 03.07.2006
Position holder informed on
Harry Neumann, 04.07.2006
2.D.3 Head of Quality Control
2.D.3.1 Individual Requirements for the Head of Quality Control
The individual requirements for the Head of Quality Control are essentially the same as those for the
Head of Production (see chapter 2.D.2.1 Individual requirements for Head of Production).
2.D.3.2 Areas of Responsibility of the Head of Quality Control
The main task of the Head of Quality Control is to check starting materials, final products and, where
necessary, intermediate products in line with written instructions and operating procedures (testing
procedures) that have been drawn up previously. The testing must be carried out in conformity with
good manufacturing practice and the accepted pharmaceutical regulations. This also applies to
containers, external casing, packaging and labelling materials as well as package inserts. The Head of
Quality Control's areas of responsibility subject to public law are determined in the EU-GMP Guideline
(see Figure 2.D-10).
The Head of Quality Control can also delegate quality control procedures to other persons within the
unit and, to a limited extent, also to third parties. This is particularly relevant when external testing
locations are assigned. Routine tests (in-process tests, end-product controls) should always be carried
out by the manufacturer. If the manufacturer does not have the suitable equipment or the necessary
personnel for certain special analyses, these can be assigned to appointed companies and institutions.
It is important to ensure, however, that the external testing location has the appropriate premises and
equipment and is able to perform the tests in line with modern scientific and technological standards.
Such tests may include sterility and pyrogen testing, or special pollutant residue analyses. In the Head
of Quality Control's areas of responsibility (see Figure 2.D-11), he or she often works with other
function owners, such as the Head of Production or Qualified Person in accordance with Article 103 of
Directive 2001/83/EC.
All areas for which the Head of Quality Control is responsible must be recorded in the job description.
It is important to clearly distinguish his or her responsibilities from those of the Head of Production and
Qualified Person. Figure 2.D-12 gives a sample job description for the Head of Quality Control.
Figure 2.D-10 Areas of responsibility of the Head of Quality Control in accordance with Chapter 2, Part I of the
EU-GMP Guideline
Areas of Responsibility of the Head of Quality Control in Accordance with Chapter 2, Part I of the EU-
GMP Guideline
1. Approving or rejecting starting materials, packaging materials and intermediate products
2. Interpreting batch records
3. Approving specifications and instructions for sampling and test procedures, as well as ensuring that these are
followed
4. Ensuring that all necessary tests are carried out
5. Approving assignments and monitoring analytical laboratories that become operational during the assignment
6. Supervising maintenance, premises and equipment for carrying out tests
7. Ensuring that the necessary validations for test procedures are carried out
8. Ensuring that testing staff receive the necessary initial and ongoing training
Figure 2.D-11 Other areas of responsibility of the Head of Quality Control in accordance with the EU-GMP
Guideline
Other Areas of Responsibility of the Head of Quality Control in Accordance with the EU-GMP Guideline
Interpreting test records
Cleaning and maintaining premises and equipment in the testing area
Qualifying premises and equipment in the testing area
Participating in the supplier and subcontractor audits
Helping process complaints
Approving specifications
Approving sampling instructions
Change control
Stability studies
Trend analyses
Participating in the compilation and adaptation of submission files for marketing
authorisation
Participating in environmental monitoring
Participating in self-inspections
Figure 2.D-12 Sample job description for the Head of Quality Control

Description of position : Head of Quality Control
Siegfried Lüdemann (50-023)
Company address
Sunny Street 4
23456 Modeltown
Tel.: 04991-87656, fax: 04991-87656, e-mail: sluedemann@muster.de
Department code
Dept. Quality control
Deputy for the position holder
Ludwig Koch, dept. Quality Control
Supervisor
reports to the personnel department.
On technical and organisational matters, the position holder reports to the head of the Quality Control
department.
In the context of the Head of Quality Control's position relating to public law, the position holder acts without
The position holder is authorised to issue instructions to the staff of the Quality Control department.
Authorisations
The position holder signs external correspondence within his or her area of responsibility with the prefix "pp".
Job specifications
Very good knowledge and several years' experience in the area of pharmaceutical
instrumental analytics, microbiology and galenical testing procedures
Basic business knowledge
Reliability
Leadership skills
Business mindset
Position objectives
Ensuring that the quality of drug products is properly tested in accordance with regulations under drug product
laws as well as EU and USA GMP regulations.
Duty R S I
Checking, approving and regularly updating test procedures as well as the necessary X
operating instructions
Checking and signing test records X
Qualifying suppliers of starting and packaging materials X X
Environmental monitoring in the manufacturing area X X
Monitoring maintenance, qualification and calibration of the premises and facilities in the X
area of quality control
Validating sampling procedures and analytical methods X
Monitoring to ensure that all personnel in the area of quality control take part in regular X
training measures
Monitoring storage conditions for samples, standards and retention samples X
Clarifying discrepancies in the area of quality control including operating an error X
prevention system
Change control X X
Fulfilling obligations to report significant changes in terms of premises and facilities in the X
area of quality control to the relevant authorities
Further developing laboratory equipment X
Planning/controlling sample research X
Budget and personnel planning X X
Self-inspections, customer audits and inspections by the authorities X X
Customer service in the area of quality control X X
Providing guidance on questions of occupational health and safety, in particular when staff X
are handling hazardous substances
Reviewed by/on
Dr. Manfred Keller (Head of QA), 28.07.2006
Approved by/on
Sally Sample (Managing Director), 31.07.2006
Position holder informed on
Siegfried Lüdemann 31.07.2006
2.D.4 Qualified Person in Accordance with

Article 103 of Guideline 2001/83/EC
2.D.4.1 Individual Requirements for the Qualified Person in Accordance

with Article 103
The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must be "suitably
qualified". No more details of these qualifications are provided in Directive 2001/83/EC. The national
laws of the member states may provide more specific requirements.
The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must be resident in a
European Union member state (Directive 2001/83/EC, Article 103).
2.D.4.2 Areas of Responsibility of the Qualified Person in Accordance

with Article 103 of Directive 2001/83/EC
The Qualified Person in accordance with Article 103 is the person that the pharmaceutical
manufacturer assigns to gather and assess information that has emerged about presumed side effects
and to coordinate the necessary measures (see figure 2.C-13). His or her area of responsibility is
finished medicinal products. A side effect, for the purposes of Article 1 No. 11 of Directive 2001/83/EC,
is "A response to a medicinal product which is noxious and unintended and which occurs at doses
normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration,
correction or modification of physiological function."
In line with Article 103 of Directive 2001/83/EC, the Qualified Person in accordance with this article
must gather all known reports of presumed side effects, in line with written procedures. The holder of
approval for placement on the market is obliged to compile a report of these side effects in accordance
with Article 104 of Directive 2001/83/EC. This report is usually delivered electronically.
Information is gathered either by word of mouth or in writing, but also as a result of an active search for
information on the part of the Qualified Person, for instance by studying literature or carrying out
computer-assisted research. The Qualified Person in line with Article 103 informs the authorities of the
member state in which the side effect has occurred. If the side effect is reported in a third country, the
European Medicines Agency (EMEA) and the authorities of the member states in which the drug
product was approved must be informed. The Qualified Person must also ensure that further
information for assessing the risk-benefit ratio of a drug product, including his or her own evaluations,
is delivered immediately and in full to the responsible authorities upon request.
The risk-benefit ratio comprises an evaluation of the positive therapeutic effects of a drug product in
relation to the risk. Risks may concern the quality, safety or efficacy of the drug product for the patient's
health or public health (Article 1 No. 28 of Directive 2001/83/EC). In the case of drug products intended
for use on animals, risks to the health of both humans and animals are assessed.
The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must also initiate the
review of reports of undesirable effects of drug products and evaluate whether or not this poses a drug
product risk. The Qualified Person in accordance with Article 103 of Directive 2001/83/EC is also
responsible for ensuring that all complaints are recorded systematically. This includes initiating an
immediate review of reports. He or she must coordinate the necessary measures and make the
Qualified Person in accordance with Article 48 of Directive 2001/83/EC aware of the issue. This
enables the Qualified Person to take the necessary measures in his or her area, in particular if the
problem could relate to quality. It is important to check the effectiveness of this procedure on a regular
basis, for instance as part of the self-inspection or simulated product complaints and recall actions.
When reviewing and evaluating the reports, the Qualified Person in accordance with Article 103 of
Directive 2001/83/EC should receive the support of the Heads of Production and Quality Control and
the Qualified Person whose areas of responsibility are otherwise unaffected.
The Qualified Person in accordance with Article 103 of Directive 2001/83/EC must inform the
responsible authorities immediately of every deficiency that could lead to a recall or an abnormal
distribution limitation, and also notify them of the states in which the drug product has been placed on
the market or implemented. Furthermore, the authorities must be informed immediately of any
reasonable suspicion of counterfeit medicinal products (Article 13 para. 1 of Directive 2003/94/EC)
(Figure 2.D-13).
Figure 2.D-13 Areas of responsibility of the Qualified Person in accordance with Article 103 of Directive
2001/83/EC
Areas of Responsibility of the Qualified Person in Accordance with Article 103 of Directive 2001/83/EC
Gathering reports of drug product risks
Assessing drug product risks
Monitoring clinical trials relating to drug product risks
Reporting serious side effects, informing the supervisory authorities in the event of
abnormal distribution limitations (for instance, delivery stop, recall)
Defining and coordinating measures for risk aversion
Record keeping
The requirements stated in Article 123 para. 2 of Directive 2001/83/EC must be taken into account for
every recall: "The marketing authorisation holder shall be obliged to notify the Member States
concerned forthwith of any action taken by him to suspend the marketing of a medicinal product or to
withdraw a medicinal product from the market, together with the reasons for such action if the latter
concerns the efficacy of the medicinal product or the protection of public health. Member States shall
ensure that this information is brought to the attention of the Agency."
To enable the Qualified Person in accordance with Article 103 of Directive 2001/83/EC to fulfil his or
her duties correctly, the pharmaceutical manufacturer must ensure that the Qualified Person in
accordance with Article 103 of Directive 2001/83/EC is informed immediately of all reports of drug
product risks and provided with the necessary personnel and material resources. This obligation arises
from the fact that the organisational power lies with the pharmaceutical manufacturer, who is
responsible for ensuring that information flows effectively to all affected departments within the
organisation.
2.D.5 Scientific Service in Charge of Information
2.D.5.1 Individual Requirements for the Scientific Service in

Charge of Information
The individual requirements are not described in more detail in Article 98 para. 1 of Directive
2001/83/EC. The only requirement is the formation of a Scientific Service in Charge of Information.
These requirements can be substantiated by the national law of the member states.
2.D.5.2 Areas of Responsibility of the Scientific Service in

Charge of Information
The Scientific Service in Charge of Information in accordance with Article 98 of Directive 2001/83/EC is
the person commissioned by the pharmaceutical manufacturer to take on the responsibility of gathering
scientific information about the drug product.
In particular, he or she is responsible for ensuring that the ban on providing misleading information
regarding drug products in accordance with Article 87 para. 3 of Directive 2001/83/EC is observed.
Misleading information includes the following situations, for example:

If drug products are attributed a therapeutic efficacy or effects that they do not possess
If the impression is falsely given that a successful result can safely be expected, or that
no harmful effects can result from the intended or prolonged use
If suitable designations, data or presentations that play a part in the assessment of a
drug product are used with the intent to deceive the public with regard to drug product quality
Furthermore, the Scientific Service in Charge of Information must ensure that the labelling, package
insert, technical information and advertising correspond to the content of the marketing authorisation or
registration.
The concept of "advertising" is defined in Article 86 of the consolidated Directive 2001/83/EC

(see Figure 2.D-14).
Figure 2.D-14 "Advertising" for the purposes of Directive 2001/83/EC

Advertising for the purposes of Article 86, Directive 2001/83/EC
Public advertising for drug products
Advertising drug products to persons who are entitled to be prescribed or dispensed
drug products
Visits by medical sales representatives to persons who are entitled to be prescribed or
dispensed drug products
Delivery of drug product samples
Incentives to prescribe or dispense drug products by means of granting, offering or
promising financial or material advantages providing that these are not of marginal value
Sponsoring sales promotion events attended by persons who are entitled to be
prescribed or dispensed drug products
Sponsoring scientific congresses attended by persons who are entitled to be
prescribed or dispensed drug products, in particular covering transportation and lodging costs
of these persons
The Scientific Service in Charge of Information also takes on tasks arising from Article 98 para. 2 of
Directive 2001/83/EC (see Figure 2.D-15) on behalf of the authorisation holder.
Figure 2.D-15 Duties of the Scientific Service in Charge of Information in accordance with Directive 2001/
83/EC
Duties of the Scientific Service in Charge of Information in accordance with Article 98, Directive 2001/
83/EC
1. The holder of approval for placement on the market establishes a scientific post within his or her organisation
that is assigned the task of providing information on the drug products that the approval holder puts into
circulation.
2. The holder of approval for placement on the market:
o Keeps a copy of every advertising text circulated by his or her organisation, as well as
a data sheet specifying the recipient, distribution type and date of first distribution available
for the authorities or posts responsible for control of pharmaceutical advertising, or delivers
these texts to such authorities
o Makes sure that the pharmaceutical advertising carried out by his or her organisation
complies with this title
o Checks whether the medical sales representatives employed by his or her organisation
are properly trained and fulfilling their obligations as per Article 93 paragraphs 2 and 3
o Provides the authorities or posts charged with controlling pharmaceutical advertising
with the information and assistance that they require in order to carry out their task
o Ensures that the instructions given by the authorities or posts responsible for
controlling pharmaceutical advertising are followed promptly and in full
The function of the Scientific Service in Charge of Information is part of the preventative consumer
protection scheme insofar as it generally ensures that only information covered by the authorisation is
enclosed with a drug product. The Scientific Service in Charge of Information acts in a preventative
manner to avoid information deficits, while the Qualified Person in accordance with Article 103 of
Directive 2001/83/EC must intervene retrospectively once an information deficit has occurred.
2.D.6 Medical sales representatives
2.D.6.1 Individual requirements for medical sales representatives
Medical sales representatives must, in accordance with Article 93 para. 1 of Directive 2001/83/EC,
have appropriate training and sufficient knowledge to enable them to give precise and as complete as
possible information about the drug products they offer. Individual member states can specify
additional requirements.
The pharmaceutical manufacturer's Scientific Service in Charge of Information should check regularly
whether the medical sales representatives are sufficiently qualified to perform their duties correctly. As
outlined in Figure 2.D-15, this obligation arises from Article 98 para. 2 of Directive 2001/83/EC.
2.D.6.2 Areas of responsibility of the medical sales representative
The medical sales representative acts as a conveyor of information between the pharmaceutical
manufacturer and members of the healing professions (seeFigure 2.D-16). He or she has to provide
them with specialist information about drug products for the purposes of Article 1 No. 2 of Directive
2001/83/EC. This task can be carried out in person on site, or by telephone. When giving advice about
individual drug products, the medical sales representative must present the corresponding technical
information. It is essential for members of the healing profession to have access to the scientific results
of drug product research and to be able to view them objectively and critically so that they can use, in
particular, newly-developed drug products in the correct manner. Due to his or her constant personal
contact with the healing professions, the medical sales representative has an important role to play.
It is his or her duty to record any information given by members of the healing processions regarding
side effects and contraindications or other risks, and to report these in writing to his or her contract
giver, the pharmaceutical manufacturer.
If the medical sales representative is instructed by the pharmaceutical manufacturer to dispense drug
product samples, he or she must keep a record of the recipients of these samples as well as the type
and volume of the samples and when they are dispensed. These records are subject to monitoring by
the authorities.
The medical sales representative must ensure that the quality of the drug product samples is not
compromised during storage in the warehouse or transportation, and that the samples are not
accessible to unauthorised persons (Figure 2.D-16).
Figure 2.D-16 Medical sales representatives in accordance with Article 93 of Directive 2001/83/EC
The "Medical Sales Representative" in Accordance with Article 93 of Directive 2001/83/EC
Medical sales representatives must receive appropriate training from their respective
employer and have sufficient knowledge to enable them to give precise and as complete as
possible information about the drug products they offer.
Every time a medical sales representative visits a member of the healing professions,
he or she must give a summary of the qualities of each drug product offered including the
new information on the sales price and refund conditions for the purposes of Article 91
paragraph 1, if this is permitted under the laws of the member state in question.
Medical sales representatives must present to the scientific post stated in Article 98
paragraph 1 all information pertaining to the application of the drug products they are
advertising, in particular regarding undesirable side effects of which they have been
informed by the members of the healing professions whom they have visited.
Summary
To ensure drug product safety, legislators have transferred duties and responsibilities to certain function owners.
The individual prerequisites and areas of responsibility are described in pharmaceutical law.
These include
The Qualified Person
Head of Production
Head of Quality Control
Qualified Person in accordance with Article 103 of Directive 2001/83/EC and the
Scientific Service in Charge of Information
Written job descriptions containing clear areas of responsibility must be compiled.
Since the duties of the Qualified Person are extensive and to avoid conflicts of interest, the Qualified Person
should work within the area of quality assurance and not attend to any operational business in manufacturing or
quality control. The Qualified Person can be substituted only by another Qualified Person. More than one
Qualified Person may be appointed if their responsibilities are clearly divided in writing.
3.A Official Requirements
Authors: Dr. Michael Hiob, Dr. Ralph Gomez / Update 08

What are the general requirements operating rooms have to comply with?
Which official requirements must be observed when designing rooms in
accordance with the EU GMP Guide and the U.S. cGMP regulations?
What do the terms "layout" and "room book" mean and what is their purpose?
"Premises and manufacturing equipment shall be located, designed, constructed, adapted and maintained to suit the intended operations."
(EC Directive 2003/94/EC, Article 8.1, see chapter C.2).
"... buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to
facilitate cleaning, maintenance, and proper operations. Any such building shall have adequate space for the orderly placement of equipment
and materials to prevent mix-ups ... and to prevent contamination."
(21 CFR Sec. 211.42 (a) (b), see chapter D.1.2 here).
Premises and equipment are the basic technical components of pharmaceutical production. From the GMP standpoint they have a great
significance, being in contact with pharmaceutical products from the raw material stage through to the finished product.
The design of rooms is crucial to the quality of the pharmaceutical products and also relates to the cost effectiveness of production - both
directly (investment costs) and indirectly (e.g. flow of materials). The construction, dimensions and layout of operating rooms contribute to the
assurance that operations can be carried out adequately regardless of type, size, number, location and facility, particularly with respect to the
faultless production, analysis, storage, packaging and distribution of medicinal products. The requirements for the design of the operating
rooms depend on the type and scope of the production processes they are used for. As a basic rule, the lighting, temperature, humidity and
ventilation (see chapter 3.A.4 Lighting, ventilation, air-conditioning) must be suitable for the relevant production step, and must not have a
negative impact on the quality of the products or operability of the facilities and equipment. Lighting is particularly important in areas where
visual checks must be carried out during the course of production. Essentially, the rooms should be built of such high quality as necessary for
the product quality and as simply and economically as possible. However, as important as controlling cost is, one must be careful not to hold
back on necessary quality in favor of lower costs.
Decreasing on quality very well may cost much more in the long run since it may lead to incidents of product reworks, rejections and, in the
extreme case, recalls. More information on design aspects is given in chapter 3.D Construction elements.
A room inside a pharmaceutical production building performs the same kinds of tasks as a cell in an organism. Essentially, while performing
the function of an envelope in which an individual processing step takes place - by isolating it from other processing steps that are running at
the same time - it must also perform a range of other tasks:
the supply of energy and utilities for the manufacturing process (see chapter 3.A.3 Installation and supply of utilities),
the creation of suitable climatic conditions (see chapter 3.A.4 Lighting, ventilation, air-conditioning);
and the supply and disposal of materials.
The optimum location of the rooms and their arrangement in relation to one another not only ensures the quality of production, but also
greatly influences cost effectiveness.
The rooms should be arranged in a way that production may be carried out using a logical step-by-step approach that
corresponds with the sequence of work steps (see chapter 3.B Material flow, personnel flow and layout).
The receipt and dispatch areas should be organized so that materials and products are protected from external
influences (see chapter 11.M.5 Storage areas).
Areas for carrying out in-process controls should be physically segregated from production. If this is not possible, suitable
measures must be taken to ensure that the controls will not be affected by current production (see chapter 11.I In-process control).
Control laboratories should be separated from the production rooms to exclude external influences. Defined and sufficient
storage conditions must exist for the storage of samples and records.
Staff rooms must be segregated from other areas.
The number of changing rooms, wash rooms and toilet facilities should be appropriate for the number of users. Toilets
should not open directly onto production rooms.
Rooms where animals are kept must be separated from other areas and also have their own access and ventilation
system.
The size of operating rooms must be adequate to ensure suitability for their intended use (see chapter 3.A.2 Size, area, height): Sufficient
space must be available in the manufacturing zone for the provision and interim storage of materials. Facilities must be assembled in such a
way that they can be accessed to carry out the necessary scope of cleaning and maintenance work. Sufficient space should also be available
in the storage area to ensure that the various categories of materials and products are properly stored. The rooms must be clean and dry and
the appropriate temperature and humidity range must be maintained (see chapter 11.M.6 Storage conditions).
Production hygiene is another important aspect to consider with view to product quality and safety: It should be possible to clean the
premises thoroughly and also to disinfect them. The compatibility of substances that act on floors and walls, as well as the rest of the facility
during production, cleaning and disinfection, must be verified. An adequate standard of hygiene in these rooms (to be specified by the
manufacturer) is essential to ensure the quality of the medicinal products (see chapter 3.A.5 Hygienic construction and chapter 11.C
Production hygiene). The use of appropriate controls assures that the required standard is maintained (see chapter 11.E Environmental
monitoring. The necessary precautions must be taken to prevent the entry of insects, rodents, birds and other animals (see chapter chapter
11.M.7 Sanitation and pest control). The operating rooms must be maintained in a good state of repair.
Cross-contamination in the production areas must be prevented through appropriate layout of the rooms, adequate material flow and
personal flow (seechapter 3.B Material flow, personnel flow and layout), but also by application of a suitable ventilation concept (see chapter
3.G Heating Ventilation Air Conditioning (HVAC)). Particular attention must be paid to the production of highly potent medicines (e.g. beta-
lactam antibiotics, hormones, zytostatics). Suitable measures, such as separate manufacturing areas and ventilation systems or campaign
manufacturing, must be utilized to ensure the prevention of cross-contamination (see chapter 11.J Prevention of cross-contamination).
Drawings of the existing operating rooms are an integral part of the company description (see chapter 15.E Site master file) and should be
available drawn to scale.
The description of rooms should include the points listed in Figure 3.A-1.
Figure 3.A-1 Description of operating rooms

Description of operating rooms
Plan, to scale
Inclusion of room numbers
Visual representation of positions of windows, doors, locks, hatches
Assignment of functions to each of the rooms
Assignment of hygiene categories to each of the rooms
The suitability of rooms used to carry out manufacturing operations that are of decisive importance for the quality of medicinal products must
be demonstrated by qualification. The type and scope of the qualification requirements depend on the specific operations that are to be
carried out in the various premises (see chapter 3.I Qualification of premises and air-conditioning systems).
Figure 3.A-2 shows the most important factors used to assess the suitability of operating rooms.
Figure 3.A-2 Factors used to assess the suitability of operating rooms

Factors used to assess the suitability of operating rooms
Location, connection with other rooms
Size: area and height
State of repair (maintenance)
Hygiene status, including pest control
Installations/supply of utilities
Lighting, ventilation and/or air-conditioning
Construction of doors and/or locks
Materials: floors, walls, ceilings
An acceptance inspection is carried out by the relevant authorities to assess the suitability of the rooms before manufacturing
authorization is granted. Manufacturing authorization may be denied to manufacturers who do not have suitable operating rooms, or
withdrawn if rooms are subsequently determined to be unsuitable.
3.A.1 Location, connection to other rooms

"Premises should be situated in an environment which [...] presents minimal risk of causing contamination of materials or products."
(Chapter 3.1 EU GMP Guide, see chapter C.4, here).
"There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent
contamination ..."
(21 CFR Section 211.42(c), see chapter D.1.2, here).
In addition to the requirement to prevent contamination a suitable room location ensures an appropriate flow of materials together with
compatibility with other manufacturing procedures in other rooms. The arrangement of rooms in the building should facilitate a linear
sequence of individual processing steps. This reduces the risk of confusion and the possibility that quality-determining manufacturing and
control steps will be missed. The arrangement of rooms in the sterile area plays an essential role in ensuring compliance with the various
room classes (keyword: locks). Additionally, the choice of location is an equally decisive factor - not only in terms of size but also for supply to
and disposal from the rooms.
When planning the arrangement of the rooms, in new buildings as well as conversions, the building features presented in Figure 3.A-3 must
also be considered in order to select suitable locations.
Figure 3.A-3 Building features
Building features
Building Construction: dimensions, materials, number and height of
structure stories, column grid, suspended ceilings, static
Building services: air-conditioning technology, utilities
(compressed air, nitrogen, steam), range of water qualities
Building use Effects of other production operations, e.g. via ventilation system
(hormones, highly potent substances)
Effects of personnel: are special access arrangements necessary?
Two examples are described below for illustration:
IPC laboratory: in a laboratory, visual controls must often be carried out and assessed (color, friability, microbiological
growth, etc.). It is therefore recommended that rooms where these kinds of activities take place be located in areas where natural
light is available.
Granulation of highly potent substances: personnel and other products are to be protected in this area. The building
features must be considered when choosing the location: is it possible to prevent contamination using air-conditioning technology?
Does the structure of the building make hermetic shielding of different areas from one another possible? Is it possible to include
locks?
3.A.2 Size, area, height

The area and floor plan required for the overall production, control and storage of a product are the decisive factors rather than the actual size
of the room itself. Only one batch of one product may be processed in a room at any time (see chapter 11.J Prevention of cross-
contamination).
Oversized rooms are often partially used as storage areas for previous or subsequent orders. If rooms are too small, materials are often
stored directly outside, e.g. in the corridor. The risk of mix-up is high in both instances.
A suitable layout plan for rooms in which several production steps are processed in sequence is the prerequisite for preventing mix-ups
through crossing-free logical structuring of operations. See Chapter 3.8 EU GMP Guide (chapter C.4, here) and 21 CFR section 211.42(c)
(chapter D.1.2, here) and Figure 3.A-4.
Figure 3.A-4 Crossing-free flow of materials in granulation operations
to enlarge, click
here!
The height of a room is largely determined by the building structure and the requirements of building legislation in relation to use. Room
height must be considered in relation to factors such as the installation height of machines, the number and type of air vents as well as room
classes.
3.A.3 Installation and supply of utilities
In addition to the type of installation that must facilitate easy cleaning, a process-oriented supply of utilities and energy must be aimed at,
where the number and dimensioning of utilities must be harmonized with the process to achieve quality and economic efficiency. See Chapter
3.10 EU GMP Guide (chapter C.4, here)
and 21 CFR 211.42(c)(10)(i) (chapter D.1.2, here).
Examples:
Main ring (loop) for purified water: the dimensions of the pipes for purified water must be harmonized for all consumers
in a loop, as the flow rate necessary to provide protection against microbial contamination may otherwise not be achieved, e.g. due
to under-dimensioning.
Power supply: the power supply may fluctuate within specific limits (400 V ± 20 V) or may fail completely. With sensitive
measuring or control equipment, or analytical instrumentation, these (permissible) tolerances may lead to inaccurate results: in
such cases, appropriate technical measures must be taken (e.g. an emergency power supply).
For more detailed information on utilities see: chapter 3.F Building services, chapter 3.H Process Gases and chapter 5 Pharmaceutical Water.
3.A.4 Lighting, ventilation, air-conditioning

Air-conditioning provides for the supply of air to rooms and processes. As well as complying with the requirements of the guidelines for
workplaces, the roomair supply must be designed to meet the requirements of the products being manufactured. The requirements range
from variations in air humidity and air temperature to pressure differentials or flow directions between individual rooms. (See chapter 3.G.5
Design criteria for the ventilation of premises.)
The process air supply must satisfy only the requirements of the product or process, as it is normally in direct contact with the products (e.g.
fluid-bed drying). Depending on the requirements, it may be necessary for the conditioning of the air to be monitored using suitable recording
systems.
The number and arrangement of lights must be determined in accordance with the guidelines for workplaces with respect to illumination levels.
See 21 CFR 211.44 (chapter D.1.2, here) and EU GMP Guide 3.16 (chapter C.4, here). To facilitate easy cleaning and maintenance of light
fittings, it is recommended, particularly in sterile areas, that these be accessible from the outside. See Chapter 3.10 EU GMP Guide (chapter
C.4, here) and chapter 3.D.4 Ceilings).
3.A.5 Hygienic construction

Production rooms must be designed in such a way that (uncontrolled) accumulation of dust and product particulate material cannot occur, or
alternatively they should be easy to clean and disinfect (if necessary). See Chapter 3.9 EU GMP Guide (chapter C.4, here) and 21 CFR,
section 211.46(b) (c) (chapter D.1.2, here). This general requirement must be weighed according to the use of the room. The requirements
are most stringent in the sterile area and are considerably lower in the packaging area. Whatever the case, suitable protective measures must
be taken to make sure that the ingress of animals and insects into the pharmaceutical production areas is prevented (see Chapter 3.4 EU
GMP Guide (chapter C.4, here) and 21 CFR, 211.56(a) (chapter D.1.2,here) and chapter 11.M.7 Sanitation and pest control). More detailed
information on constructional aspects is given in chapter 3.D Construction elements.
3.A.6 Room book and layout

When designing rooms, a range of data must be collected in order to provide appropriate solutions in response to requirements.
Figure 3.A-5 Requirements for use

Requirements for use
Requirements derived from the product Room climate
characteristics (temperature, humidity, flow
(temperature and sensitivity to moisture, warehouse direction)
stability, sensitivity to light, toxicity, etc.): Fenestration or type of
lighting
Necessity of climate
monitoring
Requirements derived from the manufacturing Quality of walls, ceilings
process and floors
(sterile, aseptic or non-sterile process, previous and Ventilation technology
subsequent processing steps and their connection, (recirculating air, fresh air,
warehouse, packaging, control laboratory etc.): laminar flow)
Type, number and area
requirements of process
equipment
Connected loads and heat
output of facilities
Type and quality of utilities
(compressed air, nitrogen, steam)
Type and quality of water
Warehouse areas for format
and spare parts
Working hours
Number of personnel
Flow of materials
Personnel flow
The "room book", as it is referred to, is a useful document in which all data relevant to the room can be compiled. Together with the layout,
the room book presents the specification of a room. Both documents may also be used to illustrate company operations during inspections
and also as the basis for the qualification of rooms.
The data for the room book (see Figure 3.A-6) and layout design are determined by the requirements for use (Figure 3.A-5).
Figure 3.A-6 Room book

Summary
Rooms have great significance from the GMP standpoint, since they surround pharmaceutical products
from the raw material to the finished product stage.
The design of rooms affects the economic efficiency of production.
The construction, dimensions and layout of operating rooms contribute to the assurance that operations
may be carried out properly, particularly with respect to the faultless production, analysis, storage,
packaging and distribution of medicinal products. The individual requirements depend on the type and
scope of the production.
The arrangement of rooms in the building should facilitate a linear sequence of individual processing
steps.
Production rooms must be designed in such a way that accumulation of dust and product particulate
material cannot occur, or alternatively, so that they will be easy to clean and disinfect (if necessary).
Rooms are specified by the room book and layout.
3.B Material flow, personnel flow and layout
Authors:

What is the significance of the personnel flow and material flow in production?
Which principles governing the material flow are applied in pharmaceutical
production?
Which design concepts does FDA recommend for an aseptic processing facility?
Uwe Schwarzat / Dr. Ralph Gomez / Update 05
3.B.1 Material flow

Material flow refers to the interlinking of all operations relevant to sourcing, processing and treatment, as well as the distribution of material
goods within specified areas. This specifically involves: processing, handling, transportation, testing, stopovers and storage. Material flow is
the sequence of individual manufacturing and storage steps, starting with the raw material and ending with the finished product. In addition to
economic considerations, the material flow has a particular significance in terms of Good Manufacturing Practices (Figure 3.B-1).
Figure 3.B-1 Functions and characteristics of material flow

Functions and characteristics of material flow
Functions Suitable for preventing the omission of quality-determining
manufacturing and control steps
Elimination of confusion
Compatibility with other manufacturing procedures in other
rooms
Characteristics Clear
Unambiguous
Crossing-free
Characterized by short routes
The material flow ultimately represents the manufacturing process in the building, which must be broken down into individual steps and
presented in a flow diagram. Each processing step must be assigned to a machine, and each machine assigned to a room. The rooms in the
building must then be grouped in a manner that reflects the material flow.
There are two main principles governing the material flow that will obviously be influenced by the building structure as well as the products:
these are the horizontal and vertical material flow.
The horizontal material flow is determined by the transportation of materials using conventional methods. Production takes place at one level,
or several levels connected by lifts. Transport and production take place at the same level. The horizontal material flow is widespread in the
case of sterile dosage forms and in solids production.
A vertical material flow, implemented for the first time by Prof. Lhoest, involves the specific use of gravity for the transportation of products.
The production equipment operates at several connected levels. Transport and production take place at different levels wherever possible.
This procedure is mainly used in solids production (see Figure 3.B-2).
Figure 3.B-2 Illustration showing the principle of vertical material flow

[Pohl, 1999]
In addition to the two main principles of material flow described, an interlinking of facilities is desirable from the GMP standpoint, particularly
for vertical material flows but also for horizontal material flows. The facilities are joined together using fixed connections such as pipes, tubes,
coils, etc.
The product may be transported from one machine to the next via these connecting elements without having to be transferred to intermediate
containers (seeFigure 3.B-3).
Figure 3.B-3 Illustration showing principle of interlinked material flow
to enlarge, click
here!
A comparison of the aforementioned principles of material flow is shown in Figure 3.B-4.
Figure 3.B-4 Comparison of principles of material flow [Pohl, 1999]

Comparison of principles of material flow
Advantages Disadvantages
Horizontal No connection with Large hygienic areas
other levels Transport and production not
Clear production separated
sequence Transportation systems
Simple tried-and- (stackers) often not compatible with
tested transportation GMP
systems
Vertical Transport and Technically complex
production separated Greater need for validation
Small hygienic areas No visual check possible
High degree of Special architectural design
automation required
Closed systems Complicated cleaning process
Interlinked Flexible transport Large hygienic areas
Closed systems to a Transport and production not
large extent separated
Can be automated Technically complex
3.B.2 Personnel flow
Many characteristics and functions of material flow also apply to personnel flow. Most importantly, logical organization of the personnel flow
serves to protect the product in addition to considerations of economy and labor legislation (Figure 3.B-5).
Figure 3.B-5 Functions of the personnel flow

Functions - personnel flow
Support of zonal concept
Prevention of cross-contamination
Product and personnel protection
Economic efficiency
To optimize the material flow, the appropriate number of personnel required to operate, monitor and maintain the machines and facilities must
be determined. The functions of individuals must then be described and the routes transferred to the layout. The personnel flow and its
iterative optimization are assessed together with the layout and material flow based on the following assumptions:
Access to pharmaceutical areas only via locks/changing rooms

Separate routes for pharmaceutical and non-pharmaceutical personnel
Short routes
3.B.3 Layout
"Layout"refers to the visual representation of machines inside rooms and also the arrangement and shape of rooms within a building. When
finding a suitable layout, personnel and material flow are also factors to consider in addition to the necessary areas or volumes and room
planning. The layout shows functions that ensure a safe manufacturing process and so when designing the layout it is recommended that
quality assurance is also considered.
Figure 3.B-6 shows the information that can be read off from the layout.
Figure 3.B-6 Layout information

Layout information
Type and size of rooms
Room layout and arrangement of machines
Traffic routes (personnel flow and material flow)
Locks for material and personnel
Staff rooms (short break areas, toilets)
Zone classification
3.B.4 Design concepts in FDA's Sterile Drug Products

Produced by Aseptic Processing guideline
The U.S. Sterile Drug Products Produced by Aseptic Processing guideline gives FDA's recommendations on issues concerning aseptic
processing. Specifically, the guideline covers buildings and facilities, personnel training, qualification and monitoring, components and
container closures, endotoxin control, time limitations, validation of aseptic processing and sterilization, laboratory controls, sterility testing
and batch record review. This guideline is an update of FDA's 1987 Aseptic Processing Guideline, which revised several areas including
cleanroom design, personnel qualification, process design, quality control, environmental monitoring, and review of production records. It also
discusses the use of isolators for aseptic processing. The guideline focuses primarily on finished drug products GMPs.
The guideline's introduction to the section describing the design of a sterile facility (section IV.E) states, "Aseptic processes are designed to
minimize exposure of sterile articles to the potential contamination hazards of the manufacturing operation. Limiting the duration of exposure
of sterile product elements, providing the highest possible environmental control, optimizing process flow, and designing equipment to prevent
entrainment of lower quality air into the Class 100 (ISO 5) clean area are essential to achieving high assurance of sterility". The guideline also
states that "design concepts discussed within this section are not intended to be exhaustive. Other appropriate technologies that achieve
increased sterility assurance are also encouraged".
The following list provides a summary of the design concepts discussed in the guideline, several of which have been discussed earlier.
Recommended facilities design concepts from the U.S. Sterile Drug Products Produced by Aseptic Processing guideline:
Optimize material and personnel flow

Optimize personnel movement and comfort
Minimize frequency of entries and exits to and from the processing room
Minimize the number of people in the room
Minimize the number of transfers into the cleanroom or isolator
Restrict movement adjacent to the critical areas
Automate whenever possible
Sterilize equipment using Sterilize-in-place (SIP) technology
Transfer product under appropriate cleanroom conditions.
Transfer partially closed sterile product only in critical areas
Provide for Class 100 (ISO 5) protection in the area between a filling line and the lyophilizer
Protect the sterile product and container-closures by equipment of suitable design
Use carefully designed curtains and rigid plastic shields to act as barriers
Use an isolator system to further enhance product protection
Define and control the dynamic interactions permitted between cleanrooms
Install airlocks between the aseptic area and lower classified areas
Install airlocks in interfaces between personnel transitions and material staging areas
Safeguard uncapped stoppered vials until completion of the crimping step
Employ devices for the on-line detection of improperly seated stoppers
Use construction materials for cleanrooms that are easy to clean and sanitize
Install seamless and rounded floors and easily accessible corners in cleanrooms
Design cleanrooms and HEPA filter banks to protect sterile products from contamination
Eliminate unnecessary equipment, fixtures and materials from cleanrooms
Equip processing equipment and systems with sanitary fittings and valves.
Insure that any drain installed in an aseptic facility is of proper design
Design equipment to facilitate ease of sterilization (CFR 211.63)
Design equipment to ensure ease of installation to facilitate aseptic setup
Address the effect of equipment design on the cleanroom environment
Avoid horizontal surfaces or ledges that accumulate particles
Design of equipment should be such that it does not obstruct airflow nor, in critical areas, disturb unidirectional airflow.
Insure that deviation or change control systems address atypical conditions posed by shutdown of air handling systems
or other utilities and the impact of construction activities on facility control
Prepare written procedures which address returning a facility to operating conditions following a shutdown
Summary
Material and personnel flow influence GMP and the economic efficiency of an operation. Horizontal
material flow is predominantly used in the pharmaceutical industry, though examples of vertical
material flow are becoming increasingly common - particularly in the production of solid dosage forms.
It is recommended that quality assurance be included when determining the layout.
FDA's revised Aseptic Processing guideline recommends many design concepts that can be applied to
an aseptic facility.
3.C Room classes
Author: Dr. Hans Schicht / Update 08
Here you will find the answers to the following questions:

Which room grades are specified in the EU GMP Guide?
Which requirements will classified rooms have to meet?
Which room grades are required for different process operations?
How can the requirements for the different room grades be met?
What are the FDA determinations for aseptic processing?
3.C.1 General GMP Requirements for Premises

Depending on their utilization, differing requirements regarding layout design, ventilation and air-conditioning, equipment and hygiene are to
be met by premises for pharmaceutical applications. The general regulatory stipulations for pharmaceutical production rooms are compiled in
chapter 3 of part 1 of the EU GMP Guide (chapter C.4 Part I Basic Requirements for Medicinal Products).
Premises are to be located, designed, constructed, adapted and maintained to
suit the operations to be carried out

aim at minimizing the risk of errors and
permit effective cleaning and maintenance
in order to avoid cross-contamination, build up of dust and dirt and, in general, any adverse effect on the quality of products.
3.C.2 GMP Requirements for Cleanrooms: Air Cleanliness Grades

Particularly high requirements are to be met by premises employed for manufacturing sterile products. Devoted to this class of products is
annex 1 to the EU GMP Guide (chapter C.6.1 Annex 1 Manufacture of Sterile Medicinal Products). Its latest revision was published in
February 2008; this new edition came into force on March 1, 2009.
Annex 1 distinguishes four air cleanliness grades (Grades A to D). The requirements for airborne particles as revised in 2008 are reproduced
in Figure 3.C-1.
Figure 3.C-1 Air cleanliness classification for sterile product manufacturing (EU GMP Guide, Annex 1,
edition 2008)
Requirements for airborne particles (EU GMP Guide, Annex 1)
Maximum permitted number of particles per m3 equal to or greater than the
tabulated size
At rest In operation
Grade 0.5 μm 5.0 μm 0.5 μm 5.0 μm
A 3 520 20 3 520 20
B 3 520 29 352 000 2 900
C 352 000 2 900 3 520 000 29 000
D 3 520 000 29 000 Not defined Not defined
In addition to the limits for airborne particle concentrations, annex 1 also stipulates limits for microbiological monitoring of clean areas during
operation, for air and for surfaces as well (Figure 3.C-2).
Figure 3.C-2 Recommended limits for microbiological monitoring of clean facilities during production, i.e.
in the occupancy state in operation (EU GMP Guide, annex 1, edition 2008)
Recommended limits for microbial contamination (EU GMP Guide, Annex 1)
Recommended limits for microbial contamination (average values)
settle plates contact plates glove print
air sample
Grade (diameter 90 mm) (diameter 55 mm) 5 fingers
cfu*/m3 cfu*/4 hours** cfu*/plate cfu*/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
* cfu = colony forming units
** Individual settle plates may be exposed for less than 4 hours
The 2008 edition of annex 1 distinguishes clearly between qualification of a sterile facility and monitoring during routine production.
Classification of clean areas is to be performed during qualification both in the occupancy state at rest and in the occupancy state in operation.
These occupancy states are defined as follows:
at rest: the condition where the installation is installed and operating, complete with production equipment, but with no
operating personnel present
in operation: the condition where the installation is functioning in the defined operating mode with the specified number
of personnel working
3
For classification measurements in grade A zones, a minimum sample volume of 1 m should be taken per sample location. For the
minimum number of sample locations the determinations according to EN ISO 14644-1 apply (see chapter 3.C.6 Cleanliness Zoning
Concepts). For room grades B to D the EN ISO 14644-1 determinations apply both for the minimum sample volume as well as for the
minimum number of sampling locations. Data evaluation is to follow the determinations in EN ISO 14644-1.
For classification purposes, portable particle counters with a short length of sample tubing should be used. This is required because of the
risk of precipitation of particles ≥5.0 μm in sampling systems with long lengths of tubing. Isokinetic sampling heads shall be used in systems
with unidirectional airflow.
Classification measurements in the occupancy state in operation may be performed during normal operations, simulated operations or
during media fills where worst-case simulation is required.
For process monitoring, annex 1 requires airborne particles to be monitored, in grade A zones, during the full duration of critical processing
including equipment assembly except in situations that might damage the particle counter. In such cases, however, monitoring should cover
the routine equipment set-up operations prior to exposure to the risk.
Grade A zones should be monitored at such a frequency and with suitable sample volumes that all interventions, transient events, and any
system deterioration would be covered. Alarms should be triggered if alert limits are exceeded. It is accepted that it may not always be
possible to demonstrate low levels of particles ≥5.0 μm at the point of fill when filling is in progress due to the generation of product particles
or droplets.
For grade B zones, a similar monitoring system is recommended, although the sample frequency may be reduced. In determining this
frequency, the effectiveness of the segregation between the adjacent grade A and B zones should be taken into consideration. Also in grade
B zones, the sampling frequency and volume should be determined so that changes in levels of contamination and any system deterioration
would be detected, and alarms triggered if alert limits are exceeded.
The monitoring of grade C and D zones in the occupancy state in operation should be performed in accordance with the principles of quality
risk management.
Airborne particle monitoring systems may consist of independent particle counters; a network of sequentially accessed sampling points
connected by manifold to a single particle counter or a combination of the two. Also during monitoring, the length of tubing should be
sufficiently short to permit adequate sampling of particles ≥5.0 μm (this means: not longer than 2 to 3 m). It is not necessary for the sample
volume to be the same as that used for classification purposes.
1
In grade A zones, unidirectional displacement airflow is to be maintained, with a homogeneous air velocity in a range of 0.36-0.54 m/s
(guidance value) at the working position. The maintenance of this airflow pattern is to be demonstrated.
3.C.3 Corresponding FDA Determinations

Similar determinations have been established by the regulatory authorities of the USA, the Food and Drug Administration (FDA). They can be
found in theGuidance for Industry Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice (see chapter
D.10). This guideline was issued to help manufacturers to meet the requirements in the FDA's cGMP regulations as compiled in the legally
enforceable federal regulations 21 CFR 210 and 211. In the context of aseptic manufacturing facilities, the most important sections of 21 CFR
211 are subparts C - Building and Facilities and D - Equipment (see chapter D.1.1 21 CFR 210 Current Good Manufacturing Practice in
Manufacturing, Processing, Packing, or Holding of Drugs; General andchapter D.1.2 21 CFR 211 Current Good Manufacturing Practice for
Finished Pharmaceuticals).
Contrary to the European determinations, FDA has established class limits only for particles ≥0.5 μm and for the occupancy state in operation
(3.C.3).
Figure 3.C-3 Air cleanliness classifications for aseptic manufacturing operations according to the FDA
Guidance for Industry for aseptic processing.
FDA air cleanliness classificationsa according to the aseptic processing guide
Clean area ISO Particles Microbiological active Microbiological settling
classification designationb 0.5 μm/m3 air action levelsc plates action levelsc, d
0.5 μm diam. 90 mm;
cfu/m3
particles/ft3 cfu/4 hours
100 5 3 520 1e 1e
1 000 6 35 200 7 3
10 000 7 352 000 10 5
100 000 8 3 520 000 100 50
a. All classifications based on data measured in the vicinity of exposed materials/articles during periods
of activity.
b. ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple
industries. An ISO 5 particle concentration is equal to Class 100 and equals EU Grade A.
c Values represent recommended levels of environmental quality. You may find it appropriate to
establish alternative microbial action levels due to the nature of the operation or method of analysis.
d The additional use of settling plates is optional.
e Samples from Class 100 (ISO 5) environments should normally yield no microbiological
contaminants.
FDA distinguishes between critical areas and supporting clean areas.
3.C.3.1 Critical Areas
As determined in § 42.c of FDA's general current GMP Guideline, i.e. 21 CFR 211, a critical area is defined as "one in which the sterilized
drug product, containers, and closures are exposed to environmental conditions that must be designed to maintain product sterility. Activities
conducted in such areas include manipulations (e.g., aseptic connections, sterile ingredient additions) of sterile materials prior to and during
filling and closing operations".
During aseptic operations it is imperative that the environment be maintained at an appropriate level of quality, especially the level of particles
in the air. Microorganisms can attach themselves to airborne particles that can potentially enter the product and contaminate it. Air handling
systems that can minimize the number of particles in the air to the appropriate level specified for a Class 100 (ISO 5) area need to be in place.
The guideline recommends measuring air cleanliness in critical areas, where the potential risk to the product, containers, and closures is the
greatest, orienting the particle counting probe in a way that a demonstrated meaningful sample is obtained and performing monitoring during
each production shift. It is also recommended to use a remote particle counting system because these types are able to capture more data
and are less invasive than portable counters.
It is recommended that HEPA-filtered air be supplied to the critical areas, employing the airflow pattern unidirectional airflow to sweep
particles away from the filling area (see chapter 3.G.3.2 Suspended matter filter - HEPA-Filter). If the air flow system is properly designed,
maintained, and operated, air monitoring of the area should not yield any microbiological contaminants in critical areas. It is cautioned,
however, that if contamination is detected, "appropriate investigative attention" should be provided.
3.C.3.2 Supporting Clean Areas
In addition to critical areas, the supporting clean areas are of importance to sterile drug products quality. Various functions can take place in
support areas. These functions include the preparation, handling and/or transferring of components, in-process materials, container/closure
systems, equipment, and formulated product. The areas can have various classifications. The environments in the support areas should be
designed to minimize particle contaminant levels in the final product and control the bioburden of articles and components that will be
subsequently sterilized.
The classification of each area is determined by the activities that will be conducted. In the guideline, FDA recommends a minimum
requirement of Class 10,000 (ISO 7) under dynamic conditions, i.e. in the occupancy state in operation. If desired, the area can be classified
as Class 1,000 (ISO 6) or the entire aseptic filling room can be Class 100 (ISO 5). Areas performing less critical activities, such as equipment
cleaning, should be classified as Class 100,000 (ISO 8).
An important cleanroom consideration is the rate of air change. The guideline recommends at least 20 air changes per hour for Class 100,000
(ISO 8) supporting rooms and significantly higher air change rates for Class 10,000 and Class 100 areas. A monitoring system should be
employed to detect atypical changes that can compromise the facility's environment. A system should be in place, which will help to restore
operating conditions to the established qualified levels before action levels are reached.
3.C.4 GMP Requirements for Premises

Regarding design, construction and operation of air cleanliness classified premises, in addition to the requirements established in chapter 3 of
part 1 of the EU GMP Guide (chapter C.4), the requirements compiled in subpart Premises of annex 1 (chapter C.6.1 Annex 1 Manufacture of
Sterile Medicinal Products) should be met:
Exposed surfaces should be smooth, impervious, and unbroken and permit the repeated application of cleaning agents,
and disinfectants where used
There should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards.
False ceilings should be sealed.
Pipes and ducts and other utilities should not create recesses, unsealed openings, and surfaces which are difficult to
clean
Sinks and drains should
o be prohibited in Grade A/B areas used for aseptic manufacture
o be provided with air breaks between the machine or sink and the drains, in other areas
Floor drains in lower grade cleanrooms should be fitted with traps or water seals to prevent back-flow
Changing rooms should be designed as air-locks
o with physical separation of the different stages of changing
o with an interlocking system or a visual and/or audible warning system to prevent the opening of more than one
door at a time
o flushed effectively with filtered air
o hand washing facilities provided only in the first stage of the changing rooms
o and the air cleanliness in the final stage of the changing room should, in the at rest occupancy state, be the
same grade as the area into which it leads
Adjacent rooms of different grades should have a pressure differential of 10-15 Pa (guidance value)
Pressure differences should be recorded regularly or otherwise documented
Airflow patterns should be demonstrated not to present a contamination risk
A warning system should be provided to indicate failure of the air supply
3.C.5 Room-specific Allocation of Air Cleanliness Stipulations

Annex 1 Manufacture of Sterile Medicinal Products (chapter C.6.1) also specifies the minimum air cleanliness requirements for the different
processing steps during the manufacture of sterile medicinal products.
Examples for allocating the appropriate room grade for the different operational steps during filling of terminally sterilized products are
reproduced inFigure 3.C-4.
Figure 3.C-4 Examples for room grade allocation for different operational steps during processing of
terminally sterilized products
Examples for room classification for selected steps during manufacture of terminally sterilized
products
Grade A Filling of products when unusually at risk
Grade C Preparation of solutions when unusually at risk
Filling of products
Grade D Preparation of solutions
Preparation of components for subsequent filling
Unusual risks are, for example:
high risks of microbiological contamination due to products

o actively supporting microbial growth
o requiring a long period between preparation and terminal sterilization
o with, e.g., preparation of solutions not mainly in closed vessels
high risk of contamination from the environment due to
o a slow filling operation
o wide-necked containers
o exposure to the environment for more than a few seconds before sealing
Components are, for example, the mechanical elements of a filling unit whose surfaces come into contact with the product.
Examples for room classification for different activities during production of aseptic preparations are given in Figure 3.C-5.
Figure 3.C-5 Examples of room grade allocation for different operational steps during aseptic production of
medicinal products
Examples for room classification for selected steps during aseptic product manufacture
Grade A Aseptic preparation and filling
Grade B Environment to grade A zones
Grade C Preparation of solutions with subsequent sterile filtration
Grade D Handling of components after washing and prior to sterilization
Isolators for protecting, for example, the filling area of an aseptic production line are less stringent in their environmental requirements. A
grade D environment is, according to the EU GMP Guide, considered as a rule to be sufficient. FDA, on the other hand, expects, in the
occupancy state in operation, an environment classified as Class 100 000 (ISO Class 8) corresponding with the European grade C.
In premises for manufacturing non-sterile active substances and medicinal products, the air cleanliness class appropriate for the different
production steps should be determined based upon risk assessments - if they require room classification at all.
3.C.6 Cleanliness Zoning Concepts

Cleanliness zoning concepts establish the quality and performance criteria to be met by the contamination controlled facilities of a
pharmaceutical enterprise. They should be conceived with comprehensiveness in mind, i.e. go much beyond the mere determination of air
cleanliness classes. Companies regularly investing in clean facilities may prefer, instead of specifying the zoning concept individually for each
investment object, to implement a generalized cleanliness zoning policy applying worldwide to all their investment objects. This will guarantee
uniform yardsticks for quality and performance - irrespective of where the facility is built and operated.
Globally operating groups of companies, as a rule, maintain highly professional engineering departments with extensive experience from
previously realized clean facilities and thus possess ample competence in developing and implementing zoning policies. Companies with a
more limited background of experience, however, may prefer to complement their in-house knowledge with a consulting firm with broad
competences in the development of contamination control zoning schemes.
Cleanliness zoning concepts are required to address a broad range of topics, e.g.:
facility layout requirements

building and construction materials and elements
process media (gases and liquids)
air-conditioning and other utilities
process equipment
computerized systems (e.g. process monitoring, building automation)
material and personnel flow including waste management
air-lock requirements
personnel issues (behavior, hygiene, garmenting, training)
visitor handling
qualification and validation concepts
cleaning, disinfection and pest control
and so on
Cleanliness zoning concepts are not specifically addressed in the GMP guidance documents. They ensure, however, that contamination
control is implemented comprehensively and in a balanced way - in line with the spirit of modern quality risk management.
Topics regarding environmental and personnel protection merit equal consideration with the GMP stipulations. A comprehensive fundament
for implementing all these requirements and converting them into competently designed, built and equipped facilities are the EN ISO
contamination control standards composed of two families: the EN ISO 14644 series for general cleanroom technology as well as the EN
ISO 14698 series devoted to biocontamination control.
A compilation of the presently available titles is given in Figure 3.C-6.
Figure 3.C-6 The EN ISO series of cleanroom technology standards

EN ISO series of standards: Cleanrooms and associated controlled environments
EN ISO Title Published

14644-1 Classification of air cleanliness 05/1999
14644-2 Specification for testing and monitoring cleanrooms for continued compliance 09/2000
with ISO 14644-1
14644-3 Test methods 12/2005
14644-4 Design, construction and start-up 04/2001
14644-5 Operation 08/2004
14644-6 Vocabulary 07/2007
14644-7 Separative devices (clean air hoods, gloveboxes, isolators and mini- 10/2004
environments)
14644-8 Classification of airborne molecular contamination 08/2006
14644-9 Classification of surface particle cleanliness (draft) 07/2008
14644- Classification of surface chemical contamination (draft) in
10 preparation
14698-1 Biocontamination control - General principles and methods 09/2003
14698-2 Biocontamination control - Evaluation and interpretation of biocontamination 09/2003
data
A valuable complement to the EN ISO 14644 series of standards is the guideline family VDI 2083 Cleanroom technology, elaborated by the
Verein Deutscher Ingenieure (Association of German Engineers). They are published bilingually (left column of each page in German, right
column English). On the one hand, these guidelines develop the determinations of the EN ISO series into greater detail and depth. On the
other hand, they deal with topics which are not - or not yet - taken up by ISO. They cover, for example, process media and process media
systems: topics which are not addressed at EN ISO level and are not going to be addressed there in the future.
A survey of the available titles is given in Figure 3.C-7. The guidelines 2, 4, 5, 6, 8, 9 and 14 have been formally withdrawn.
Figure 3.C-7 VDI 2083 guideline family on cleanroom technology

VDI cleanroom technology guidelines
VDI
Title Published
2083
Part 1 Particulate air cleanliness classes 05/2005
Part 3 Metrology and test methods 07/2005
Part 4.1 Planning, construction, and start-up of cleanrooms 10/2006
Part 4.2 Energy officiency (draft) 10/2009
Part 5.1 Cleanroom operation 09/2007
Part 5.2 Cleanroom operation - decontamination of multiple use cleanroom clothing R 10/2008
Part 7 Cleanliness of process media 11/2006
Part 8.1 Molecular contamination of cleanroom air (AMC) 07/2009
Part 9.1 Compatibility with required cleanliness and surface cleanliness 12/2006
Part 10 High-purity/Ultra-high-purity (HP-/UHP-) media supply systems 02/1998
Part 11 Quality assurance 01/2008
Part 12 Safety and environmental aspects 01/2000
Part Quality, production and distribution of ultrapure water - fundamentals 01/2009
13.1
Part Quality, production, and distribution of ultrapure water -microelectronics and 01/2009
13.2 other technical applications
Part Quality, production and distribution of ultrapure water -pharmaceutical and other 06/2009
13.3 life science applications (draft)
Part 15 Personnel at the clean work place 04/2007
Part 16 Barrier systems (isolators, mini-environments, cleanroom modules): Effectiveness 06/2009
and certification (draft)
3.C.7 Converting GMP Stipulations into Reality

When GMP stipulations have to be converted into pharmaceutical production systems, a lot of aspects have to be considered. A compilation
of topics is given in Figure 3.C-8. A preventive, holistic, and interdisciplinary approach is indicated in the design, realization, and qualification
phases.
Figure 3.C-8 Aspects to be considered in design, construction, and operation of GMP compliant facilities
Aspects to be considered in design, construction and operation of GMP compliant, contamination
controlled premises
Civil engineering layout development;
considerations airlock concepts for personnel and material;
conceptual options and materials for walls, ceilings,
and floors;
requirements for ancillary rooms
Processing sequences material and personnel flow;
removal of waste and waste water
Process equipment machines and apparatus;
furniture;
material transfer systems
Safety installations interruption-free energy source;
emergency power installations;
work safety and environmental protection
Ventilation and air- air cleanliness requirements;
conditioning filter systems for supply and extract air;
pressure grading;
temperature and humidity of air;
airflow patterns;
noise level
Materials and process media packaging materials;
pharmaceutical ingredients (active and not active);
cleaning and disinfection substances;
process media (gases and liquids);
heating and cooling media
Computerized systems process monitoring;
building automation;
data management (with and without paper)
Personnel training, garments, comportment
Organizational procedures qualification;
production flow and work procedures;
automation;
maintenance and repair;
quality control and quality management;
cleaning and disinfection;
visitor management
Some short comments:

Air cleanliness: Grade A areas require terminal HEPA filtration of the supply air (at least filter class H 13 according to
EN 1822) plus unidirectional airflow; in grade B to D rooms HEPA filtration can be combined with turbulent mixing airflow. The
higher the air cleanliness requirement, the higher the air change rate will have to be. Extract air filtration - again with HEPA filters -
is required for extract air contaminated with pathogenic, highly toxic, radioactive or live viral or bacterial materials or products.
Materials for walls, ceilings, and floors: Detailed guidance is compiled in the guideline VDI 2083 Part 4.1. Frequently,
modular wall and ceiling systems are used; for floors, epoxy coatings, pharma terrazzo or the particularly resilient welded PVC
flooring are in the foreground.
Safety considerations: Whether an emergency power source should be foreseen has to be decided case by case. Fire
sectors should be as extensive as permitted by the fire police, taking into consideration that fire risks are, as a rule, rather low in
clean facilities.
Pressure grading: Pressure grading in steps of 15 Pa is recommended. This ensures that, notwithstanding the inevitable
tolerances to be taken into consideration for sensors and actors of the control units, no reversal of flow direction can occur in leaks
in the room enclosure so that it will always be directed from clean to less clean.
Computerized systems: Computerized systems should always be connected to an interruption-free power source as
even a brief drop in tension or a power cut for seconds - or a fraction of a second - can have very undesirable consequences. The
GMP stipulations for computerized systems are found in annex 11 to the EU GMP Guide (chapter C.6.11 Annex 11 Computerised
Systems). The most comprehensive and up-to-date guidance on this topic can be found in the GAMP 5 manual edited by ISPE, the
International Society for Pharmaceutical Engineering, to which authors from the American and European regulatory authorities have
contributed substantially. The totally revised and largely extended GAMP 5 edition was published early in 2008.
Summary:
The EU GMP Guide defines, in its annex 1, room grades A-D and the specific requirements for
premises devoted to sterile production.
FDA also stipulates room classes, in its Guidance for Industry document on sterile drug products
produced by aseptic processing, and establishes requirements for the critical rooms and adjacent
supporting clean areas.
Compliance with the limit values for airborne particles and microorganisms is achieved, above
all, by appropriate conception of premises and their ventilation and air-conditioning systems.
The development of zoning concepts is recommended in order to cover systematically all
relevant aspects of contamination controlled facilities.
Actions and countermeasures have to be established preventively for coping with situations
where the limit values for airborne particles and microorganisms are exceeded.
It is recommended to establish air cleanliness requirements not only for sterile facilities, but also
for non-sterile production if this is indicated through risk assessment.
3.D Construction elements
Authors: Uwe Schwarzat, Dr. Ralph Gomez / Update 05

What details must be observed when designing rooms for pharmaceutical
purposes?
What are the advantages and disadvantages of various components from the
GMP standpoint?
Construction elements are selected with the following in mind: manufacturing procedure, products to be processed, room classes and
economic efficiency.
3.D.1 Walls
It is possible to differentiate between two wall types: solid walls and stud construction walls.
Solid walls are usually external walls or structural partition walls. Solid walls are made of concrete or masonry and are characterized by high
mechanical and thermal stability. They are therefore particularly suitable for rooms, where operations involving heavy loads (stacker) or
potentially-explosive substances (solvents) are carried out. A disadvantage of solid walls is that they offer a low degree of flexibility due to
the high costs and mess involved during demolition/reconstruction.
Concrete or masonry walls may be untreated, plastered, painted, plastered and painted, papered, papered and painted or tiled depending on
the requirements. Paints used in production areas and laboratories must be easy to clean, and must not release solvents or softening agents
under working conditions. Latex and epoxy paints are most commonly used.
Stud constructions (see Figure 3.D-1) may be used for partition walls, as well as facing for solid walls. Stud walls consist of a substructure
(known as studs) and sandwich elements/panels. The materials most commonly used for the substructure are wood, aluminum, galvanized
steel and stainless steel. Timber substructures should no longer be used in production areas due to the need for regular cleaning in these
areas.
Figure 3.D-1 Principle - wall stud systems

Sheeting materials used to cover the studs include plasterboard (painted, papered, tiled), laminated timber, powder-coated sheet steel,
stainless steel, glass and plastics. In order to accommodate GMP requirements regarding cleanability and prevention of contamination, the
details for the various locations described below are always important, irrespective of the wall type used. To reduce the investment costs,
finishes required in sterile areas should not be used in areas where requirements are less stringent. It is always worth investigating the
options for simple cost-effective details with all parties involved (pharmacist, engineer, microbiologist, quality assurance).
The junction between the wall and the floor (see Figure 3.D-2) must be considered very carefully, particularly in sterile areas and in rooms
where wet cleaning is frequently carried out. The wall/floor detail must not incorporate a joint, where dirt and micro-organisms could collect.
Figure 3.D-2 Wall/floor junction with recess

It must be leak-tight to prevent water from penetrating the substructure or neighboring rooms. A wall system must be chosen appropriate to
the flooring used, and the junction between the wall and the floor must be easy to clean. For sterile areas and rooms where wet cleaning is
frequently carried out, recessed junctions are indispensable, but in rooms with less stringent requirements, e.g. packaging operations, simpler
versions are permissible (see Figure 3.D-3).
Figure 3.D-3 Simple wall/floor junction

The wall/ceiling connection is important for preventing the entry of particles from adjacent areas (see Figure 3.D-4).
Figure 3.D-4 Wall/ceiling junction

The penetration of walls is necessary in all areas to connect utilities (pipes, electrical fixtures such as light switches and sockets, warning
lamps, measuring instruments, etc.) from the technical areas to the production rooms. From the GMP standpoint, these points are critical as
they are a potential source of leaks, particle release and contamination - particularly if facings are also mounted. However, it is also important
for flexibility to be able to make wall penetrations quickly, simply (without interfering with operations) and economically.
For construction reasons, most stud walls have joints between the individual cladding elements. As a general rule, the fewer joints there are
the more complex and expensive the wall will be. To this end, a range of partition wall systems exist for sterile areas that incorporate fewer
joints and allow windows and doors to be installed flush with the wall. An inexpensive alternative is plasterboard (requires no joints) with a
suitable paint or coating.
However, this solution has limitations, if it is necessary to apply high mechanical loads to the walls or if the rooms must be wet cleaned
regularly.
In sterile areas rounded corners are a further detail that can be used to make the cleaning of walls easier (see Figure 3.D-5).
Figure 3.D-5 Rounded off junctions
Figure 3.D-6 shows a selection of wall systems commonly used in pharmaceutical production with an assessment of their compatibility with
GMP requirements..
Figure 3.D-6 Overview of commonly used wall systems

3.D.2 Doors and windows
An important requirement for sterile areas is that it must be possible to install windows and doors flush with the walls without creating any
surfaces or edges on which dust could gather.
Windows, while improving the visual appearance of a room, have the disadvantage that they must be cleaned more often than non-
transparent elements. The flush installation of windows is a state-of-the-art approach employed in sterile areas. For the remaining
pharmaceutical manufacturing areas this is also desirable but should not be adopted as the standard approach due to increased costs.
Generally, windows to the outside must be kept sealed; emergency exit windows must have at least one seal; windows in external walls in
sterile areas must be flush and fully integrated (Figure 3.D-7).
Figure 3.D-7 Flush windows

The above also applies for the flush installation of doors. In addition, care must be taken to ensure that windows, and hardware in the door
leaves, are installed flush. Doors must generally be kept closed to maintain the pressure characteristics of the rooms and to avoid cross-
contamination so it is recommended that doors be equipped with closers. Door thresholds must be avoided as they are difficult to clean.
Interlocking doors must be used in locks. Doors may also be combined with access authorization systems. For areas with special
requirements, there are doors with inflatable gaskets or lip seals at the foot. Wooden doors should not be used in areas that have to be
cleaned regularly. Powder-coated sheet steel, aluminum, stainless steel and plastic are all suitable materials (Figure 3.D-8).
Figure 3.D-8 Door seals

A distinction is made between manually-operated and power-operated doors. Manually-operated doors are generally swing doors, also with
two leaves (one active and one inactive), possibly equipped with a mechanical closer. These doors may easily be installed flush. Floor holes
to accommodate locking bolts for the inactive door leaf are microbiologically critical.
Power-operated doors are advantageous in that they may be opened and closed automatically (via buttons or remote control). They are
indispensable where automated transport equipment is used. The following types are commonly used:
Sliding doors: advantage: they save space. Disadvantages: the drive is difficult to clean and they are problematic where
high positive pressure exists in the room. Sliding doors may only be used in production areas, if the floor strip can be omitted. Areas
of use: warehouse, pharmaceutical manufacturing, and packaging, but not in sterile areas.
High-speed doors: (roll-up door or folding door) door made of plastic foil or lamellas. Advantages: space-saving, fast-
opening. Disadvantages: plastic ages and is difficult to clean. Areas of use: warehouse, pharmaceutical manufacturing and
packaging, not in sterile areas.
Swing doors: advantage: they are easy to clean. Disadvantage: they take up space. Areas of use: pharmaceutical
manufacturing including sterile areas.
3.D.3 Floors
Floors must meet many functional criteria: they must be easy to clean and conductive, mechanically, chemically and
thermally resistant, smooth, non gas forming and also visually attractive, i.e. light in color. Often nearly all of these criteria must be
satisfied together. Flooring that meets all requirements does not exist, so the most suitable covering for the intended purpose must
be selected. As an example, flooring that is subjected to a high degree of mechanical stress by the movement of stacking
equipment, may be made of ceramic coverings with joints. In the sterile area, only seamless, smooth floors incorporating a recess
can be considered.
Flooring consists of a substructure made of reinforced concrete, or precast concrete elements, and a covering. The latter
may be made up of many individually-applied layers that ensure adhesion to the substructure, smooth out unevenness, bridge
cracks, ensure conductivity and protect the floor against the penetration of dirt, water and micro-organisms.
Two types of floor finishes are used in pharmaceutical manufacturing and packaging: floors laid without seams and floors
with seams. For seamless floors, a differentiation is made between floors with welded seams (e.g. PVC coatings) and coverings
such as epoxy resin flooring or pharma terrazzo. In both cases, the standard of installation workmanship is decisive for the quality
and durability of the floor.
An advantage of seamless floors is that they have a completely smooth surface, are easy to clean and are chemically-
resistant. Disadvantages are their lack of both mechanical and thermal resistance. The surface must have sufficient surface
rawness and must also be pore free. Places of use: sterile areas, standard production areas, PVC floors also in laboratory, social
areas, and corridors used by personnel.
Where appropriately constructed, tiled floors or floors with ceramic coverings, have a high mechanical load capacity.
Conductive versions of ceramic coverings are now available. The disadvantages of tiled floors are the number of joints and the
difficulty of constructing openings for gullies or pipe bushings. It is now possible to face-grind tile coverings, and then apply a
sealing coat. Places of use: pharmaceutical production and packaging; wash rooms, social areas. In sterile areas, only to be used
with a surface seal.
Figure 3.D-9 provides an overview of the advantages and disadvantages of various floor finishes.
Figure 3.D-9 Flooring
Place of use Advantages Disadvantages
Pharma terrazzo sterile areas, solids Seamless, easy to clean, Mechanical and
manufacturing, washing conductive, with recess, thermal resistance,
rooms resistant to chemicals, easy costs, skid resistance
to work with
Coating Packaging areas without Seamless, easy to clean, Mechanical and
(epoxy/polyurethane) stacker traffic, solids conductive, cheaper than thermal resistance, no
production, warehouse pharma terrazzo, resistant to recess, skid resistance
chemicals, easy to work with
Tiles, ceramic Solids manufacturing, Chemical, thermal, Higher number of
coverings washing rooms, mechanical resistance. joints, complex
packaging areas with Recess possible, conductive installation
stacker traffic versions available
Chemical laboratories
Linoleum/PVC Laboratories, IPC, Easy to clean, recess, Mechanical, chemical,
offices, corridors inexpensive thermal resistance
Concrete, Warehouse, stacker Mechanical resistance, Difficult to clean
sealed driveways inexpensive
The following details are especially critical for all floor finishes from the GMP standpoint:
Building expansion joints, junctions between different floor finishes: although these construction features are generally
unavoidable, they should be used as little as possible. If these elements have to be included, they must be detailed very carefully:
slits, cracks, ruptures, inaccessible joints, sharp edges and corners must be avoided. Junctions must be leveled out evenly as
otherwise the flooring may fail due to high wheel loads of stackers passing over uneven junctions. High-quality materials such as
stainless steel strips and plastics with long-term durability (15 years) must be used.
Gradients: the flooring must always be laid to fall in the direction of the floor inlet or center of the room to allow cleaning
waste water to drain off, and to ensure that it cannot gather under walls, in corners or under machines. In practice this seemingly
simple requirement may be more difficult to achieve, so particular care must be taken in laying the floor.
Recesses: these are a suitable means of making cleaning easier and preventing the diffusion of water into walls and
adjacent rooms. Recesses are wall skirtings, covered ideally with the same material as the floor and also seamlessly joined to it.
They should have a radius of at least 2 cm. Recesses are also available for tiled floors.
3.D.4 Ceilings
The ceiling construction, in addition to sealing off a room from adjacent areas, has a significant role to play in ensuring a GMP-compliant
supply of rooms. The ceiling accommodates lighting as well as supply and exhaust ventilation systems. In many cases, utilities are also
supplied to rooms from above for cleaning and flexibility. Ceilings must satisfy the same requirements as walls: they must be smooth and
1
easy to clean, and must not shed particles; they must also be capable of being sealed in sterile areas .
Depending on the building design, the ceiling may be suspended from the building structure or it may be solid (concrete). The building
services (utilities, ventilation ducts and power cables, etc.) must always be outside the room in production and packaging areas, i.e. routed in
a services zone above the ceiling. Services in laboratories and storage areas may also be exposed, providing that they are cleaned regularly.
Unfinished ceilings, painted or plastered and painted, are also possible in pharmaceutical manufacturing and packaging areas, with the
exception of laboratories, and excluding sterile production.
Suspended ceilings consist of a raster with screwed-on or inserted elements. Depending on the requirements, the raster is constructed from
galvanized, powder-coated steel or stainless steel and sometimes wood in exceptional cases (office, warehouse). The ceiling elements
consist of plasterboard, plastic, powder-coated metal, anodized or stainless steel. Perforated ceiling panels with insulating material on the
upper face may be used for soundproofing in manufacturing and packaging operations. Care must be taken to ensure that the insulation is
protected and cannot shed particles (e.g. shrink-wrapped in foil). Special sound-absorbing panels for sterile areas are available that can be
mounted flush in the ceiling.
Figure 3.D-10 Flush-mounted ceiling lighting
If services to the rooms are supplied from above, it is recommended that this service zone be large enough to be accessed from outside the
production rooms. This is the only way to ensure that maintenance and repair may be carried out regularly without the production rooms being
adversely affected. This requirement of the EU GMP Guide (Annex 1.33) and the U.S. GMPs (21 CFR 211.63) should also be observed in
non-sterile areas as this shortens cleaning times and downtimes. Particular attention must be paid to the air outlets and lighting (21 CFR
211.44). Other openings must be made as described inFigure 3.D-10.
Summary:
Particular attention must be paid to the detailing of components when designing rooms. The room class
must be considered when selecting materials and construction methods: the higher the room class, the
more complex and expensive the construction will be.
3.E Barrier systems and isolators

What are isolators and how are they used in the pharmaceutical industry?
What safety features are offered by isolators for product and personnel
protection?
What are the regulatory requirements to be met?
How is biodecontamination of isolators by means of vapour phase agents (e.g.
vapour phase hydrogen peroxide VPHP) performed?
What are Restricted Access Barrier Systems (RABS concepts) and which design
options are distinguished?
When should preference be given either to an isolator or a RABS concept?
3.E.1 Protection concepts for maximized sterility assurance

A pharmaceutical product is considered as sterile if not more than one microbiologically contaminated unit is found among a million dosage
-6
units. This requirement - i.e. a sterility assurance level (SAL) of at least 10 - has of course to be met by terminally sterilized products.
-3
Until shortly ago, a SAL value of 10 (i.e. one contaminated dosage unit in 1 000) - proven with an upper confidence limit of 95 % - has been
considered acceptable for aseptic processing.
In its current Guidance for Industry for aseptic processing (chapter D.10 Guidance for Industry Sterile Drug Products Produced by Aseptic
-4
Processing - Current Good Manufacturing Practice) FDA has now pushed this limit to almost a SAL value of 10 (Figure 3.E-1).
Figure 3.E-1 Harmonized media fill requirements according to Annex 1 and the FDA Guidance for Industry
for aseptic processing
Number of filled units Positives Actions
less than 5 000 1 failed, revalidate
5 000 to 10 000 1 investigate, consider repeat of media fill
2 failed, investigate, revalidate
more than 10 000 1 investigate
2 failed, investigate, revalidate
The same limits have been adopted into the revised Annex 1 to the EU GMP Guide in February 2008 (chapter C.6.1 Annex 1 Manufacture of
Sterile Medicinal Products). This is an improvement, but still two orders of magnitude away from the sterility assurance level of terminally
sterilized products.
It is therefore plausible for the regulatory authorities to continue to require that products should be submitted to terminal sterilization whenever
possible. However, the percentage of parenterals not permitting terminal sterilization is steadily increasing: this is due, to a large extent, to the
increasing number of protein-based active substances. Therefore, there is a continuing challenge to improve the protection schemes for
aseptic processing operations towards still higher levels of sterility assurance. Long term, the goal to be met is obvious: to achieve the same
-6
level of sterility assurance as that applying to terminally sterilized products, i.e., a SAL value of 10 . The objective of isolators and other
barrier technologies is to achieve this quantum leap.
3.E.2 Pharmaceutical isolator technology
3.E.2.1 Conceptual features of pharmaceutical isolators

1
Isolators are compact and self-contained units, minimized in their dimensions and featuring an enclosure with a high degree of airtightness,
capable of shielding processes strictly from their environment and from direct contact with persons, and capable also of shielding persons
against risks originating from the process.
Isolators combine the traditional safety features of the conventional cleanroom concepts - i.e. establishing contamination control by means of
HEPA filtered air and appropriate airflow patterns - with four additional safety features:
consequent separation of process and operator

isolator-internal air circulation independent from the room air-conditioning system
the feasibility of effective bio decontamination of the internal surfaces of the isolator, as a consequence of the isolator's
independent air circulation system and its airtight enclosure
sterile transfer of materials and objects into and out of the isolator
Glove/sleeve units or half-suits integrated into the isolator contour permit operator manipulations without breaking sterility (Figure 3.E-2).
Figure 3.E-2 Main features of an isolator.

DPTE = Double Door Transfer Port
(Copyright: Getinge-La Calhène, Vendôme/France)
Special transfer modules such as the Double Door Transfer Port DTPE (Figure 3.E-3) permit the sterile transfer of materials to and from the
isolator.
Figure 3.E-3 Double door transfer unit for feeding sterile material into an isolator (Copyright: Getinge - La
Calhène, Vendôme/France)
Such DTPE units have been designed to avoid any mishandling capable of prejudicing the chain of containment during the transfer phase.
The DPTE operation principle:
Two assemblies, ALPHA and BETA - two seals meeting at the juncture
Four elements mutually shielding each other's external surfaces, are locked together by rotation
1. Put the container in position

2. Lock by rotation
3. Open the double door
Figure 3.E-4 Isolator for performing sterility tests
(Copyright: Skan Ltd., Allschwil/Switzerland)
For ventilation purposes, both turbulent mixing or unidirectional airflow may be employed according to circumstances. For isolators protecting
batch processes, turbulent airflow with its modest air flow rate requirements may well be adequate, whereas unidirectional airflow is, as a rule,
more appropriate for the protection of continuous processes.
When protecting batch processes, the key features of an isolator can be converted almost ideally into technical reality. An example of a batch
process is the sterility test of ampoules and vials after filling. The unit shown in Figure 3.E-4 is composed of two modules: a loading and
biodecontamination module for the containers to be tested (the outside surfaces of which are microbiologically contaminated before
biodecontamination), from where, after biodecontamination, the containers are transferred into the subsequent working module for performing
the sterility test of the containers' contents. In comparison with sterility testing in clean work stations, the risk of false positives can be
2
eliminated almost completely when performing the test in an isolator (Akers et al. 1995 ). Therefore, isolator technology for performing this
test has now become generally accepted worldwide.
Figure 3.E-5 Isolator-protected high-performance filling line for syringes (Copyright: Airex Ltd.,
Nagoya/Japan)
When protecting continuous processes such as high-productivity filling operations, deviations from the strict isolator principles are inevitable:
the isolator then provides no longer an absolute barrier against contamination, but rather a partial barrier protection. The sterilized and
depyrogenized primary packing units (e.g., vials) enter the isolator in a continuous stream and leave it, after filling and closing, in a continuous
stream again. The stoppers are fed into the isolator in such a way that their sterility remains unbroken. The strict principle of separating the
processing area from its environment by means of impervious physical barriers - i.e. walls - is thus broken locally at these spots: aerodynamic
barriers, driven by overpressure, have to assume the function of efficiently isolating the inside against the outside environment.
The openings indispensable for a continuous material flow - the so-called mouseholes - should be kept as small as possible. As example for a
large-scale filling process, Figure 3.E-5 shows an isolator protecting a filling line for syringes.
There exist two alternatives for realizing the isolator enclosure: the soft wall and the hard wall concept. The use of the soft wall concept with a
flexible enclosure (welded, transparent PVC sheets attached to a stainless steel structure) is now almost exclusively limited to laboratory
applications. In isolators protecting production lines, the hard wall principle dominates (a stainless steel structure into which stainless steel
panels with extensive glassing, sometimes manufactured as double wall units, are incorporated).
With its particular combination of features isolator technology improves considerably upon the high safety level offered by up-to-date
cleanroom concepts. A chain of safety features, however, is only as strong as its weakest link. Isolators alone are not enough: a prerequisite
of their utilization is a consequent assessment and analysis of weaknesses and risks of the entire production process and the incorporation of
the knowledge thus gained into an all-embracing safety concept.
3.E.2.2 Isolator-specific regulatory and normative guidance
Annex 1 to the EU GMP Guide dedicates, in §§ 21-25, a short chapter specifically to isolator technology. Therein, the potential of the isolator
in significantly reducing the risk of microbiological contamination of aseptically manufactured products is recognized. However, there are
isolator-specific risks which have to be addressed in suitable form.
The most important determinations are:
Isolators require appropriate validation. All critical factors should be taken into account, for example the quality of the air
inside and outside the isolator, its sanitization, transfer processes and isolator integrity.
Monitoring should be carried out routinely and should include frequent leak testing of the isolator and its glove/sleeve
system.
Air cleanliness within the isolator must, for aseptic processing, of course correspond with room grade A; the air
classification for the background environment should be at least grade D in this case.
FDA devotes, in their 2004 Guidance for Industry document on aseptic processing of sterile drug products, a complete 5-page Annex to
isolator technology. Contrary to the European determinations, FDA expects, for the background environment of the isolator, an air cleanliness
level corresponding to room grade C.
3
PIC/S, the Pharmaceutical Inspection Co-operation Scheme, has devoted its Recommendation PI 014-3 - published in 2007 - to the
inspection of isolators used for aseptic processing and sterility testing. A most comprehensive and practice-oriented monography on
4
pharmaceutical isolator technology including qualification and validation has been published by PDA, the Parenteral Drug Association of the
United States of America in 2001.
Complementary to these guidance documents and the PDA monography devoted specifically to aseptic processing of medicinal drugs and
5
the corresponding sterility testing, the International Standard ISO 14644-7 merits mentioning too . Like all standards of the ISO 14644 series
(see chapter 3.C.6 Cleanliness Zoning Concepts) it is of general character, i.e. it addresses all application areas where barrier technologies
are employed in the cleanroom technology context.
3.E.2.3 Biodecontamination of the isolator's internal surfaces
Biodecontamination of the isolator's internal surfaces by means of highly potent gaseous or vapourized agents is an important feature of
pharmaceutically utilized isolators. This capability distinguishes isolators from conventional cleanroom technology and from other barrier
technologies which instead employ disinfection by wiping and/or spraying for the sanitization of surfaces. Employing these highly potent
agents requires a high degree of airtightness for the isolator shell, as well as the capability of 100 % closed loop internal air recirculation. All
mouseholes have to be hermetically closed before starting the biodecontamination cycle.
As biodecontamination agent, vapour-phase hydrogen-peroxide (VPHP) is nowadays clearly predominant. Four process steps are
distinguished:
Pre-conditioning, i.e. drying the air within the isolator to a relative humidity of approximately 20 %
Injection of VPHP into the isolator and building up its concentration until almost saturation; at that point, capillary
condensation effects on the surfaces of microorganisms and their spores are already effective; on the other hand, the internal
surfaces of the isolator and the process equipment contained therein remain to a large extent still without surface condensation.
Some suppliers of VPHP biodecontamination technology, however, prefer to go above the condensation level and accept the then
inevitable condensation on all surfaces within the isolator.
Biodecontamination during a time interval long enough to ensure that all microorganisms and their spores present in the
isolator are killed with a very high degree of probability.
Purging the VPHP catalytically, i.e. decomposing the H2O2 molecules into water (H2O) and oxygen (O2) molecules, until
a concentration value below 1 ppm is reached - the maximum permitted concentration for work places. The VPHP traces still
remaining then are subsequently vented off to the atmosphere.
The duration of the biodecontamination cycle is established isolator-specifically during operational qualification. Spore strips, each containing
at least 106 spores of geobacillus stearothermophilus, a species whose spores are particularly difficult to kill, are exposed on the surfaces
within the isolator.
Figure 3.E-6 The VPHP biodecontamination cycle (from Bässler)

The duration is considered as sufficient if growth can no longer be detected on any of these exposed strips, even on those which are difficult
to reach for the biodecontamination agent. The spore strips should cover these difficult-to-reach positions particularly densely. The sequence
6
of the process steps is shown schematically in Figure 3.E-6 . Details regarding the physics and the optimization of the VPHP process are
7
discussed in the 2008 paper by Unger-Bimczak et al .
3.E.3 Restricted access barrier systems (RABS technology)

Regarding the protection of aseptic filling operations, an alternative barrier isolation concept is RABS, the Restricted Access Barrier System.
A prerequisite for the feasibility of technologies of this kind was the quantum leap in reliability of filling processes - a development strongly
driven by isolator technology.
Figure 3.E-7 Filling process protected with Figure 3.E-8 Filling process protected with isolator
conventional technology (from Rauschnabel 2006)
cleanroom technology
(from Rauschnabel 2006)
Point of departure for the development of RABS concepts were the two cornerstones of protecting aseptic filling operations:
conventional cleanroom technology

isolator technology
8 9
Figure 3.E-7 , shows schematically a filling process where the aseptic core is protected by means of conventional cleanroom technology.
Operators interfere into the processing area with their sterilely gloved hands through the lateral curtains or partitions which separate the
aseptic core from the surrounding environment. After protecting the aseptic core, the air spills over into the surrounding environment where an
air cleanliness according to room grade B has to be maintained (air cleanliness class ISO 7 in the occupancy state in operation). From there,
it is returned to the air handling unit and recirculated as supply air both into the aseptic core and into its environment. Sanitization of the
internal surfaces in the aseptic core is done by means of periodical disinfection (wiping and/or spraying with, for instance, highly concentrated
ethyl alcohol).
Figure 3.E-9 Filling process protected with a passive Figure 3.E-10 Filling process protected with an
RABS unit (from Rauschnabel 2006) active RABS unit (from Rauschnabel 2006)
Isolator protection of the aseptic core (Figure 3.E-8), on the other hand, is distinguished by strict separation of process and personnel as well
as isolator-internal air recirculation independent from the room air circulation system. Operators interfere into the aseptic core by means of
glove/sleeve systems. Due to the exact fit of the isolator walls to the filling machine and the high degree of airtightness of the entire isolator
shell the isolator also permits safe protection of the operator against the active substances being processed: with the present trend towards
highly potent protein-based active substances this is a particular welcome feature of the isolator especially when processing powderous
substances with their extensive liberation of product particles during filling. Instead of employing the classical sanitization procedures the
isolator permits a highly effective biodecontamination by means of, for example, VPHP. The drawback of this procedure is that it is very time-
consuming: hours may well be required for biodecontamination of a voluminous isolator. For the isolator's environment, an air cleanliness
level of room grade C (FDA requirement corresponding to class ISO 8 in the occupancy state in operation) or room grade D respectively is
stipulated (minimum requirement according to Annex 1 of the EU GMP Guide).
Regarding RABS technology, interferences into the aseptic core is by means of glove/sleeve systems incorporated into the side walls of the
RABS enclosure.
Two design alternatives are distinguished (see also Rauschnabel 2006 and Lysfjord 2005):
passive RABS units (Figure 3.E-9), connected to the central air-conditioning system of the facility (an example is shown
in Figure 3.E-13)
active RABS units (Figure 3.E-10), i.e. stand-alone units equipped with an integrated air handling unit with terminal HEPA
filtration for maintaining the conditions required for the aseptic core and drawing its supply air from the surrounding room.
In both cases, after having provided protection to the aseptic core, the air spills over into the surrounding room - in the same way as in
conventional cleanroom technology. As a consequence of this air spill-over into the environment the same air cleanliness stipulations for the
background of the core area as in conventional filling operations have to apply: room grade B corresponding to ISO Class 7 in the occupancy
state in operation.
Figure 3.E-11 Filling process protected with a Figure 3.E-12 Filling process protected with an active
passive cRABS unit (from Rauschnabel 2006) cRABS unit (from Rauschnabel 2006)
A modification of the basic RABS concept is the closed RABS, also denominated cRABS. Here, the airflow protecting the aseptic core is
recirculated internally - just as in an isolator. Again, distinction is made between two design alternatives:
the passive cRABS (Figure 3.E-11), where the central air-conditioning system of the facility is responsible for supplying
the aseptic core with HEPA-filtered air, and
the active cRABS (Figure 3.E-12), equipped with its own stand-alone air-conditioning unit, with terminal HEPA filtration
and cRABS-internally recirculated air; the additional air requirement for pressurization purposes is drawn from the environment
surrounding the aseptic core.
What distinguishes a cRABS from an isolator? For sanitization of the cRABS, the same procedures apply as for "normal" RABS units;
therefore a high degree of airtightness of the cRABS envelope is neither necessary nor attempted. Because of this low degree of airtightness
of the cRABS enclosure, these units also require a room grade B environment (air cleanliness class ISO 7 in the occupancy state in
operation).
Figure 3.E-13 Example of a passive RABS installation

(from Rauschnabel 2006)
3.E.4 Application options for RABS and isolators

Due to the easy access to the interior of the RABS and the subsequent rapid sanitization procedure by spraying and/or wiping - in comparison
with the time-consuming VPHP biodecontamination procedure employed for the isolator - RABS protection schemes are distinguished with a
faster start-up: format changes and change-over from one product to the next are definitely more straightforward and quicker. RABS and
cRABS concepts are equal in these respects. Contract manufacturers therefore tend to gravitate towards RABS technology because of its
10
operational flexibility . Operated correctly and with a high degree of discipline, i.e. with a minimum of interference into the aseptic core, RABS
and cRABS protected filling lines achieve almost the same Sterility Assurance Levels as isolator-protected ones.
Due to the very low air leakage level of the isolator's envelope providing a highly effective barrier between the aseptic core and the
environment, the isolator is to be given preference where both the product and the operator require reliable protection. Therefore, the isolator
is indeed the technology of choice where highly active or toxic products require to be handled - especially where crystalline substances are to
be processed.
The chore of decision making
Which technology should be given preference? An exhaustive comparative assessment of RABS concepts and isolator technology versus
11
conventional cleanroom technology has been compiled by Agalloco et al. (2007 ). They took a total of 22 project criteria into consideration,
and there were, of course, pros and cons for each of the assessed technologies. An application-specific decision is therefore indicated.
The mentioned authors expect that both the isolator and RABS technology will achieve a breakthrough where protection of aseptic filling
operations is concerned, and that they will replace conventional cleanroom technology almost entirely. They bring this statement to the point
by asking the question: will - in ten years time - a conventionally protected aseptic filling line still be GMP-compliant?
Summary:
Isolators permit a particularly efficient protection against microbiological contamination risks, which is
last but not least due to their compatibility with biodecontamination by means of gassing with potent
agents such as vapour phase hydrogen peroxide (VPHP).
They also offer safe protection of persons against risks originating from the processing of highly active
substances, especially if composed of solid particulate matter.
Important additional application areas are the sterility test of aseptically filled preparations, and the
preparation of solutions.
Other barrier systems such as the different conceptual alternatives of Restricted Access Barrier Systems
(RABS concepts) offer - if operated correctly - almost the same potential regarding protection of aseptic
filling operations against microbiological risks. Regarding changes of container format and product they
are markedly more flexible than isolators.
1
Coles T.: Isolator technology - a practical guide. Interpharm Press, Buffalo Grove IL/USA; 1998
2
Akers J. E., Agalloco J. P., Kennedy E.M.: Experience in the design and use of isolator systems for sterility testing. In: PDA Journal of
Pharmaceutical Science and Technology 49 (1995) 3, 140-144.
3
PIC/S PI 014-3; Isolators used for aseptic processing and sterility testing; Pharmaceutical Inspection Co-operation Scheme; Pharmaceutical
Inspection Convention; Geneva (2007)
4
Design and validation of isolator systems for the manufacturing and testing of healthcare products; PDA Journal of Pharmaceutical Science
and Technology 55 (2001) 5, Supplement TR 34
5
EN ISO 14644-7; Cleanrooms and associated controlled environments - Part 7: Separative devices (clean air hoods, gloveboxes, isolators,
mini-environments); International Organization for Standardization ISO; Geneva (October 2004)
6
Bässler H.-J.: Die Biodekontamination von Isolatoren in der pharmazeutischen Produktion mit Wasserstoffperoxid-Dampf in niedriger
Konzentration (Biodecontamination of isolators in pharmaceutical production with hydrogen peroxide vapour in low concentrations); Swiss
Pharma 4-S/1994, S. 31-36.
7
Unger-Bimczak B. et al.: The influence of humidity, hydrogen peroxide concentration, and condensation on the inactivation of geobacillus
stearothermophilus spores with hydrogen peroxide vapor; Journal of Pharmaceutical Innovation 3 (2008) 2, 123-133.
8
Rauschnabel J.: Zwischen Isolator und Sterilraum - Restricted Access Barrier System (RABS) (Between isolator and sterile room - Restricted
Access Barrier System (RABS)); Pharm. Ind. 68 (2006) 6, 767-773.
9
Lysfjord J.: The ISPE RABS definition - an introduction; Pharmaceutical Engineering 27 (2005) 11/12, 116-117.
10
Lysfjord J.: Using RABS and isolators in pharmaceutical applications. In: CleanRooms 21 (2008) 1, 24-26.
11
Agalloco J., Akers J., Madsen R.; Choosing technologies for aseptic filling. "Back to the future, forward to the past?"; Pharmaceutical
Engineering 27 (2007) 1, 8-16.
3.F Building services
Author: Dr. Thomas Schreiner / Update 08

What has to be taken into account during installation of building services in
clean rooms?
How can the requirement "easy to clean" be achieved?
The term building services comprises the following subsections:
Air handling systems (chapter 3.G Heating Ventilation Air Conditioning (HVAC)
Heating
Sanitary plumbing and sewage
Utilities, e.g. Process gases (see chapter 3.H Process Gases), pharmaceutical water systems (see chapter 5
Pharmaceutical Water), solvents, etc.
Electrical installations incl. IT-management and control systems.
These services are necessary for the operation of process equipment and clean rooms respectively for the manufacturing of products. This
chapter describes quality relevant aspects which need to be considered in the planning of clean rooms.
3.F.1 Basic requirements for installation

The following details should be considered for all installations of building services:
The EU GMP Guide gives recommendations in several chapters:
Pipework, light fittings, ventilation points, and other services should be designed and sited to avoid the creation of
recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the
manufacturing area (see chapter C.4 Part I Basic Requirements for Medicinal Products, 3.10 here)
Pipes, ducts, and other utilities should be installed so that they do not create recesses, unsealed openings, and surfaces
which are difficult to clean (see chapter C.6.1 Annex 1 Manufacture of Sterile Medicinal Products, point 49 here).
All these requirements are valid for all process rooms with open product handling. The realization should be based on risk assessment. In
reality this means that pipe and cable trays should be installed outside the clean area in adjacent technical areas or above suspended ceilings.
Horizontal installations in clean room supplying equipment should be as short as possible. The vertical installation of pipes and cables should
be the preferred solution in clean rooms as much as technically possible and reasonable.
The following GMP requirements should be considered additionally:
Pipes, pipe connections and pipe fixings should be easy to clean. Easy access for cleaning has to be ensured during
installation
Appropriate materials for pipes in clean rooms are stainless steel and some particular plastics
Fittings and couplings for utilities with direct product contact (pharmaceutical water qualities, solvents) should be
designed for complete emptying and should be, if necessary, sanitizable
Cables should be installed in panels suitable for clean rooms or in appropriate, vertical cable ducts (plastic or stainless
steel), which should be sealed towards the wall (e.g. with silicone)
Power and data line sockets should be installed in clean room panels. The backside should be sealed. Airproof
installations are required for rooms for the manufacture of sterile and high potent drugs. Due to different air pressures and
fluctuations caused due to technical and operational reasons (even if the very same air pressure is specified) airborne
contaminants might be carried over via the opening at the back of the sockets with any air flow between the two process rooms
Necessary openings in floors, walls or ceilings to supply clean rooms with building services should be air/waterproof and
easy to clean (see chapter 3.D Construction elements). An example is shown in Figure 3.F-1. Pass-through trough ceilings and
walls have to be covered with appropriate plastic or stainless steel covers and should be sealed (e.g. with silicone)
Figure 3.F-1 Pass through floor

3.F.2 Heating
Radiators should not be installed in clean rooms where the open product is handled, because they bear the risk of particulate accumulations
and are difficult to clean. Heating in such areas is performed by the air handling system. If radiators inside rooms (e.g. staircases) cannot be
avoided, easy- to- clean hygienic radiators (as for hospitals) should be used. In areas where closed products are handled (e.g. secondary
packaging) radiators may be used if heating is not possible by the air handling units. Nevertheless, cleanability also has to be considered.
3.F.3 Sanitary plumbing and sewage

Waste water sewage systems should not be connected directly to process equipment. An adequate air break between equipment and floor
drain has to be planned to avoid back contamination from floor drain to equipment. In case of direct connection contamination could occur by
back siphonage in the drain system or growing of germs from the drain system to the process equipment. The EU GMP Guide prohibits floor
drains in A/B grade areas. Floor drains should be limited as much as possible and adequately closed during non-usage in other process
rooms for sterile and non-sterile manufacturing. Closures should only be opened during cleaning activities. Floor drains should be equipped
with siphons and should be easy- to-clean resp. sanitizable (see alsochapter C.4 Part I Basic Requirements for Medicinal Products, point
3.11 here and chapter C.6.1 Annex 1 Manufacture of Sterile Medicinal Products, point 50 here).
3.F.4 Electrical installations incl. IT-management and control systems

Room lighting should be adequate with respect to the type of lighting, installation of the lighting, and light intensity for the planned activity in
the room especially if visual inspection is performed [see also EU GMP Guide, point 3.16]. Blinding effects have to be avoided especially for
control activities as well as for workstations. Further requirements can be found in specific local guidelines for work environments.
The electricity supply has to be sufficient. The demand results from the required power consumption of the equipment. Special GMP
requirements are not given except where an uninterrupted power supply (UPS) system may be necessary for equipment.
Electrical cabinets for building services should normally not be installed in clean rooms as they may emit particles from the cooling fan. In
addition, the installation in technical areas is more reasonable with regards to preventive maintenance and repair activities. The installation of
electrical cabinets for process equipment in clean rooms should be assessed via a risk analysis. If it is necessary to install electrical cabinets
in clean rooms, they should be made of stainless steel and should be easy to clean. Cooling air from fans should be exhausted outside the
clean room.
Measurement and control technology is necessary for air handling units. This technology is normally only required for the control of the
system and should follow Good Engineering Practice. An independent monitoring system with its own sensors and integrated alarm system
should be installed to monitor and record GMP relevant parameters. This system should be engineered together with the air handling system.
The following aspects have to be taken into consideration:
Which parameters have to be monitored?

Which accuracy has to be planned for the sensors?
How many sensors with which range are necessary? Where should they be located for representative monitoring?
How should the recording be performed?
Is it necessary to indicate violations of limits and respective alarms? If so, how should this be realized (indicators,
acoustic alarm signal, flashlight)?
Monitoring systems have to be validated in compliance with the requirements for computerized systems. GAMP requirements have to be
taken into consideration accordingly (see chapter 9 Computer Validation).
3.F.5 Qualification
Building services only have to be qualified partly (e.g. air handling systems, utilities with product contact, pharmaceutical water systems).
However building services, which do not have to be qualified (e.g. sanitary plumbing, electrical installations), are rated as "indirect-impact"
systems by ISPE. As a consequence, possible risks coming from these indirect impact systems have to be covered during qualification of the
respective clean rooms or process equipments.
Summary
Building services should be installed outside process rooms as much as possible.
Short, straight and vertical installation of cable and pipe trenches are preferred.
Pass-throughs of floors, walls and ceilings are critical areas to be adequately sealed
Building services are mainly to be considered as indirect-impact systems during qualification.
3.G Heating Ventilation Air Conditioning (HVAC)
Authors: Benno Weckerle, Dr. Ralph Gomez / Update 08

What is the meaning of the term "air technology"?
What kind of air technology systems exist?
What is the function of air filters?
How are air technology systems maintained?
3.G.1 Introduction
Pharmaceutical rules and specifications often contain very precise but also generally formulated requirements of air conditioning technology,
such as "temperature, humidity and ventilation of premises should be adequate". This generally formulated requirement is partially
substantiated in the supplementary guideline of the EU GMP Guide for the manufacture of sterile products as it is in the FDA GMP
Regulations (21 CFR 211.46 (b), chapter D.1.2).
The following chapters give a practical description of the extensive, and sometimes complex, field of air conditioning technology in terms of
the requirements that result from the pharmaceutical environment in question.
The term air conditioning technology and its further sub-divisions are described in DIN 1946/Part 1. Two basic types are distinguished by the
terms roomventilation technology and process air conditioning technology. Both types are found and required in the pharmaceutical
manufacturing sites. The essential task of a ventilation system is to supply the desired room conditions, such as temperature, humidity and
cleanliness. In contrast, the process air systems must guarantee the required process parameters. Figure 3.G-1 shows the structure of the
term "air conditioning technology"(extract from DIN 1946/Part 1) with reference to deployment in the pharmaceutical manufacturing sites.
Figure 3.G-1 Structure of air conditioning technology
1. Belong to the equipment in the pharmaceutical manufacturing sites, e.g. fluid bed spray granulation, drying processes, coating
processes
2. Both types of ventilation systems "with"and "without"ventilation functions, as well as a combination of both are found in the
pharmaceutical manufacturing sites
3. Not represented in the pharmaceutical manufacturing sites
In the air conditioning technology structure, a distinction is made between ventilation systems with and without ventilation functions. The
term ventilationfunction means that the air in the room is exchanged with external air. The further sub-structure shows the number of
thermodynamic air handling functions with which the ventilation system is equipped. The thermodynamic air handling functions shown
in Figure 3.G-2 apply for the preparation of the inlet air: heating, cooling, humidifying and dehumidifying.
Figure 3.G-2 Classification of ventilation systems

Recirculating Recirculating
Classification of room Ventilation Recirculating Partial air Air
air partial air
ventilation systems facilities facilities conditioner conditioners
air conditioners conditioners
Number of thermodynamic None or one Two or three Four
air handling functions
The terms for classification of ventilation systems do not provide any information on the filtering of the inlet air.
The next chapters deal exclusively with room ventilation facilities. No detail is given of the engineering-related planning of ventilation
systems, but instead the focus is placed on the fundamental design, planning, solution options and implementation in terms of the
pharmaceutical requirements.
3.G.2 Room ventilation systems

The room ventilation systems are designated according to the available thermodynamic air handling functions in a ventilation system (acc. to
DIN 1946 / Part 1, see Figure 3.G-2 classification of ventilation systems).
The respective design and structure of the ventilation systems results from the requirements and conditions made of the ventilation system
(see chapter 3.G.4 Principles for the design and planning of air conditioning ventilation systems).
The following criteria can play a role in the selection of the system to be used:
Influence of outside air

Climatic conditions of site
Operational costs of the different systems, especially the costs for energy consumption: current, heat, cold (cooling,
dehumidification) and humidification
Cleanliness requirements
Flexibility
In pharmaceutical manufacturing, essentially the following ventilation systems are used.
3.G.2.1 Pure (100%) external air conditioning system
The inlet air to the rooms always consists of 100% external air. The external air is prepared in the ventilation system according to the defined
conditions (temperature, humidity, purity). With a pure external air facility, impurities/contamination cannot enter the inlet air system via the
exhaust air system. When using a heat recovery system, it must be ensured that the two systems cannot be connected via the heat recovery
components (Figure 3.G-3).
Pure external air conditioning systems are used with the following conditions:
Supply of different production areas through a joint ventilation system

The exhaust air from the rooms is so highly contaminated with impurities that the safe elimination of impurities can not be
assured by the cleaning/filter phases of the ventilation system.
Flexibility is required, i.e. at any time, a manufacturing site for a different product group with other requirements can be
supplied without a risk of cross-contamination.
Figure 3.G-3 Diagram of a pure external air plant

3.G.2.2 Central recirculating air/mixed air conditioning system
The inlet air to the rooms consists of some external air and some recirculating air. The share of "external air" and "recirculating air"can be
fixed or can be variable according to the external temperature.
It is important that the amount of external air be properly adjusted to accommodate the number of people working in the manufacturing site
(Figure 3.G-4).
Central recirculating air/mixed air conditioning systems are used with the following conditions:
Supply of one production area (dedicated equipment).

The concentration of impurities in the exhaust air from the rooms is low enough that the safe elimination of the impurities
is achieved via the cleaning/filter stages of the air technology system.
Direct heat recovery without additional heat exchanger (low investment costs).
No flexibility - i.e. a manufacturing site for a different product group with other requirements cannot be supplied without a
risk of cross-contamination.
Figure 3.G-4 Diagram of a central recirculating air/mixed air plant
3.G.2.3 Decentralized recirculating air/mixed air conditioning system with

central external air preparation
The air supply and exhaust air of a room or a zone is conveyed via a recirculating air facility. Conveying centrally-prepared external air
guarantees the required external air share for the personnel in the rooms (Figure 3.G-5).
The recirculating air facility is usually fitted with a condenser and a filter stage. Decentralized recirculating air/mixed air facilities with central
external air preparation are used with the following conditions:
Supply of different production areas through a joint external air preparation system
The concentration of impurities in the exhaust air from the rooms is so low that safe elimination of the impurities is
achieved via the cleaning/filter stages of the decentralized recirculating air facility.
Flexibility, i.e. a manufacturing site for another product group with other requirement can be supplied at any time, if the
central external air preparation is carried out with a "pure external air plant".
Figure 3.G-5 Decentralized recirculating air/mixed air conditioning system
with central external air preparation
3.G.2.4 Pure recirculating air conditioning system
The air supply and exhaust air of a room or a zone is conveyed via a recirculating air facility. No prepared external air is supplied. The pure
recirculating air facility is therefore only used for areas, which are not permanently staffed and where the inlet of external air could influence
the air quality (Figure 3.G-6). Typical applications are partially high-quality clean room zones in a clean room, e.g. zones of cleanliness class
A in a sterile room, LF work benches.
Figure 3.G-6 Pure recirculating air conditioning system

3.G.2.5 Systems for tempering and volume flow regulation
The following two systems have proven their worth in practice for tempering and volume flow regulation:
Single duct system: temperature regulation takes place either by room or by zone via post-heating registers or
aftercoolers. The air currents (air volume) are today usually configured or regulated with volume current regulators. With constant
air currents, a very simple setting can be made via throttles such as flaps and perforated plates (Figure 3.G-7).
Figure 3.G-7 Room supply with a single duct system
Dual duct system: after the central air preparation facility, the inlet air is split across two differently tempered air supply
ducts. The air in the warm duct is heated to a temperature of 25 to 35 °C, while the air in the cold duct is cooled to 15 to 18 °C, for
example. Before a room or zone, the two air flows are mixed in a blending box according to the required room temperature and
heat burden, and blown in as inlet air. With the blending boxes, constant air currents (air volume) or variable volumes can be set
(Figure 3.G-8)
Figure 3.G-8 Room supply with a dual duct system
3.G.2.6 Control-systems of the air volume flows
In principle, a distinction is made between a constant or variable inlet and exhaust air current supply for individual rooms, zones or areas. The
two supply strategies differ as shown in Figure 3.G-9.
Figure 3.G-9 Comparison of volume current systems

Constant air volume flow Variable air volume flow
A fixed volume current is set via a Depending on the heat in the room or in a zone and/or the
constant volume current regulator, activity, the air volume currents (inlet and exhaust air) can be
blending box, flap or other throttle. raised from an initial value to a maximum value, e.g. via the
With a single duct facility, temperature temperature regulator. With decreasing heat and/or activity, the
regulation takes place either by room air currents are reduced to the initial value.
or by zone via post-heating registers or
aftercoolers.
Advantages: Advantages:
Simple design Low energy consumption/costs
Steadily working More flexible system, e.g. in terms of
systems highly changeable heat burdens
External influences can be ruled out, e.g.
by pressure regulation due to changing wind
pressure.
Disadvantages: Disadvantages:
High energy More complex design
consumption/costs Higher level of automation required
Cannot react to
influences, or only
marginally
3.G.2.7 Utilities for the operation of room ventilation systems
Different kinds of energies (and utilities) are required to operate ventilation systems, in order to convey the air, filter it and enable
thermodynamic air handling functions such as heating, cooling, dehumidifying and humidifying. Energies that are used for heating, cooling
and dehumidifying do not usually have any direct contact with the air to be prepared. The air is passed through heat exchangers, which are
equipped with lamellas on the air side. The energy supply is via pipes that are connected to the lamellas.
The essential energies (and utilities) used in ventilation systems are described in Figure 3.G-10.
Figure 3.G-10 Energies and utilities for ventilation functions

Physical or thermodynamic
Type of energy or utility
functions
Air delivery Current
Heating Hot water (pumping warm water, e.g.
80/60 °C)
Steam
Current
Cooling/dehumidifying Cooling water (e.g. 6/12 °C)
Coolant
Humidifying Water
Steam
3.G.3 Filters
To attain the required air quality and conditions in the premises of a pharmaceutical manufacturing site, different standard components are
used to configure an air technology system.
The required purity of the air in the premises can only be achieved with effective cleaning of the external air or recirculating air. This requires
a suitable, correctly designed filter.
Air filters are components through which particles and gaseous impurities are filtered and separated from the air. The ambient air is
penetrated by substances of different particle sizes and materials. This mixture of ingredients must be cleaned by suitable filters so that the
required cleanliness conditions are complied with in a manufacturing site.
Separation in the air filters (filter medium) is based on different physical effects (see Figure 3.G-11).
Figure 3.G-11 Physical separation effects at

the individual fibres of a filter medium
The most important separation effects are
Diffusion effect: the diffusion effect is a consequence of Brownian molecular movement and is therefore only effective
for very small particles. The molecular movement causes a diffuse movement of the particle along a virtual streamline. It is
separated at the fiber if it remains sufficiently close to the fiber for a long enough time.
Inertness effect: the inertness effect causes separation at the fibers, if the particle is of a particular size and thus cannot
follow the course of the streamline.
Blocking effect: the blocking effect always occurs, if a particle is on a streamline whose distance from the fiber during
circulation is less than half the particle diameter.
Sieve effect: the sieve effect only occurs for a particle whose diameter is greater than the free cross-section between the
fibers (pore width).
The different filter qualities are split into coarse, fine and suspended matter filters according to the separation capacity of the different
particles. This division is based on standardized testing procedures.
Today, following many intermediate steps, the following are two valid European standards for air filters
DIN EN 779 Particle air filter for general ventilation

DIN EN 1822-1 Suspended matter filter (HEPA and ULPA) are the specifications and testing bases for all filter
manufacturers.
Figure 3.G-12 Structure of the air filter in accordance with DIN 24183 (E) Part 1
3.G.3.1 Particle air filter
The particle air filters are classed in "coarse (G1 to G4)"and "fine (F5 to F 6)" filter groups in accordance with DIN EN 779 (see Figure 3.G-13).
Figure 3.G-13 Classification of particle filters according to DIN EN 779

Initial effectiveness (EA) EA < 20% EA ≥ 20%
Characteristics Average separation rate Am (%) Average effectiveness Em (%)
Filter group Filter class Class limits
Coarse (G) G1 Am < 65 -
G2 5 ≤ Am < 80 -
G3 80 ≤ Am < 90 -
G4 80 ≤ Am -
Fine (F) F5 - 40 ≤ Em < 60
F6 - 60 ≤ Em < 80
F7 - 80 ≤ Em < 90
F8 - 90 ≤ Em < 95
F9 - 95 ≤ Em
Am = Average separation rate compared with synthetic dust
Em = Average effectiveness compared with atmospheric dust
For pharmaceutical manufacturing sites, the coarse filters are irrelevant as the separating power of these filters is too low to achieve the
required purity; total effectiveness of the filter >95 %. This total effectiveness can only be achieved with fine filters in the 1st and 2nd filter
stage of air technology equipment.
The following combinations of filter classes are used today for two filter stages in series:
1st filter stage F 6 or F 7

2nd filter stage F 9
With this filter combination, the following targets are achieved:
Total effectiveness > 95%

High period of use of the filter
Manageable energy costs
With all mechanical filters, it must be taken into account that the separation power is not constant, but changes due to the following factors:
Fluctuating dust content of the external air: due to the season (e.g. pollen in spring) and environment (e.g. emissions of
hazardous substances from neighboring plants), the dust content of the external air fluctuates.
Velocity at which the air passes through the filter medium: with a reduced volume flow in relation to the test volume flow,
the separation rate tends to increase.
Filter cakes: with the increasing contamination (build-up of a filter cake) of the filter, the separation rate increases due to
the additional filtration through the collected dust.
Air humidity: in hygiene areas, the air filter should be prevented from dropping below the dewpoint, as bacteria and
fungus growth is encouraged near the dewpoint. The relative humidity of the air flushing through should therefore not exceed a
maximum value of 95 %.
The filter media used consist of fiberglass or synthetic-organic fibers, which are then connected thermally or chemically with binding agents.
The following models are generally used (see Figure 3.G-14):
Filter mats → Filter classes G1 to F 6

Conveyor belt filter → Filter classes G 1 to F 5
Pocket filter → Filter classes G1 to F 9
Cassette filter → Filter classes F 5 to F 9 (rigid filter)
Figure 3.G-14 Models of air filters
Figure 3.G-15 Comparison of DIN EN 779 and Eurovent 4/9

Today, the separation rate or effectiveness of the particle air filters is determined as a percentage in comparison with "atmospheric dust"or
"synthetic dust", without producing a reference to a particle size.
The first investigations and standardization activities aim to determine a fractional separation rate for a defined particle size for the
comparison of the efficiency of a particle air filter.
The diagram (see Figure 3.G-16) shows a comparison of the separation rate (%) for the different particle sizes by pocket filters with different
filter classes. At present, the fractional separation rate should be calculated according to the Eurovent draft standard with a particle size of
0.4 μm.
Figure 3.G-16 Comparison of fractional separation rates of pocket filters

3.G.3.2 Suspended matter filter - HEPA-Filter
For clean rooms with defined particle counts in the room air, usually a 3rd filter stage must be provided in addition to the two particle air filter
stages. As the 3rd filter stage, the suspended matter filter should be fitted as near as possible to the end of the room, i.e. just before the entry
of the inlet air into the clean room.
With suspended matter filters, dust, suspended matter and aerosols can be separated in a range up to 0.1 μm.
For the specification of the suspended matter filter, the different national standards were transferred into a European standard "DIN EN
1822/T 1-5" (Figure 3.G-17).
Figure 3.G-17 DIN EN 1822 Suspended matter filter (HEPA and ULPA)
DIN EN 1822 Suspended matter filter (HEPA and ULPA)
Part Title Status/Valid
1 Classification, performance test, labeling July 1998
2 Aerosol generation, measuring instruments, particle count statistic July 1998
3 Check of the planned filter medium July 1998
4 Leak test on the filter element (scan procedure) Open
5 Separation rate test of the filter element Open
According to the above-mentioned DIN standard, suspended matter filters have the filter classes illustrated in Figure 3.G-18 with the
associated filtration performances.
Figure 3.G-18 Classification of HEPA and ULPA filters according to their filtration performance in
accordance with DIN EN 1822-1)
Integral value Local value
Filter
class Separation Forward Separation rate Forward
rate (%) rate (%) (%) rate (%)
H10 85 15 - -
H11 95 5 - -
H12 99.5 0.5 - -
H13 99.95 0.05 99.75 0.25
H14 99.995 0.005 99.975 0.025
U 15 99.999 5 0.000 5 99.997 5 0.002 5
U 16 99.999 95 0.000 05 99.999 75 0.000 25
U 17 99.999 995 0.000 005 99. 999 9 0.000 1
HEPA filter (H) => High Efficiency Particulate Air Filter
ULPA filter (U) => Ultra Low Penetration Air Filter
To assess the suspended matter filters, a testing procedure was defined in DIN EN 1882 in which the separation rate is determined in the
separation rate minimum. The physical basis is the characteristic minimum curve, which describes the separation behavior of fiber filters and
thus also of suspended matter filters (see Figure 3.G-19).
Figure 3.G-19 Characteristic minimum curve for describing

the separation behavior of fiber filters
The minimum lies in the transition area between stochastic movement (diffusion) through Brownian molecular movement and inertness effect
as the determining separation mechanisms.
The position of the suspended matter filter's separation rate minimum, both in terms of the percentage separate rate and also of the particle
size with the highest penetration, depends on the velocity of the air flow through the filter medium. The particle size with the highest
penetration for a defined filter medium flow velocity is called the Most Penetration Particle Size (MPPS = separation rate minimum).
Through the connection between the filter medium flow velocity and separation performance, the separation performance of a suspended
matter filter can be increased by reducing the medium velocity (see Figure 3.G-20).
Figure 3.G-20 Two minimum curves of a suspended matter filter
medium at different filter medium flow velocities
The determination and assignment of the individual suspended matter filters to the filter classes is carried out in accordance with DIN EN
1822. The suspended matter filters of classes up to H 14 can be tested with the so-called oil strand test. Starting with filter class U15, a leak
detection of the particle count method must be carried out, although it is advisable to perform the particle count method starting with filter
class H 13.
Leakage test
With the oil strand test a leak is visually detected. The filter element is acted upon by a high concentration paraffin cloud at the raw air side
and a tester check, if identifiable oil strands are present at the pure air side. Every identified oil strand indicates the position of a leak
(Figure 3.G-21).
Figure 3.G-21 Schematic test structure for carrying out the

leakage test on LF units
The leak detection and separation rate determination using the particle method has the following advantages:
High precision of the measurements

Determination of the total separation rate in the separation rate minimum
Determination of the local separation rate
Determination of leak positions
For the particle method, DIN EN 1822 prescribes the following procedure:
Determination of the Minimum Penetration Particle Size (MPPS) with a defined filter medium flow velocity on a flat filter
medium
Fully scan the finished filter element with specified volume flow using MPPS particles
Calculation of the integral and local separation rates
Classification of the filter in the corresponding filter class
The test methods described in DIN EN 1822 can be implemented by the filter manufacturers with corresponding test benches. The tests
cannot usually be fully implemented when testing fitted suspended matter filters.
The test structure shown in Figure 3.G-21 is possible when using the particle count method for fitted suspended matter filters:
The test aerosol is applied to the suspended matter filter at the raw air side of the filter as follows.
LF unit: the aerosol is applied via the ventilator aspiration or the aspiration channel.
Suspended matter filter air outlet: the aerosol is applied via a connection fitted to the raw air side of the inlet air duct.
The particle concentration of at least 106/ft3 particles of 0.3 μm to be applied on the raw air side exceeds the count range of the particle
counter. Therefore, the aerosol concentration is diluted before the particle counter by a dilution stage of 1:10 or 1:100. Each individual
suspended matter filter is then tested for leaks by slowly and completely passing over the entire filter surface on the raw air side with the
particle counter's isokinetic sensor.
A leak is defined as follows: a leak is present, if the permissible penetration rate of the suspended matter filter is exceeded or its permissible
separation rate is undershot. A distinction is made between integral and local leaks.
An integral leak is present, if the ratio of the particle concentration measured over the entire filter at the inlet and exhaust side is not achieved
in accordance with the separation rate or penetration rate prescribed in the filter class.
A local leak is present, if the ratio of the locally measured particle concentration at the inlet and exhaust side is not achieved in accordance
with the separation rate or penetration rate prescribed in the filter class.
Designs
The filter media of suspended matter filters have a relatively high pressure differential. In order to accommodate as many filter surfaces as
possible on the limited designed space, the filter medium is folded (see Figure 3.G-22 and Figure 3.G-23).
Figure 3.G-22 Separator technique
Figure 3.G-23 Strand design

The older type of fold is the separator technique. The filter medium is folded lengthwise and widthwise alternately and a separator of
corrugated aluminum is inserted in the resulting chambers, which prevents the filter medium from coming into contact with itself and thus
creating an unusable filter surface. A disadvantage of the corrugated and sharp-edged aluminum separators is that they can tear the filter
medium and create holes in it. This hazard applies during production, transport, fitting and in current operation through pulsing air currents.
The further development of the folding technique led to the strand design. The strand design technique allows the filter medium to fold with
narrower spaces than the separator design. Thus, a greater filter surface can be realized in a suspended matter filter with a strand design of
the same dimensions. The contact points of the spacers on the filter medium are significantly lower with the strand design than with the
separator design
This technique results in the following advantages for suspended matter filters with a strand design:
No mechanical stress on the filter medium through metal separators

Lower height with the same dimensions and filter surface
Lower pressure losses.
3.G.3.3 Air Filtration in the FDA's Sterile Drug Products Produced by

Aseptic Processing guideline
The Sterile Drug Products Produced by Aseptic Processing guideline gives FDA's recommendations on air filtration in aseptic processing
facilities.
Compressed air, nitrogen, and carbon dioxide are commonly used in cleanrooms. These, and all other utilized gases, must be of the requisite
purity and after filtration their microbiological quality and particle content should be at least equal to but preferably superior to the air into
which the gas is introduced.
Membrane Filters: membrane filters are capable of generating sterile compressed gases which can be used in processes involving sterile
materials, such as components and equipment. The FDA guideline recommends "that sterile membrane filters be used for autoclave air lines,
lyophilizer vacuum breaks, and tanks containing sterilized materials. Sterilized holding tanks and any contained liquids should be held under
positive pressure or appropriately sealed to prevent microbial contamination. Safeguards should be in place to prevent a pressure change
that can result in contamination due to back flow of nonsterile air or liquid".
Any moisture on gas filters may cause blockage and permit the growth of microorganisms. Therefore, precautions should be taken to assure
that these filters are dry. Employing hydrophobic filters and, if possible, applying heat to the filters averts difficulties with moisture residues.
The guideline recommends that any filters that are used to maintain sterility that can affect product be integrity tested at installation and
periodically during its lifetime. The filters should also be tested after any activities that may compromise the filter. Any failures during integrity
testing must be investigated. Also, filters should be replaced at scheduled intervals.
High-Efficiency Particulate Air (HEPA) Filters: in order to insure aseptic conditions, the integrity of HEPA filters (chapter 3.G.3.2 Suspended
matter filter - HEPA-Filter) must be preserved. One way of verifying the integrity of the filters is to perform leak testing at installation and
periodically, such as twice per year in the aseptic processing room. Leak testing should also be performed, when the air quality is found to be
unacceptable, when renovations have taken place in the area, or an investigation is conducted due to a media fill or product sterility failure.
Filters in dry heat depyrogenation tunnels and ovens should also be leak tested. The guideline allows for the use of alternate methods for the
testing of HEPA filters in the hot zones of depyrogenation tunnels and ovens. However, a justification for the use of alternate procedures must
be provided.
Typical aerosols used for leak testing include dioctylphthalate (DOP) and poly-alpha-olefin (PAO). Caution has to be used when choosing
alternate aerosols, since some increase the risk of microbial contamination of the environment. Therefore, it is imperative that these alternate
aerosols be tested to determine if they support microbial growth.
Efficiency testing differs from filter leak testing in that the former is designed to establish the filter rating while the latter detects leaks from the
filter media, frame or seal. The efficiency test is conducted by using a monodispersed aerosol of 0.3 micron sized particles and measuring
downstream. The obtained measurements are an average over the filter surface. Efficiency tests are not designed to detect filter leaks. An
acceptable filter retains at least 99.97 percent of particulates greater than 0.3 μm in diameter.
The leak test is conducted by using a polydispersed aerosol of particles with a light-scattering mean droplet diameter between 0.3 mm and 1
micron, but which includes a sufficient number of particles at approximately 0.3 mm. An aerosol composed of known concentration and
particle size is introduced upstream of the filter. The filter is scanned with a probe and the leakage is calculated as a percent of the upstream
challenge. The testing procedure and results obtained should be documented in writing. A result of 0.01 percent of the upstream challenge is
considered as a significant leak and requires either the replacement of the HEPA filter or, when appropriate, repair. In the event of a repair, its
success should be confirmed by performing a retest of the leak test.
In addition to leak testing, filter performance must also be monitored by measuring other filter attributes, such as uniformity of velocity across
the filter and relative to adjacent filters. HEPA filters should be replaced when nonuniformity of air velocity across an area of the filter is
detected. Nonuniformity of air velocity across an area of the filter will adversely affect airflow patterns. If this occurs, the HEPA filter should be
replaced. The principles discussed in this section of the guideline are also appropriate for use with ULPA filters.
3.G.4 Principles for the design and planning of air

conditioning ventilation systems
When planning an air technology system, the principles must be clearly and unambiguously defined. For the ventilation systems to be
designed and planned for a pharmaceutical manufacturing site, the external conditions of the site (see Figure 3.G-24), the requirements of the
premises (see Figure 3.G-25), the production factors that influence the room climate (see Figure 3.G-26) and the layout-dependent
requirements (see Figure 3.G-27) must be known. Only if all conditions and requirements are known, can an optimal ventilation system be
designed and planned. The data should be summarized in a room log, which must be available to every person involved in the planning.
(See chapter 3.A.6 Room book and layout.)
Figure 3.G-24 External conditions of the site

External conditions of the site
External temperature Specified values for the minimum and maximum external temperature.
Air humidity Minimum and maximum values
Sound limits Noise technical instructions, day/night limits (compliance with sound limits
for the neighborhood)
Emissions of harmful Air limits technical instructions (dust, solvent, odors, etc.)
substances
Altitude Important, as the key fields of pumps and ventilators, for example, relate to
the standard conditions.
Cardinal points Orientation of the building
Wind directions Main wind direction, wind speeds
Figure 3.G-25 Requirements of premises
Requirements of premises
Purity Cleanliness class of the rooms in accordance with the EU GMP
Guide, FDA Drug Products Produced by Aseptic Processing guideline,
CFR (FDA), DIN EN ISO 14644-1, VDI 2083.
Special data on the required laminar ranges (cleanliness class
A). Define size and position in the layout.
Pressure Negative/positive pressure (e.g. 12.5 PA positive pressure
conditions between cleanliness classes)
compared with Alarm values, alert values
bordering With defined pressure conditions, it must be defined how the
rooms/areas pressure is built up/relieved over different resistances (e.g. doors).
Doors may have to be locked against each other.
Air flow Define overflow direction per room (in, out or neutral)
direction
Temperature Temperature range (e.g. 19-25 °C), required temperature value
(e.g. 22 °C), summer compensation, tolerance (e.g. ± 2 °), alarm
values, separate values for non-working time
Humidity Humidity range (e.g. 40- 65 % r.h.), required dehumidification
and/or humidification value, tolerance, alarm values, separate values
for non-working time
Monitoring Particle concentrations
devices Temperatures
Air humidity
Pressure conditions
Air flow direction
Noise e.g. sound pressure level for production rooms
50-70 dB (A)
Figure 3.G-26 Usage-dependent requirements
Usage-dependent requirements
Manufacturing type Solid, liquid, sterile production, etc.
Hazard potentials of production Toxicity, MAC values, radioactivity,
materials or of the drug(s) biological substances (viruses, bacteria)
Production times 1, 2, 3 shift operation
Reliability Redundancy required: yes/no
(if yes → e.g. 100 % split to 2 x 50% → 50%
still available if a system fails, 2 x 70% → 70%
still available if a system fails, 3 x 50% → 100%
still available if a system fails, etc.)
Recirculating air possible Yes/no (increase of harmful substance
concentration possible, cross-contamination,
validation possible, etc.)
Special process air facilities for Required (inlet air and/or exhaust
process equipment air) → e.g. coating facilities, granulating facilities
etc.
Sources of harmful Dust
substances that have to be recorded Solvent
Disinfectant
EX - protection requirements EX - zone classification of premises for
production and engineering areas and for
equipment
Heat sources
Persons Number/activity
Lighting Power input, number
Production e.g. tablet press, coating facilities, filling
equipment equipment, autoclave, freeze-drying facility, etc.
Containers, pipes Uninsulated, hot areas
Sterilization Hot surfaces, emanating steam, etc.
processes Through windows, walls, ceilings
External heat loads Important point to determine the "peak
Simultaneity and load"
duration of processes
Staff clothing Type of clothing that must be worn by the
personnel
Particularly important for temperature
definitions, if clean room clothing is worn.
Figure 3.G-27 Layout-dependent requirements/dimensions
Layout-dependent requirements/dimensions
Number of rooms Main usage areas, auxiliary usage areas, traffic areas
Size of the rooms Room areas in m² or ft2, length and width
Height of the rooms Room height in m or ft
Definitions for the Possibilities for the routing of supply and removal streets
facilities Definition of the philosophy in terms of the operation and
infrastructure maintenance of air technology components (e.g. volume flow
regulator, filter change from pure to impure area).
Technology areas Function areas, premises for the assembly of the air
technology systems
Evaluation of the principles
Using the formulated requirements and conditions, an air volume table can be compiled in relation to the rooms. The air volume table can be
used to summarize all important data for the air technology system. Figure 3.G-31 to Figure 3.G-32 and Figure 3.G-28 contain two examples
of a summary of the most important data, including
General room data (room number, room name, area, height, volume etc.)
Volume of inlet air, exhaust air, overflow air (min./max. values; per room)
Air exchange (min./max. values; per room)
Air volumes of special air technology systems
Figure 3.G-28 Air volume table

The second example shows the determination of the heat load in the room. This diagram is shown at the end of chapter 3.H-5 (Figure 3.G-
31 to Figure 3.G-32).
3.G.5 Design criteria for the ventilation of premises

The design of a room ventilation system for supplying the rooms is not specified accurately in the various GMP specifications and rules. The
ventilation systems are to be designed so that adequate ventilation is achieved.
The actual implementation of the requirements for supplying the rooms with air means dealing with the following design criteria:
How is the inlet air brought into the room? → Inlet air flow pattern
How many filter stages are required and with what quality?
→ Air filter/stages/air filter quality
Room conditions → Temperature/humidity/summer compensation
What air change is required? → Air change
How should the exhaust air be aspirated from the room? → Exhaust air flow pattern
Are pressure differences or defined flows required between rooms or areas?
→ Room pressures/pressure stages/defined flows
How are locks designed? → Door locking/air flow pattern
Figure 3.G-29 lists the basic design features with solution approaches for the design of the room supply. The data does not relate to the
design of air technology equipment.
3.G.5.1 Air technology design of a sterile room with negative

pressure plenum
A sterile room with a negative pressure plenum has the following construction principles (see Figure 3.G-29).
Above the sterile room, a second room is created, which is connected to the sterile room via recirculating air ducts. The LF areas (filter fan
units) are integrated in the ceiling between the sterile room and plenum. The filter fan units convey the air in the circuit between the sterile
room and the plenum. The air is aspirated from the sterile room via aspiration points near the floor and conveyed to the plenum. In addition,
the required fresh air is brought into the plenum as inlet air. The recirculating air and the inlet air are brought into the sterile room as initial air.
Further inlet air can be brought in via area B through suspended matter filter air outlets. The excess air is allowed to flow into bordering areas,
e.g. locks, engineering areas of autoclaves, etc. The overflow openings with constant air volumes are designed as gratings. Overflow
openings can be fitted with adjustable flaps to control the pressure.
The diagram shows the main possibility of how a sterile room can be designed with a negative pressure plenum. Details about the technical
solutions for all listed components can be found.
Figure 3.G-29 Sterile room with negative pressure plenum

3.G.5.2 Pressure stages and design of the pressure differential
measurement for a sterile area
In accordance with the requirements, a pressure differential is realized between each cleanliness class. If each cleanliness area is
measured at a reference point, this results in a clearly traceable record, e.g. with a line writer as the lines of the individual cleanliness areas
are always offset by the pressure differential. As the individual traces must be offset and parallel, it is easy to recognize, if the cleanliness
areas have always been in the prescribed pressure area.
The diagram (see Figure 3.G-30) shows how the individual pressure differentials are always measured in relation to a reference point. The
alarms are determined from the differences between the cleanliness classes.
For example, the following values could result from the individual pressure differential measurements:
PDIS 1: 12.5 Pa (pharmaceutical area/D area)

PDIS 2: 25 Pa (pharmaceutical area/C area)
PDIS 3: 32.5 Pa (pharmaceutical area/lock to sterile room)
PDIS 4: 37.5 Pa (pharmaceutical area/sterile room)
Figure 3.G-30 Pressure stages and design of the pressure differential measurement for a sterile area
3.G.5.3 Pressure Differentials in the FDA's Sterile Drug Products

Produced by Aseptic Processing guideline
The FDA's Sterile Drug Products Produced by Aseptic Processing guideline addresses clean area separation and the maintenance of positive
pressure differentials from higher to lower cleanliness rooms (section IV.C). The FDA's recommendation is to ensure a positive pressure
differential of at least 10 to 15 Pa between rooms of different classifications that are adjacent to one another and with doors closed. If the
doors are open the outward air flow should be sufficient to keep contamination from entering the room. It is important to establish a time limit
for how long the door can remain ajar or open.
For adjacent rooms that have the same classification, the guideline states that "maintaining a pressure differential (with doors closed)
between the aseptic processing room and these adjacent rooms can provide beneficial separation". If the aseptic processing room is adjacent
to an unclassified room, then the guideline recommends maintaining an over pressure from the aseptic processing room of at least 12.5 Pa. If
the pressure differential falls below the recommended level then the environmental quality in the aseptic room may be compromised. It is then
important to restore the air quality of the aseptic processing room and confirm that it meets the requirements. The guideline further
recommends that pressure differentials should be continuously monitored and recorded and any alarms that signify a deviation from the
established range should be documented and investigated.
Air change rate is also important for cleanrooms. For Class 100,000 rooms, FDA recommends 20 air changes per hour. For Class 10,000
and Class 100 areas, much higher air change rates are needed.
Finally, a reliable facility monitoring system is critical to quickly detect atypical changes that can affect the environment and assist in the
restoration of the appropriate operating conditions to qualified levels before action levels are reached.
Ventilation design criteria for GMP-conform production rooms
Figure 3.G-31 Calculation of cooling loads
3.G.6 Maintenance of air ventilation systems
For pharmaceutical manufacturing sites, safe operation and functioning of the ventilation systems is an important requirement to be able to
guarantee the manufacture of pharmaceutical products in accordance with specific requirements and conditions for the premises.
The required activities and concepts in relation to the operation of a ventilation system can be shown based on DIN 32541 (see Figure 3.G-
33).
Figure 3.G-33 Structure of the operation of a ventilation

system based on DIN 32541
For operation, maintenance is an essential factor for preserving safe, fully functional and economic operation in terms of the required statuses
(chapter 4.H Maintenance). FDA's Sterile Drug Products Produced by Aseptic Processing guideline emphasizes maintenance as an important
criterion to insure the proper functioning of air ventilation systems. In section IV.A, the guideline states, "...even successfully qualified systems
can be compromised by poor operational, maintenance, or personnel practices".
The following are targets for air technology systems with planned and regularly executed maintenance measures (Figure 3.G-34):
Guaranteeing and complying with physical parameters, such as temperature, humidity, pressure differences, etc.
Guaranteeing a hygienic operation (purity, particle count etc.)
Ensuring and increasing availability
Guaranteeing economic operation (low energy costs)
Identifying and eliminating weaknesses
Maintaining the value of the system (longer life)
Figure 3.G-34 Maintenance measures

Maintenance
Grouping of the measures
Inspection Maintenance/Service Repair
Targets of the measures = Definition in acc. with DIN 31051
Establishment and assessment of the Preserving the required Recovery of the required
actual status status status
Individual measures/activities
Test Test Repair
Measure Adjust Replace
Assess Exchange
Amend
Lubricate
Preserve
Clean
The "Building services engineering maintenance working group of the VDMA (association of German facility designer)" has issued data
sheets, which act as a standard for the execution of maintenance measures in the field of building services engineering. For all building
services engineering areas, there are data sheets for maintenance (see Figure 3.G-35).
Figure 3.G-35 Composition of maintenance-related VDMA data sheets for building services engineering
Status/
VDMA data sheets
Valid
24 Inspection of air technology equipment and other technical equipment in buildings 1/90
176
24 Performance program for maintenance of air technology equipment and other 9/96
186 technical equipment in buildings
Part 0 Overview and structure, numbering system, general instructions 9/96
Part 1 Air technology systems 9/88
Part 2 Heating systems 9/88
Part 3 Cooling systems 9/88
Part Electrically driven house heating pump systems for heating purposes 4/86
31
Part 4 Measuring and control technology equipment and building automation systems 9/88
Part 5 Electro-technical equipment and facilities 4/96
Part 6 Sanitary systems 5/92
24 Buildings management, terms and performances 8/96
196
24 Emissions reduction of cooling agents from cooling systems
243
Part 1 Introduction 5/94
Part 2 Construction and planning 5/94
Part 3 Assembly; Repair 5/94
Part 4 Maintenance; Repair; Disposal 5/94
Part 5 Specialist training, specialist plant equipment, operating instructions 5/94
Inspection is the subject of the VDMA 24176 "Inspection of air technology equipment and other technical equipment in buildings" data sheet.
Inspection includes testing and measuring activities, with the evaluation and assessment of the results being an essential task, which should
only be carried out by a specially trained employee. Exact knowledge of the actual status is an important requirement for planning
maintenance measures.
Servicing includes the actual core task of planned maintenance. It includes all measures to ensure the required status of the ventilation
system and is the subject of the VDMA 24186 "Performance program for servicing of air technology equipment and other technical equipment
in buildings" data sheet. Details of the various crafts of the technical building equipment are given in parts 0 to 6.
Based on the VDMA data sheets, it is possible to establish the measures to be executed for inspection and servicing and their documentation.
From the extensive collection of activities in these data sheets, the corresponding performance pattern for the respective system can be
compiled both for inspection and for servicing.
The deadlines and intervals for inspection and servicing are to be established in a maintenance plan (see Figure 3.G-38). Based on
experience, the manufacturer's specifications and the significance of the facility, periods must be defined in which an inspection or service is
to be carried out (seeFigure 3.G-36).
To this end, the permissible tolerance periods within which the inspection or servicing must be carried out should also be established
(see Figure 3.G-37).
Every maintenance measure must be documented. In general, for every activity on a ventilation system, an entry should be made in the log
book to be stored on-site or in the operating diary of the respective system.
Documentation of the inspection or servicing activities that have been executed is carried out in the form of records, which are filled in by the
person executing the activity and counter-signed by a checker.
The following tables, records and diagrams show proven practical examples for the following maintenance activities for air technology
systems:
Time intervals for carrying out inspections or servicing (Figure 3.G-36)

Tolerances for inspection and servicing deadlines (Figure 3.G-37)
Maintenance plan (Figure 3.G-38)
Forms: inspection of air technology equipment and systems (Figure 3.G-39)
Forms: servicing of air technology equipment and systems (Figure 3.G-40)
Form: log book for air technology systems (Figure 3.G-42, Figure 3.G-43, Figure 3.G-44)
3.G.6.1 Time intervals for carrying out inspections or servicing

Figure 3.G-36 Time intervals for carrying out inspections or servicing
Frequency specifications relate to one year
Intervals No servicing 1 x servicing 1 x servicing
1 x servicing and
(only as required) and no 1 x inspection
and 3 x
Components and 2 x inspections inspection inspection
Ventilation equipment for:
Offices x
Non sterile x
manufacturing
Laboratories x
Clean rooms x
(D, C, A + B)
Room control systems x
Process air systems x
Suspended matter filters x
Laminar flow units x
3.G.6.2 Tolerances for inspection and servicing deadlines

Figure 3.G-37 Tolerances for inspection and servicing deadlines
Deadlines for inspection and servicing Tolerance
monthly ± 2 weeks
quarterly ± 1 month
half-yearly ± 2 months
yearly ± 3 months
3.G.6.3 Maintenance plan

Figure 3.G-38 Maintenance plan
3.G.6.4 Forms for the inspection and servicing of ventilation systems
The following examples of "Forms for the inspection and servicing of ventilation systems"are based on the VDMA data sheets. The activities
listed are a selection from the "Performance program for the servicing of air technology equipment and other technical equipment in buildings"
from VDMA data sheets 24186 part 1 and 4.
The design and handling of forms is intended as follows. The following entries are to be made in the header of the forms:
the building
the storey
the facility name
the facility number
the component (if required)
The following columns are to be filled in as shown, in the rows with the individually described activities: (the "available yes/no"column can be
omitted if the forms only contain the components that are available on the air technology systems).
Figure 3.G-39 Inspection of air technology equipment and systems in accordance with VDMA 24176
Figure 3.G-39 Inspection of air technology equipment and systems in accordance with VDMA 24176
Figure 3.G-40 Servicing of air technology equipment and systems in accordance with VDMA 24176
3.G.6.5 Log book for air technology systems
The log book can be bound or can consist of individual sheets. A bound version has proven better in practice, as this prevents the loss of
individual sheets.
The example is structured as follows:
Figure 3.G-41 Figure 3.H-44 Completion of VDMA data sheets 24186 part 1 and 4
Column Entry
"Available yes/no" Cross the corresponding box
"Condition OK / Cross the corresponding box
not OK"
"Report or Findings, actual values, conditions that are not OK, executed activities, servicing
comment" activities, etc. are to be described in words here.
A cover sheet (see Figure 3.G-42)

"Inspection, servicing, repair, malfunction" form (page 1 to 20) (Figure 3.G-43)
"Filter inspection, filter change" form (page 1 to 3) (see Figure 3.G-44).
Figure 3.G-42 Example cover sheet
Figure 3.G-43 Example log book page

Figure 3.G-44 Example filter
Principles for entries in the log book
(See chapter 15.B GMP-conforming documentation.)
Entries in the log book are made on-site in chronological order (date and time) in the intended forms, by the person
executing the activity
The log book entry should be made during or immediately after completion of the activity. However, under no
circumstances should it be signed before completion of the activity in question.
After entry, any remaining blank fields are to be crossed out.
After completion of the activity by the person executing the work, the entries are confirmed through the legible entry of a
name and signature.
The entries in a log book page must be checked for completeness and accuracy and initialed by a person in charge.
Entries should only be made with permanent ink pens.
The following entries must be made:
Date/time of activity
Type of activity, event (e.g. visual control, servicing, calibration, repair, malfunction)
Signature or signatures
An entry can be corrected by crossing it out. However, the old entry should still be legible after it has been crossed out. It
is not permissible to cover the entry or delete it with Tipp-Ex® or Liquid Paper®. Correction or crossing out of an entry must then be
confirmed by the person executing the task by his signature and adding details of when it occurred.
Summary
The term "air technology" is split into the two terms "ventilation technology" and "process air
technology".
The ventilation system used is essentially determined by the following factors:
Influence of outside air
Climatic conditions of site
Operational costs of the different systems
Cleanliness requirements
Flexibility
In principle, it must be clarified if a recirculating air system is possible.
In order to guarantee the purity of the air in the premises of a pharmaceutical manufacturing site,
suitable filters must be used.
The design of a suitable ventilation system requires detailed recording of the planning principles
and specification of the GMP requirements in implementable designs.
The safe, fully functional and economic operation of a ventilation system requires a maintenance
system.
3.H Process Gases
Author: Dr. Thomas Schreiner / Update 08

What are the regulatory requirements for process gases?
How are generation and distribution systems to be planned and installed?
What must be considered for sterile process gasses additionally?
What must be considered during qualification/validation?
Process gases used in pharmaceutical manufacture can be distinguished with regards to the needed amounts
into compressed air and other gases (nitrogen, carbon dioxide, etc). In addition, they can be divided in sterile and
non-sterile gases. Process gases are also termed as pharmaceutical gases due to the specific quality
requirements.
Smaller amounts of different gases for analytical purposes are frequently used in quality control laboratories.
Larger amounts of compressed air are normally used in pharmaceutical production.
Compressed air for use in production can be further grouped in:
1. Compressed air with direct or indirect product contact, e.g. for drying of equipment parts, transport of
substances trough pipelines, for pressurization of solutions in storage tanks, etc.
2. Compressed air for technical purposes, e.g. pneumatic operated valves.
3. Breathing air for operators wearing full suits, e.g. during processing of high potent drugs.
Air with direct or indirect product contact represents the main pharmaceutical interest.
Compressed air for pneumatic drives is of pharmaceutical interest in case the air is exhausted into clean rooms.
In such cases, the exhausted air should be collected in an exhaust air pipe. Where not possible, the air should
have the same quality as the air supplied to the clean room. Valve exhaust air in rooms for sterile manufacturing
should principally be exhausted via a collection pipe.
For other technical purposes (means without possible impact on product quality or use as breathing air)
respective technical and work safety guidelines and norms must be considered.
3.H.1 Quality Requirements

Official GMP guidelines contain only a few details for quality requirements of gases with direct or indirect product
contact. PIC/S PI 009-3: Aide mémoire Inspection of Utilities refers in chapter 5, section chapter 4. Area of
operation/Items Pharmaceutical gases to general points of the EU GMP Guide (seechapter F.6, chapter C.4,
Chapter 3 Premises and Equipment, and chapter C.6.15.) Additionally, the document makes a reference to ISO
8573, Compressed air, part 1 to 7 (see Figure 3.H-1).
Figure 3.H-1 Structure of ISO-Norm 8573 Compressed Air

Structure of ISO-Norm 8573
Part 1: Contaminants and purity classes
Part 2: Test methods for aerosol oil content
Part 3: Test methods for measurement of humidity
Part 4: Test methods for solid particle content
Part 5: Determination of oil vapor and organic solvent content
Part 6: Determination of content of gaseous contaminants
Part 7: Test methods for viable microbiological contaminant content
Part 8: Test methods for solid particle content by mass concentration
Part 1 of the above mentioned norm defines purity classes with limits for:
Solid particles (class 0 to 7)
Humidity (class 0 to 6) resp. water content (class 7 to 9)
Oil content (class 0 to 4)
Beside technical requirements for compressed air purity as defined in ISO 8573, quality requirements can also
be derived from the European Pharmacopoeia. The monograph Medical air describes air which, e.g., is used for
artificial respiration of patients. This monograph contains, amongst others, limits for oil and water content. From a
pharmaceutical perspective, it seems to be acceptable that an air quality, which is used directly for patients, is
also adequate for medicinal products for non parenteral use.
The respective monograph of the European Pharmacopoeia does not define limits for particulate contamination.
Therefore, either the respective limits of the ISO 8573 or of the room air quality as defined in GMP guidelines (e.g.
grade D) can be applied.
Nitrogen, nitrogen with low oxygen content for inertization of medicinal products, oxygen, helium and carbon
dioxide are also monographed in the European Pharmacopoeia. Figure 3.H-2 summarizes the purity
requirements of the relevant Pharmacopeial Monographs.
Figure 3.H-2 Monographs of European Pharmacopoeia for process gases

Process gas
Nitrogen with low Medical Carbon
Requirement Nitrogen Oxygen Helium
oxygen content air dioxide
Content ≥99.5 % 20.4 % to ≥99.5% ≥99.5 % ≥99.5 %
21.4 % O2
CO ≤5 ppm ≤5 ppm ≤5 ppm ≤5 ppm - ≤5 ppm
NO/NO2 - - ≤2 ppm - - ≤2 ppm
Methane - - - - ≤ 50 -
ppm
SO2 - - ≤1 ppm - - ≤ 1 ppm
(Sulphur)
O2 ≤50 ppm ≤5 ppm - - ≤ 50 -
ppm
CO2 ≤300 ≤300 ppm ≤500 ppm ≤300 -
ppm ppm
H2 O ≤67 ppm ≤67 ppm ≤ 67 ppm ≤67 ppm ≤ 67 ≤67 ppm
ppm
Oil - - ≤0.1 mg/m3 - - -
Sum - < 0.5 % - - - -
Contaminants (Oxygen, Argon)
If not mentioned otherwise, all values are in volume percentage. Norms or purity statements from suppliers can
be used for other inert gases (e.g. Argon) or propane (e.g. German norm DIN 51622 for propane).
The US Food and Drug Administration guideline Sterile Drug Products Produced by Aseptic Processing requires
oil and water free compressed air to be used for these products. It should be taken into consideration that the
definition of free of water and oil depends on the analytical method used. Therefore, an absolute limit should be
defined for the oil and water content.
The particulate and microbial contamination should be in accordance with the clean room class in which the
compressed air is blown resp. exhausted. This requirement for particulate and microbial contamination is, as
already outlined before, commonly used in the pharmaceutical industry, also for non-sterile processes.
3.H.2 Generation, Storage and Distribution
3.H.2.1 Compressed Air
Normally, a compressor is used to generate the demand of compressed air. A compressor can be operated oil-
free or with oil. Bottled compresseded air is only used for less demands (e.g. for analytical purposes).
The compressor unit is generally connected to a buffer tank to guarantee sufficient compressed air supply also
for peak demands. If the compressed air pressure is below the minimal operating pressure of the process
equipment, correct functionality is not ensured. In general, this minimal pressure is monitored by the respective
process equipment. If the pressure falls below minimal pressure, an alarm should be generated.
After generation and buffering, compressed air passes through the filters. Particle filtration is in general sufficient
in case of oil-free generation. If oil is used in the compressor unit, an additional oil filtration is required. It should
be mentioned that compressors which use oil are not "state of the art" any longer for preparation of compressed
air for pharmaceutical use.
Compressed air is distributed to the consuming equipment via stub piping. It is common practice to install
different piping systems for different uses (pneumatic air, breathing air, air with direct resp. indirect product
contact). Additional filtration steps may be performed in the piping system to guarantee the required air quality for
the respective purpose.
3.H.2.2 Other Pharmaceutical Gases
Bottled pharmaceutical gases

Many pharmaceutical gases with low demand are delivered in bottles. These gas bottles can be stored
decentrally near the points of use (e.g. laboratories) or centrally in respective storage areas. In case of central
storage a respective distribution system comparable to compressed air has to be installed.
Pharmaceutical gases for liquid storage in tanks

In case of higher demands, e.g. nitrogen for purging or inertization of large volume parenterals or propane, used
for fusion of ampoules, gases are often stored in liquid form in insulated tanks.
Transport of the respective liquid gas and delivery has to be performed in compliance with GMP requirements.
Neither the delivery truck nor the filling of the storage tank should have a negative impact on quality. Docking
stations have to be constructed in a way to avoid contamination by external substances. Additional filtration steps
may be employed to ensure the required quality parameters.
Quality agreements have to be conducted with the suppliers. These quality agreements should comprise, besides
the required gas quality (specification), at least the following points:
Type of used road tanker inclusive materials allowed to be transported with these trucks. If
necessary, respective cleaning has to be defined.
Supply process, especially docking.
Adequate quality checks (e.g. documentation, identity, oxygen content) should be performed by
the pharmaceutical manufacturer before the start of filling to ensure that there is no negative impact if the
storage tank is not empty. It also has to be considered that emptying of such tanks is normally not easy
to perform in case quality problems are identified after filling. It is only allowed to start the filling process
after formal approval by the quality control/quality assurance unit.
3.H.2.3 Sterile gases

Sterile gases must be used for aseptic processes. It can be supplied via the general distribution system through
sterile filtration with hydrophobic filters (point of use filters). The subsequent distribution is performed in pipes that
can be sterilized. To ensure the sterilization of the filter and the pipe, the point-of-use-filtration should be
assigned to the subsequent equipment. The sterilization procedures should include integrity testing by a water
intrusion test (WIT).
The filtration at the point of use is also recommended for gases with direct or indirect product contact during the
production of non-sterile semisolid or liquid products. The particle content (viable and non-viable) can be reduced
significantly.
3.H.3 System design

The subsequent chapter focuses on GMP relevant requirements. It should be noted that further technical
requirements have to be considered (e.g. absence of oil and grease in pipes and instruments in case of oxygen
contact). Technical requirements can be found in respective norms like VDI 2083, part 10, clean room technology
- clean media (German bilingual technical standard).
GMP relevant design requirements are:
Installation of distribution systems

Materials of construction and finish
Selection of system components
Indication, controlling and recording of relevant parameters
Documentation and other requirements
Specific requirements for sterile gases
3.H.3.1 Installation of distribution systems

Generation and storage systems are usually located in technical areas. From there, gases are distributed via pipe
systems to the consumers. Users in clean rooms are supplied by stub lines connected with the piping system
from adjacent technical areas or from a suspended ceiling. The following points have to be considered:
Stub lines in clean rooms should be as short as possible

Pipes should be installed vertically (particle accumulation on horizontal pipes)
Break- through through clean room ceilings/walls/floors should be adequately sealed (stainless
steel collar with silicone seal)
Accessibility for cleaning should be possible
Pipes have to be adequately labeled (gas, flow direction)
3.H.3.2 Materials of construction and finish

Material requirements for generation, storage, and distribution of pharmaceutical gases are lower compared to
pharmaceutical water or clean steam systems, e.g. with regards to steel qualities. However, it has become
general pratice to have similar steel qualities like pharmaceutical water or steam systems at least downstream
after the final filtration step. The usage of copper pipes, commonly utilized in the past, cannot be considered
acceptable any more as it cannot be excluded that traces of copper could come into the subsequent process. As
copper serves as a catalyst for different processes, this could have a negative impact.
Specific requirements with regards to surface roughness are not necessary from a pharmaceutical perspective as
a forming of bio films in such systems is not likely due to the dryness of the air resp. gas.
The following technologies should be employed for the installation of distribution systems for pharmaceutical
gases:
Orbital resp. hand welding of pipes

Pipe connection via press-fitting
Under all circumstances particle/fibre shedding materials (seals and gaskets, filters) must be excluded.
3.H.3.3 Selection of system components

Adequate component construction has to be considered during component selection. This especially includes the
avoidance of points where particles could be accumulated. Vibrations could lead to a sudden release of particles
into the gas stream with a possible negative impact on products.
Additional pharmaceutical requirements for special system components are displayed in Figure 3.H-3.
Figure 3.H-3 Pharmaceutical requirements for system components
Pharmaceutical requirements for system components
Compressed air generator

Efficient air drying especially in case of high humidity outside air.
Adequate condensate drainage.
Distribution system
Use of defatted pipes (Note: Grease used during manufacturing process for
pipes produced by tension. This could result in exceeding limits for oil
contamination)
3.H.3.4 Indication, controlling and recording of relevant parameters

There are normally no quality relevant parameters to be permanently recorded in generation and distribution
systems. After initial qualification the regular monitoring of oil, particle, and water content is sufficient for
adequately planned and installed systems.
In case the gas pressure is relevant for operation of connected systems this should be controlled, alarmed, and, if
necessary, recorded by the respective control system of the equipment. The process gas system has only to
guarantee that the requested system pressure is maintained. This is a task for engineering.
Some companies permanently monitor the dew point to allow permanent control of humidity. But the
measurement of particulate and microbial gas contamination is of higher importance from a pharmaceutical
perspective.
3.H.3.5 Documentation and other requirements
Documentation
Adequate documentation is required for qualification and operation. This comprises amongst others:
Technical system documentation (e.g. P+I diagrams, electrical system documentation, list of
components, data sheets for components and measuring devices, spare parts list, list of software
structure, if applicable)
Material certificates, as required, and welding documentation, instructions resp. reports for
maintenance and calibration
Operating Instructions
System log books
Other requirements
Besides the above mentioned aspects an additional point has to be considered:
Quality assurance during installation
This includes a "clean" installation environment and closure of open ends during delivery, storage on site, and
installation.
3.H.3.6 Specific requirements for sterile gases

As the point of use, the sterile filter is frequently part of the distribution system. The following aspects, as
occasionally already mentioned before, must be taken into account:
Filter integrity test by water intrusion should be possible. Respective relevant adapters have to
be planned
Sterilization of the filter by clean steam should be possible
Filter must be dried after sterilization to avoid filter blocking
Procedure for maximal lifetime, service life and filter replacement must be prepared. Differential
pressure measurements can indicate the filter load and can provide guidance for the required filter
exchange
The sterile filter and the sterilization thereof should be regulated (SOPs) within the organization together with and
in terms of control installed in the respective equipment (together with the distribution system following the sterile
filter). A clear differentiation is established between the non-sterile process gas system and the sterile equipment
for validation and operation.
3.H.4 Qualification and monitoring

Main contents resp. tests to be performed during qualification phases DQ, IQ, and OQ are described in the
subsequent sections.
Design Qualification (DQ)

All relevant design specifications (User Requirement Specification, URS) have to be defined on the basis of a
GMP risk analysis and general GMP requirements. This URS is the basis for suppliers for quotation. During
supplier selection it must be guaranteed that these requirements are fulfilled and become part of the supplier
specification (e.g. Functional Design Specification, FDS). The compliance with the URS is formally checked
during Design Qualification.
Figure 3.H-4 shows exemplary a possibility for such a formal comparison.
Figure 3.H-4 Comparison between User Requirement Specification and Functional Design
Specification (Example)
Test point Chapter/ Fulfilled
Chapter/ Page URS Date / Sign
Reference to risk analysis Page FDS (yes/no)
Gas filtration Chapter 1.1
(Risk analysis, point 4) Page 8
Material requirements Chapter. 2.1
(Risk analysis, point 8) page 11
Relevant test points are mainly shown in chapter 3.H.3 System design.
Installation qualification (IQ)

Typical IQ-tests for pharmaceutical gases are given below:
Check of correct system installation against P+I-diagrams resp. isometrics

Check of correct and damage free installation of single system components against
o Component lists from Design Specification
o Component data sheets as well as installation instructions from component suppliers
Check of electrical installations against design specifications
Distribution system drain points and slope to drain points in case of sterilization
Check of system documentation, e.g.:
o Factory Acceptance Test (FAT) report including proof of remediation of defects
o Operating and maintenance instructions
o Availability of log books
o System description
o Material certificates incl. clear reference to the respective component
o Welding documentation, if available
Tests can occasionally be combined with safety aspects. As this is not GMP relevant, it is not mandatory.
Operational Qualification (OQ)

Typical test points for process gas systems are listed below. Tests have to be performed in comparison to the
functional descriptions of the supplier specifications.
Start up and shutdown procedure of generation system to assess system behavior

Alarm check to identify system failures
Correct parameters (temperature, pressure, time) during sterilization of filters for sterile gases
Initial measurement of microbial and particulate contamination at point of use to draw
conclusions for subsequent monitoring
Initial measurement of oil and water content at point of use
Check of calibration, if GMP relevant measuring points have been defined during risk analysis
The analytical method for determination of oil and water content is more or less expensive depending on the
respective limit. If limits are chosen from the European Monograph Medical air, measurement with adsorption
tubes and limit identification via colour indication is possible. Respective connection points including pressure
reducing device, if necessary, have to be planned. If lower limits are required more expensive measuring
systems have to be used (e.g. adsorption tube with subsequent gas chromatographic oil determination).
In any case, the used analytical methods have to be validated (supplier certificate) resp. described in
Pharmacopoeias or technical norms.
For the determination of microbial contamination by active air sampling, time and air volumes have to be
validated. It has to be considered that due to the use of dry gases an exsiccation of the growth medium with
negative influence on growth promotion is avoided.
Performance qualification (PQ)

The performance qualification (PQ) is the final step of qualification. The PQ for pharmaceutical gases is
performed for a longer period of time.
The PQ should prove that the systems are able to deliver the required quality at the points of use under the
defined operational parameters. Additionally, the process gases, especially compressed air, are tested together
with connected systems.
It is recommended to perform an intensive monitoring after the initial quality measurements during operational
qualification. Especially points of use with the longest distance to generation resp. storage tank should be taken
into consideration.
Possible monitoring principles are as follows:
Weekly measurement of oil, water, and particle content at each piping system for three months
Assessment of any failure during this time period
The required gas quality should be an acceptance criterion during PQ
After the performance qualification measures of preventive maintenance (e.g. exchange of filters), re-calibration
of measuring devices, and routine monitoring serve as permanent system control.
Monitoring and preventive maintenance

Routine monitoring has to be defined after successful finalization of performance qualification. Routine monitoring
should be based on the PQ, but can be performed with reduced frequency.
The following criteria should be considered:
Results of performance qualification

Usage of pharmaceutical gases
GMP relevant aspects besides technical topics have to be considered for preventive maintenance. Based on
quality considerations it may be, e.g. necessary to exchange filters more frequently than due to technical reasons.
Re-calibration frequencies of quality relevant measuring points have to be defined together with the quality
assurance organization.
Routine monitoring in combination with preventive maintenance and re-calibration serve as regular system
requalification.
Summary:
Quality requirements for process gases with direct or indirect product contact have to be defined
according to existing Pharmacopoeial monographs and technical standards.
Generation, storage, transport, and distribution systems have to be engineered in order to avoid any
negative influence on quality.
For sterile gases special consideration has to be taken for terminal sterile filters and the subsequent
distribution system.
Systems for generation, storage, and distribution of process gases with direct or indirect product contact
have to be adequately qualified: Sufficient quality monitoring has to be established for routine
operation.
3.I Qualification of premises and air-conditioning

systems
Author: Dr. Hans Schicht / Update08
Here you find answers to the following questions:

What is the objective of qualification of premises and air-conditioning systems?
What qualification stages are distinguished?
How are qualification master plans, qualification plans and qualification
reports for premises and air-conditioning systems being developed?
What regulatory and normative provisions are to be observed?
When is qualification required and when is a technical acceptance procedure
sufficient?
How can checklists for systematic handling of qualification activities be
compiled?
When is requalification of the air-conditioning system required?
3.I.1 Objectives of qualification

It is a requirement of Annex 15 to the EU GMP Guide that premises as well as equipment and utilities installed
there and devoted to manufacturing processes, which are of considerable relevance for the quality of medicinal
products, must be assessed for their suitability, i.e. be qualified (see chapter C.6.15 Annex 15 Qualification and
Validation).
The legislative and regulatory fundamentals of qualification, the documentation required, the responsible persons
and the procedures for performing it are discussed exhaustively in chapter 6 Qualification. That chapter is mainly
focusing on process equipment. The subsequent text will complement the matter discussed there from the
perspective of the qualification of premises and their infrastructure systems.
Elements of the infrastructure systems, also called utilities, are:
the HVAC systems (heating, ventilating and air-conditioning systems) with their measurement
and automatic control systems, including the eventual connection to a facility management system
(see chapter 3.G Heating Ventilation Air Conditioning (HVAC))
the process media systems (purified water, water for injection, process gases, compressed air
etc.), together with their measurement and automatic control systems (see chapter 5 Pharmaceutical
Water and chapter 3.H Process Gases)
the pharma monitoring system (see chapter 3.J Monitoring of HVAC systems)
the electrical installations (illumination, interlocking of doors, alarms etc.) (see chapter 3.F
Building services)
and many other elements.
Objective of the qualification of premises and building infrastructure systems is the systematic and documented
proof, based upon risk assessment, that they are adequate for the intended utilization, compliant with GMP
requirements and capable of meeting the specified performance criteria. Doing so, they contribute substantially
towards manufacturing the foreseen products safely and reproducibly in the specified quality.
In cases where toxic or highly active products are manufactured or processed, the objective of the qualification of
premises and utilities beyond these GMP aspects is to ensure the required protection against risks to persons, i.e.
to protect the persons involved in the manufacturing process and the environment of the facility against health
and contamination risks caused by such substances.
The extent of the qualification activities for rooms and building infrastructure systems depends on the purpose of
the production facility and on the room classes according to Annex 1 of the EU GMP Guide which may eventually
have to be met (see chapter 3.C Room classes and chapter C.6.1 Annex 1 Manufacture of Sterile Medicinal
Products).
An investment object will not only comprise systems requiring qualification, but also many others, whose
technically flawless operation must also be ensured and verified. In the case of a compressed air circuit
distinction is required between compressed air coming into contact with the product and compressed air for
technical purposes (see chapter 3.H Process Gases). The compressed air coming into contact with the product
presents a potential contamination risk to it. Therefore qualification is required here, in addition to the technical
acceptance tests. On the other hand, technical acceptance tests according to Good Engineering Practice are
sufficient for technical compressed air as it will not come into contact with the product anywhere. Qualification
and technical acceptance tests therefore are complementary. On drawings and functional diagrams the limits
between qualification and technical acceptance have to be clearly identified.
Premises and the utilities integrated into them are designed and built individually for each investment object.
From this individual character results an increased risk of deficiencies which have to identified and corrected in
time, so that they can't endanger the quality of the medicinal products manufactured therein.
3.I.2 Regulatory and normative fundamentals of qualification

The general regulatory base for the qualification of premises and their infrastructure systems in the
pharmaceutical industry is Annex 15 to the EU GMP Guide (chapter C.6.15), in the case of facilities for the
manufacture of sterile products also Annex 1 to that Guide (chapter C.6.1). For details regarding the air
cleanliness classification of the premises reference is made in Annex 1 to EN ISO 14644-1.
For air cleanliness measurement procedures as well as for all other physical metrology topics in contamination
controlled areas reference should be made to EN ISO 14644-3, where detailed guidance can be found regarding
the following physical measurement parameters important for qualification of pharmaceutical production facilities:
Airborne particle count

Air velocity and air flow rates
Air pressure difference tests
Installed filter system leakage test
Airflow direction test and visualization
Temperature and relative humidity of the room air
Sedimentation and deposition of particles
Recovery test
Containment leak test
Beyond this guidance regarding the execution of tests the minimum performance requirements for the
instrumentation are also specified in EN ISO 14644-3.
Alternative practice-oriented guidance for qualification measurements can be found in the guideline VDI 2083
Part 3 Metrology and test methods which however - as published prior to EN ISO 14644-3 - is not completely
harmonized with it.
Additional important guidance regarding qualification and the qualification parameters can be found in Annex C to
EN ISO 14644-4 and in Chapter 7 of VDI 2083 Part 4.1.
The complete literature references regarding the documents mentioned above are compiled in chapter 3.K
References.
3.I.3 Project development and qualification

Basis for the qualification of premises and utilities are the determinations given in Annex 15 to the EU GMP
Guide (see chapter C.6.15 Annex 15 Qualification and Validation).
Therein, four qualification stages are distinguished:
Design qualification (DQ)

Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)
Due to the project-specific design and realization of premises and their technical infrastructure there is
considerable risk for errors during the design phase, and important aspects may well be overlooked or decisions
deferred until it is too late. Such design deficiencies should be detected prior to realization and commissioning of
the investment object: corrections during the design and calculation stage are straightforward, fast and cost-
effective. Thus, thorough design qualification can contribute relevantly to reduce the risk of design deficiencies:
all the participants in project development are thus forced towards careful design and dimensioning. To discover
and correct shortcomings at a later stage, i.e. during construction and installation, will consume a lot of time and
money. Frequently, also conflicting requirements between different supplies will then impede an optimal solution.
Thus, design qualification is, beyond the GMP aspects, also a highly effective tool for controlling costs and
meeting deadlines.
After having taken the general decision for going ahead with an investment object, two stages of design
development are distinguished:
basic design as basis for the invitations for tendering for the different elements of the realization
of premises and utilities, and for the selection of suppliers
detail design subsequent to the decision process, as basis for the realization of the investment
object
In order to guarantee optimal design quality, it is advantageous to realize design qualification in two steps:
Design Qualification 1 (DQ 1) as documented proof that the concept specified as result of the
basic design for premises and utilities is suitable for the intended utilization, and that it complies with the
GMP determinations and the performance and quality criteria established in the specified standards and
guidelines and mature for the invitations for tendering to be emitted
Design Qualification 2 (DQ 2) as documented proof that the detail design meets the
requirements established in the basic design and that it is mature for realization.
3.I.4 Qualification Master Plan

It is good practice to elaborate a specific Qualification Master Plan (see also chapter 6.C.1 Qualification master
plan) as baseline for all qualification activities for premises and the building infrastructure. Among other things, it
is the appropriate instrument for clearly determining the delimitation between design elements requiring
qualification activities besides technical acceptance, and those, for which technical acceptance is sufficient. This
Qualification Master Plan is a sub-module to the Validation Master Plan required in Annex 15 to the EU GMP
Guide (chapter C.6.15 Annex 15 Qualification and Validation).
As far as the following items have not yet been specified in the Validation Master Plan, the Qualification Master
Plan for the premises and the utilities installed therein could cover the following topics:
Objective of the investment object and its localization on the company area or within a building
Company policy regarding product quality, qualification and process monitoring
Protection requirements of the project regarding product, process and personnel plus
determinations regarding the required room classes for air cleanliness
Applicable regulatory compendia, standards, guidelines and company-internal directives and
procedures
Definitions (if necessary)
Conclusions from risk assessment as basis for
o determination of the requirements regarding premises and utilities for ensuring product
quality
o determination of the scope of the qualification tests
Brief description of the contamination control system with emphasis upon its contributions for
enhancing process and product safety
Outline of the qualification concept including the delimitation between qualification and technical
acceptance tests
Time schedule, responsibilities and signature requirements
Identification of the qualification parameters and their acceptance limits
Outline of the process monitoring concept and identification of the parameters to be monitored
including alarm and action limits
Determinations regarding requalification (see chapter 6.H.4 Maintenance of the qualified status)
Determinations of the change control requirements and procedures (see chapter 19.C Change
control and chapter 6.H.4 Maintenance of the qualified status)
Determination of the structure of the qualification files and assignment of the responsibility for file
management
Under the item "regulatory compendia" of the Qualification Master Plan a determination is due whether in addition
to the EU GMP Guide also guidance documents from other authorities (e.g. FDA) require consideration.
Regarding change control, the Qualification Master Plan should establish, for example, the exact starting date.
As appropriate starting date, the conclusion of DQ 2 has proved to be practical, as design activities should then
have come to an end.
3.I.5 Qualification Plans and Qualification Reports

The detailed qualification activities to be performed are determined in Qualification Plans. Separate plans will
have to be prepared for premises and each utility system, one each for each qualification phase. Successful
conclusion of each qualification stage is then recorded, again separately for the premises and each utility system,
in a Qualification Report.
Qualification Plans and Qualification Reports should be structured identically, for instance as follows:
Objective of the specific qualification plan/report

Short description of the system to be qualified
Applicable regulatory guidance, normative and company-internal directives and procedures
Terms and abbreviations
A detailed compilation of the required checks and tests, in which each single item requiring
assessment is individually addressed, together with (where applicable) standardized measurement forms
complete with acceptance criteria
Formal requirements for drawings and functional diagrams
Signature lists
Assignment of responsibilities
For further details regarding the Qualification Plan including examples see chapter 6.C.2 Qualification plan.
The Qualification Report will summarize the results of all checks and tests in detail, followed by the concise
statement "passed/not passed". Core element of the Qualification Report are the fully completed checklists of the
Qualification Plan (see chapter 3.I.6 Qualification checklists); supplementary information may be added to them.
Eventual omissions, deficiencies, missing data and gaps identified during the qualification stage under
consideration may be condensed into a list of actions. Only when all pending items have been successfully
concluded, the qualification stage can be considered as terminated.
For additional information regarding the Qualification Report see chapter 6.C.3 Qualification report.
3.I.6 Qualification checklists

Basis for all qualification activities are the following documents:
Qualification Plans
Qualification Reports
Updated layout and sectional drawings together with the corresponding cleanliness zoning and
pressurization schemes
For the realization of qualification activities detailed checklists are very helpful: they permit systematic and
comprehensive execution of all necessary tasks. It is recommended to incorporate such checklists into the
respective qualification plans and reports. The first set of the detailed sample checklists compiled below
comprises the qualification tasks required for the qualification stages DQ to OQ, and are devoted to the
topics premises and HVAC systems. After successful termination of the OQ exercise the responsibility for the
investment object will pass from the designer/contractor team to the buyer/operator. The operator will then be
responsible for the performance qualification PQ. In order to incorporate as many specific subject items into
these sample checklists, a technically complex investment object has been selected as base, i.e. a facility for
aseptic filling of liquid parenterals. In the case of technically less ambitious investment objects the checklists can
and should be simplified.
Items subject to technical acceptance procedures have not been incorporated into the checklists. Chillers, for
example, supplying the air coolers of the HVAC system with cold water are therefore not included in the
checklists. Subject to qualification here, and at the same time the qualification limit, will be the control valve
feeding the cold water into the air cooler.
3.I.6.1 Design Qualification 1 and 2 (DQ 1 and 2)

DQ 1 is required for all documents developed during basic design relevant for the invitations for tendering, e.g.
those regarding premises and the HVAC system. The compilation in Figure 3.I-1 does not claim to be exhaustive,
on the other hand, not all items listed may be needed in case of a less exacting investment object. The column
o.k. yes/no will state whether a document has been accepted or not. A "no" requires inclusion of the respective
item in a list of actions. Only after conversion of all "no" answers into a "yes", the qualification stage can be
considered as terminated.
Figure 3.I-1 DQ 1 checklist for premises and HVAC system

Document
no., o.k.
Document identification Date Signature
revision, yes/no
date
Premises
DQ 1 plan, premises
Description of the basic design
Layout and sectional drawings including reserve spaces
Area utilization concept
Cleanliness zoning concept
Pressurization concept
Design base and requirement profiles for realization of the
construction work
Enclosure: risk report
Realization concept
Specification of the wall and ceiling system complete with cut-
outs, wall/ceiling/floor penetrations, reinforcements etc.
Specification for the air-lock control system
Specification for wall/floor and wall/wall connections
Specification for flooring including electrical resistance
requirements
Enclosure leakage: determination of limit values
GMP conformity statement regarding relevant specifications,
especially:
Wall and ceiling elements incl. doors,
windows, etc.
Air-lock door control system
Furniture and material pass-throughs
Floors, walls, ceilings, as well as furniture
easy to clean and disinfect
Compatibility of floor/wall/ceiling materials
and furniture with cleaning and disinfection fluids
Sealing concept of ceiling panels
Piping, cables and their floor/wall/ceiling
penetrations
Prevention scheme for backflow in sinks and
drains
Design concept of personnel and material
airlocks
Room program and room book
Illumination concept
HVAC system
DQ 1 plan, HVAC system

Basic specification of general requirements (calculation concept,
performance requirements)
Functional diagram of HVAC system
Description of HVAC system including operating and monitoring
concept
HVAC system: risk report
Cooling load calculations with resulting air flow rates/air change
rates
Redundancies, e.g. double fans (eventually with list of additional,
so far unapproved proposals)
Provisional layout of machine room for air handling units and
other technical equipment
Provisional layout for supply air, return air, extract air ducts
including eventual connections to isolators, RABS units, safety
work stations, material pass-throughs etc.)
Provisional layout of work areas with unidirectional airflow (if
integrated into the HVAC system)
Specification of air handling units (including reserve
requirements)
Specification of ductwork including maximum permitted leakage
rates
Specification of components such as
Constant and variable airflow control valves
Filter housings and fan-filter-units (FFU's)
Air filters including HEPA filters
Motorized and manually operated dampers
Fire dampers
Outside air dampers
Supply air diffusers and return air capture
elements
Others
GMP conformity of the specifications for
Room pressurization scheme
HVAC system concept
Air flow rates sufficient for meeting recovery
test requirements and microbial limit values (where
applicable)
Airflow pattern requirements
Alarm functions
Pharma monitoring concept
Functional diagram and specification for automatic control
system
Functional diagram and specification of pharma monitoring
system
All qualification-relevant documents serving as base for the realization of the investment object have to be
submitted to DQ 2.
The compilation shown in Figure 3.I-2 does not claim completeness.
Figure 3.I-2 DQ 2 checklist for premises and HVAC systems

Document
no., o.k.
revision, yes/no
date
Premises
Qualification report DQ 1, premises

DQ 2 plan, premises
Layout plans and sectional drawings (updated)
Cleanliness zoning concept (updated)
Pressurization concept (updated)
Enclosure risk report (only if updating is necessary)
Wall and ceiling system complete with cut-outs, wall/ceiling/floor
penetrations, reinforcements etc.:
Approved specification
Installation drawings
Certificates (e.g. fire resistance)
Air-lock door control system:
Approved specification
Enclosure leakage:
Confirmed limits
Description of measurement procedure
Flooring:
Approved specification including electrical
resistance
Installation description
Supplier statement regarding compatibility
with cleaning and disinfection products and
procedures and with other relevant chemicals
Maintenance and repair instructions
Certificates (e.g. fire resistance)
Floor/wall/ceiling penetrations of piping, cables etc.
Detail design
Statement regarding cleanroom compatibility
and leaktight design
Connections to adjacent sectors of the facility (e.g. to existing
walls):
Design concept
Lighting: installation drawings
Logbook for change control, premises (if not supplied by user)
Change proposal, approval and assessment form (if not supplied
by user)
GMP conformity statement regarding detail design, especially for:
Facility layout with corridors, doors,
windows, transfer hatches etc.
Furniture as ordered
Compatibility of room enclosure with
cleaning and disinfection materials and procedures:
supplier statements
Sealing of ceiling panels: detail design
Floor/wall/ceiling penetrations for piping,
cables etc.: detail design
Prevention of backflow in sinks and drains:
detail design
Door control system for personnel and
material airlocks: detail design
HVAC system
Qualification report DQ 1, HVAC system

DQ 2 plan, HVAC system
Updated functional diagram of air circulation system, complete
with identification and positioning of control dampers, positioning
of sensors, etc.
Updated system description including operation and monitoring
concept
HVAC system risk report (only if updating was necessary)
Confirmation by contractor of correctness of cooling load
calculations
Detailed layout of machine room for air handling units and
associated equipment
Ducts (supply, return, extract air):
Detailed arrangement drawings
Specification and drawings regarding thermal
insulation where required
Details of duct connections to isolators, RABS
units, safety work stations, material pass-throughs,
location of sensors plus aerosol injection points for
the installed filter leak test
Updated layout plans and installation drawings for work areas
with unidirectional airflow (if integrated into the HVAC system)
Air handling units: complete documentation with installation
drawings, component lists and technical data
Supplier documentation with technical data and component lists
for:
Volume flow valves (constant and variable)
Fire dampers
Outside air dampers
elements
Others
Specification for air duct cleaning after installation and before
commissioning
Updated description of the pharma monitoring strategy
Updated functional diagram of the pharma monitoring system
plus material specifications and wiring diagrams
Updated description of the automatic control system including,
where applicable, its incorporation into the building management
system
Updated functional diagram of the automatic control system plus
material specifications and wiring diagrams
Deviations from suppliers specified in the invitations for
tendering
Standard operation procedure for testing air handling units and
ductwork for airtightness
Calibration plans for measuring instruments
Logbook for change control, HVAC system (if not supplied by
user)
Change proposal, approval and assessment form (if not supplied
by user)
Competence and training certificates
Project and qualification manager for

Facility
HVAC system
Supervisor for
Civil construction work
Wall and ceiling system installation
Floor system installation
HVAC system installation
3.I.6.2 Installation Qualification (IQ)

Sophisticated equipment, such as isolators and barrier systems according to the RABS principles (see Chapter
3.E Barrier systems and isolators) will require, before proceeding to the jobsite, a Factory Acceptance
Test (FAT). For the key components destined for the premises such as wall, ceiling and flooring systems as well
as those for the HVAC system, Factory Acceptance Tests are, as a rule, not necessary. After termination of the
installation work and prior to commissioning, the time has come for Installation Qualification IQ.
Objective of IQ is documented proof that the realization of the investment object has been done in conformity with
the determinations established in the detail design, which had been DQ 2 approved. At that stage, checks are
also due for verifying that all project changes authorized by means of the change control procedure have been
duly realized as specified and documented accordingly.
Figure 3.I-3 summarizes the documents to be submitted and approved during IQ.
Figure 3.I-3 IQ checklist for premises and HVAC systems

Document
no., o.k.
revision, yes/no
date
Premises
Qualification report DQ 2, premises

IQ plan, premises
Area delimitation to surrounding building areas correctly
signposted and labelled
Access control operational as specified
Revision drawings for wall and ceiling systems updated and
corresponding with reality
Statement that the revision drawings incorporate all changes
authorized through the change control procedure
Statement that all interfaces with other supply areas have been
duly assessed and that there are no remaining pending items
Statement that all connections to adjacent facility sectors (e.g. to
existing walls) have been executed correctly and are correctly
shown in the revision drawings
Statement that the airlock control systems has been installed
correctly and tested (including alarm and emergency functions)
Statement that the floors have been installed and documented
correctly as specified
Statement, complete with test report, that the electrical resistance
of the floor is within specification
Rooms correctly labelled
Statement that the rooms have been built, equipped and furnished
according to the requirements of the room program and, where
applicable, room book
Statement, complete with test report, that the enclosure leakage
test has been successfully passed
Pipe and cable penetrations through walls/ceilings/floors executed
as specified and airtight
GMP conformity assessed of installed
Walls with doors, windows etc. including
sealing
Correct function of the door control system
of personnel and material airlocks (incl. emergency
functions)
Furniture and wall-integrated elements (e.g.
pass-throughs)
Ceilings (especially airtightness)
Correct installation of piping and cables and
airtightness of their floor/wall/ceiling penetrations
Prevention of backflow in sinks and drains
(where permitted) successfully checked
Change control logbook correctly filled-in, complete and up-to-
date including IQ
Change control forms correctly filled in, complete and up-to-date
up to IQ status
Changes according to change control system correctly realized
and those requiring qualification completely qualified up to IQ
status
HVAC system
Qualification report DQ 2, HVAC system

IQ plan, HVAC system
Functional diagram updated and corresponding with "as built"
status
Revision drawings of the HVAC system corresponding with the
"as built" status
All components installed and functional (checked by means of
functional diagram and component lists):
Constant and variable air volume flow valves
Fire dampers
Outside air dampers
elements
Others
Labelling of air handling units correct and complete
Copy of "as built" functional diagram of HVAC system attached
to air handling unit in prominent position
Flow direction and character of air (e.g. outside air, supply air)
correctly and well visibly marked on air ducts
Air duct insulation, where required, in place and undamaged
Leakage test of air handling units and air ducts successfully
performed and documented
Air handling units and air ducts correctly cleaned
Operation and maintenance manuals provided, complete and
approved
Maintenance plan complete and approved
Spare parts list provided, complete and approved
Initial spare parts stock purchased and stored
Standard operational procedures for OQ measurements available,
complete and approved, e.g. for
Installed filter leak test
Pressure differences
Room air classification
Air flow rates
Air velocities (areas with unidirectional
airflow only)
Air flow visualization
Recovery time (if required)
Room air temperature and relative humidity
Noise level
Interfaces to other utility installations without conflicts and
without pending items
Correct availability of media required for operating the HVAC
system (chilled water, cooling water, warm water, technical
compressed air etc.)
Pharma monitoring system: statement regarding completeness,
correct installation and functionality
Automatic control system: statement regarding completeness,
correct installation and functionality plus, where applicable,
statement of connection to the building automation system
Measurement instrumentation correctly installed and calibrated
according to calibration plan
Calibration certificates and protocols in accordance with
specification and complete
Training manuals for operational personnel prepared and
complete
date including IQ
Change control forms correctly filled-in, complete and up-to-date
up to IQ status
Changes requiring qualification correctly realized and qualified
up to IQ status
Certificates (incl. personnel training)
Competence and training certificates for:

Commissioning personnel
Qualification managers for facility and HVAC
system
Qualification measurement team
Maintenance personnel successfully trained
Valid factory test certificates for HEPA filters
Calibration certificates for instruments (where required)
Conformity declarations
3.I.6.3 Operational Qualification (OQ)

After terminating IQ, the HVAC system can be commissioned and the room-specific air flow rates can be
adjusted to the specified levels. Following technical acceptance, OQ is performed as final proof that rooms and
their infrastructural services are mature and fit for handing over to the purchaser and user.
The objective of OQ is to prove that premises and the utilities installed therein meet the specified requirements.
The many single elements for proving this are compiled in Figure 3.I-4. In order not to impair the commissioning
of the process equipment, single OQ steps for the premises can be tackled already during the IQ stage. This is
particularly indicated for the balancing of the air flow rates and for the installed filter leak test for the terminal
HEPA filters. Changing damaged HEPA filters at a later point in time might prejudice the OQ of the process
equipment.
Figure 3.I-4 OQ checklist for premises and HVAC systems

Document
no., o.k.
revision, yes/no
date
Premises
Qualification report IQ, premises

OQ plan, premises
Access control operating successfully
Airlocks completely furnished according to specification
Airlock control system successfully tested including alarms and
emergency functions
Rooms completely furnished
Pictograms regarding standard operational procedures (e.g.
garmenting, hand washing and disinfection procedures) in place
and correctly positioned
Room lighting after furnishing and installation of process
equipment in agreement with specifications
Simulation of an electrical blackout: Required functions
regarding emergency lighting, emergency power (if required),
uninterrupted electricity supply successfully tested and
documented
date until OQ status and readiness for transfer of ownership
Change control forms correctly filled-in, complete, and up-to-date
until OQ status and readiness for transfer of ownership
and those requiring qualification completely qualified until OQ
status and readiness for transfer of ownership
Standard operational procedures for microbiological surface
measurements including sampling plans completed and approved
(if required)
Room cleaning and, where required, room disinfection before
transfer of ownership successfully completed
Room surface cleanliness (particles, microorganisms) according
to specifications
Qualification report, OQ for premises
Qualification documentation for premises (DQ 1 through OQ)
complete and ready for transfer of ownership
Transfer of ownership documentation for premises complete and
ready for signature
HVAC system
Qualification report IQ, HVAC system

OQ plan, HVAC system
Reserve capacities of air handling units tested for compliance
with specification
Room specific air flow rates/air change rates correctly adjusted
and in conformity with specifications
Qualification measurements in the "at rest" occupancy state
successfully performed and documented:
Pressure differences across HEPA filters
Installed filter leak test (HEPA filters only)
Room pressurization during normal and
reduced operation (where specified)
Room air cleanliness classification "at rest"
Air flow rates during normal and reduced
operation (where specified)
Air velocity (only areas with unidirectional
airflow)
Air flow visualization (only areas with
unidirectional airflow)
Recovery test where required
Room air temperature and relative humidity
(for specified outside air summer and winter
conditions)
Noise level in specified working rooms
Worst case situations for air handling systems completely and
successfully checked
Simulation of an electrical blackout: Specified HVAC emergency
operation successfully tested
Test certificate confirming correct functioning of pharma
monitoring system including alarm and safety functions
Test certificate confirming correct function of automatic control
and, where applicable, its connection to the building management
system including alarm and emergency functions
date to OQ status and readiness for transfer of ownership
Change control forms correctly filled-in, complete, and up-to-date
until OQ status and readiness for transfer of ownership
and those requiring qualification completely qualified up to and
including OQ status and readiness for transfer of ownership
Standard operational procedures for microbiological air
measurements including sampling plans completed and approved
(if applicable)
Qualification report, OQ for HVAC system
Proposal for PQ plan, HVAC system (if required)
Qualification documentation of the HVAC system (DQ 1 through
OQ) complete and ready for transfer of ownership
Transfer of ownership documentation for HVAC system
complete and ready for signature
Certificates (incl. personnel training)
Valid calibration certificates for:

Optical particle counters
Aerosol generators and dilution devices
Other measurement instruments requiring
periodical recalibration
Valid factory certificates for:
Spare HEPA filters
Other spare parts requiring certificates
Training of newly contracted maintenance personnel successfully
completed
3.I.6.4 Performance Qualification (PQ)

Performance qualification PQ is documented proof that premises and utilities, in harmony with the production
equipment, are suitable for manufacturing the product in the specified quality. Performance qualification is the
responsibility of the user of the facility and is initiated immediately after the transfer of facility ownership from the
contractor to the user.
Regarding premises and the infrastructure systems installed therein, not many surprises are to be expected at
that point in time. During operational qualification, air cleanliness measurements have been performed in the "at
rest" occupancy state. During performance qualification, they are repeated in the "in operation" occupancy state,
i.e. with the numbers of persons present as foreseen for normal production.
During PQ, the infrastructure systems and the process equipment operate, for the first time, as an integrated
entity. For the first time, all machinery and other elements contributing to the heat load are now active in parallel.
Therefore, only now it is possible to assess whether the HVAC system is capable of meeting its performance
requirements at the extreme thermal load conditions regarding air temperature and air relative humidity specified
for summer and winter as calculation base for dimensioning.
In addition, during performance qualification the human being is present for the first time in the facility in his
condition as dissemination source for microorganisms. Now, for the first time, is it possible to assess - where this
is relevant -whether the limits established for microbiological monitoring are met. For sterile manufacturing, they
are stipulated in Annex 1 to the EU GMP Guide (see chapter 3.C.2 GMP Requirements for Cleanrooms:
Air Cleanliness Grades). In all other cases where microbiological risks have to be taken into consideration, they
have to be specified case-specifically upon risk assessment considerations.
A selection of suggested PQ checks and tests are compiled in Figure 3.I-5.
Figure 3.I-5 Checklist for performance qualification (HVAC related topics only)
Document
no., o.k.
revision, yes/no
date
PQ plan, production system including utilities (HVAC related
topics only)
Room air temperature and relative humidity at full heat load
(including full operation of process equipment) for specified
limits, per room:
Summer
Winter
Room-specific air cleanliness classification in the occupancy
state "in operation"
in agreement with specified limits
performed with calibrated instruments (with
calibration certificates attached to test report)
Microbiological tests (if required) regarding
Airborne microorganisms
Microbial sedimentation
Surface cleanliness
Glove test (5 fingers)
successfully passed
Air flow pattern visualization (where required), e.g.
Unloading areas of autoclaves into room
areas with unidirectional airflow
Transfer belts penetrating walls
Worst case situations regarding the interactions between
infrastructure and production systems simulated completely and
successfully
Media fill successfully performed
Production operators successfully trained and qualified, e.g.
regarding
Garmenting procedures
Operation of equipment (contamination
control aspects)
Emergency actions
Performing the media fill
As now the manufacturing process and everything related to it is considered as an entity and as all interferences
between the different elements of the premises, equipment, the HVAC system, process media and the human
being are now fully active, no longer a distinction is made in this table between the different infrastructure
systems now acting together.
3.I.7 Requirements for measurement and test reports

During qualification activities numerous measurements and tests are necessary which must be documented
adequately. Basic requirement in preparing measurement and test reports is that they are capable of showing
who has tested

what
when
how and with what instrumentation
and with which results.
For that reason, test and measurement reports and the forms used for data registration must contain at least the
information compiled in Figure 3.I-6.
Figure 3.I-6 Documentation of test results

Necessary statements to be incorporated into test reports
Name and address of organization contracted for the measurement and test
task
Identification of the test object
Identification of the sampling locations (room identification and coordinates of
the sampling positions)
Identification of the measurement instrumentation (manufacturer, type,
identification no.)
Identification of the standards and guidelines in compliance of which
measurements are performed
Specified limits with tolerance band and - in air cleanliness measurements -
indication of the occupancy state of the room
Measured values (raw data and subsequent calculations where necessary)
Yes/no statement whether specified limits have been met
Other information and data if necessary
Name and signature of person in charge of measurement plus date of
measurement
Name and signature of author of the test report (if not identical with the
person performing the measurement) plus date of emission of the report
Copies of the valid calibration certificates and, where required, original measurement strips (e.g. of particle
measurements), duly identified, have to be added to the report.
3.I.8 Requalification
In periodical intervals the entire production process is to be submitted to a revalidation procedure. This also
implies in requalification of the HVAC systems. For requalifications of cleanroom systems, ISO 14644-2 is the
appropriate base. Therein, two situations are distinguished:
periodical requalification, normally performed once a year in the case of pharmaceutical

cleanroom systems
extraordinary requalification
Extraordinary requalification is performed after
completion of remedial action implemented to rectify an out-of-compliance condition

a significant change from the current performance specification, such as a change in operational
use
any significant interruption of air movement which affects the operation of the installation
special maintenance which significantly affects the operation of the installation (e.g. change of
final filters)
According to ISO 14644-2 requalification should at least comprise:
confirmation of the air cleanliness class (or room grade)

air pressure difference between rooms
airflow velocity (in the case of unidirectional airflow) or air flow rate (in the case of turbulent
airflow)
Requalifications are, as far as physical parameters are concerned, normally performed in the "at rest" occupancy
state, and they are frequently contracted out to company-external specialized firms. Performing the tests in the
"at rest" occupancy state also permits evaluation of the physical performance parameters with greater precision -
without influence of the human being as disturbance factor.
For HVAC systems having to meet the FDA requirements for aseptic manufacturing, the installed filter leak
test has to be performed twice a year. Such a test should however be incorporated into the requalification
program for each HVAC system protecting sterile manufacturing operations - even if no FDA requirement has to
be met.
In addition to the aforementioned tests ISO 14644-2 identifies the following optional test parameters:
containment leakage
airflow visualization
recovery
Eventual further parameters for requalification tests may be added on a case-by-case basis, if risk assessments
or special protection schemes (e.g. isolator technology) suggest this.
During periodical requalification, the microbiological status of air and surfaces should be checked where
necessary in addition to the measurement of physical data - in that case, of course, in the occupancy state "in
operation" and with personnel present as specified. The objective is to confirm that the limits established for
microbiological monitoring as stipulated in Annex 1 to the EU GMP Guide continue to be met (see chapter 3.C.2
GMP Requirements for Cleanrooms: Air Cleanliness Grades, Figure 3.C-2).
The opportunity to incorporate a thorough trend analysis into the requalification program should not be missed.
For this, not only the data of previous qualifications and requalifications should be taken into consideration, but
also the data from process monitoring (see chapter 3.J Monitoring of HVAC systems). Conclusions resulting from
trend analysis are an effective point of departure for improving systems and their performance.
Summary:
Premises and the utilities serving them - of which the HVAC system is an important element - require
qualification if they are of considerable relevance for product quality.
Qualification should be concentrated upon the aspects relevant for product and personnel safety. For all
other aspects and parameters necessary for the correct operation of premises and their HVAC systems,
technical acceptance tests are sufficient.
Point of departure for complex qualification tasks is a Qualification Master Plan establishing the basic
requirements to be met by the detailed qualification plans for premises and the utilities installed therein.
Four subsequent qualification stages are distinguished. Successful completion of each qualification
stage is documented by means of a qualification report. The extent of the qualification activities
depends on the complexity of the investment project and on the product requirements, for example,
regarding air cleanliness. Detailed checklists are a powerful tool for establishing the exact extent of
qualification activities.
In order to ensure and document continued compliance with the capabilities and performance levels
demonstrated during initial qualification, HVAC systems subject to qualification require periodical
requalification, where physical parameters and, where necessary, also microbiological parameters are to
be verified. It is recommended to include a trend analysis exercise into the requalification activities.
3.J Monitoring of HVAC systems

Here you find answers for the following questions:

What is the purpose of the pharma monitoring of HVAC systems?
What distinguishes pharma monitoring systems from the automatic control
systems of HVAC systems?
Which physical and microbiological parameters require monitoring?
What is the objective of alert and action limits?
3.J.1 Objectives of process monitoring
In the context of monitoring pharmaceutical production processes, i.e. the collection and recording of production-
relevant data, the collection, recording and storage of data regarding air cleanliness and other parameters related
to the air in production rooms is frequently required.
Distinction must be made between
data relevant for product quality and safety which require incorporation into the batch
documentation
data whose measurement and compilation is necessary for maintaining the correct function of
the HVAC system
Data important for product quality and safety must be collected, processed, recorded and stored in the pharma
monitoring system of the HVAC system, which is an integrated element of the general pharma monitoring
system of the production process. On the other hand: collection, processing, recording and storage of technical
data relevant for the correct and stable operation of the HVAC system is the responsibility of that
system's automatic control systemwhich frequently is integrated into the general building management system of
a facility.
3.J.2 Data management stipulations

Data proving the correct and stable operation of the HVAC system are an essential element of quality assurance
in the context of manufacturing sterile and other sophisticated pharmaceutical products. As a consequence, such
data become an integral part of the batch documentation. Which data require collection and recording, and to
what extent, must be decided case-specifically for each production task. Computerized systems are employed
for continuous or at least frequent collection, processing and storage of data. Such computerized systems are
required to meet the regulatory requirements stipulated in Annex 11 to the EU GMP Guide (see chapter C.6.11)
and in the respective FDA determinations (chapter D.1.3).
Computerized systems of this kind require validation (see chapter 9 Computer Validation). The most appropriate
base for doing so is the exhaustive GAMP 5 Guideline edited by ISPE, the International Society for
Pharmaceutical Engineering. The regulatory authorities of Europe and the USA have contributed substantially to
the preparation of this guideline.
Core elements of computerized data protection schemes are:
Only authorized persons must be capable of entering data into the system and for changing them
Unauthorized persons must not be able to enter into the system
Data must be protected against accidental or willful damage and against loss
Data storage must meet stringent safety criteria
Records and signatures must be safeguarded against falsification
Access to data must be assured for a long period of time: at least well beyond the expiry date of the product. In
many nations also legislative requirements for data storage must be observed.
Automatic control systems of HVAC systems and the superior building management systems are, as a rule, not
capable of being validated - due to their extensive ramifications throughout the entire building complex of a site.
Therefore, it is imperative that data management for process monitoring purposes be completely independent
from the building control system: it must be impossible for the building control system to interfere into process
monitoring. Persons authorized for interference into the building control system will, as a rule, not have access to
the pharma monitoring system.
Buildings and their HVAC systems employed, for example, for the manufacture of sterile products, will require
monitoring of both physical and microbiological parameters. At today's state-of-the-art only physical
measurement parameters permit data collection, recording, evaluation and long-time storage by means of
automatic computerized systems. Only computerized systems are capable of generating and recording automatic
alarms.
Where the continuous collection of measurement data makes little sense or where this is impossible due to
fundamental reasons - as, for example, data collection with present-day microbiological procedures -
measurements may be performed and recorded manually. A physical parameter for which manual measurement
is indicated is surveillance of the pressure difference between the upstream and the downstream side of HEPA
filters. Here quarterly, half-yearly and even annual data recording is sufficient.
Measurement instruments utilized in the context of pharmaceutical process monitoring for data collection of
physical and microbiological parameters must be recalibrated in periodical intervals, independently whether they
are incorporated into computerized monitoring systems or serving for periodical manual measurements. The
interval between recalibrations is normally one year.
3.J.3 Air cleanliness and other room air data

In the following only parameters shall be discussed which are of general relevance in the context of pharma
monitoring of HVAC systems.
Figure 3.J-1 Data types for pharma monitoring

Data type 1 Data type 2
Recording continuous or frequent periodical
frequency
Recording automatic manually
procedure
Examples Maintenance of positive or Particle concentrations
negative pressure in grade C and D areas
Temperature and relative Pressure difference
humidity of air across HEPA filters
Particle concentrations in
grade A and B areas
Besides the data type 2 physical parameters identified in Figure 3.J-1 all microbiological measurement
parameters are subject to periodical measurement and assessment. Such microbiological parameters are
particularly important in the context of process control of sterile processing operations, however there are cases
even in non-sterile production where such data should be collected and stored.
Regarding microbiological monitoring of sterile manufacturing operations, differences exist between European
and US requirements: In its Guidance for Industry on Sterile Drug Products Produced by Aseptic Processing,
FDA requires only the active sampling of airborne microorganisms, complemented by measurement of microbial
sedimentation as an optional test (see chapter 3.C.2 GMP Requirements for Cleanrooms: Air Cleanliness
Grades). Annex 1 to the EU GMP Guide, on the other hand, includes the sedimentation test into the specified
monitoring parameters, and also requires surface cleanliness tests of critical processing areas as well as the
testing of sterile gloves if they serve for interference into Grade A areas (see Figure 3.C-2). The numerical limits
in the FDA Guidance for Industry are not identical with those in the European GMP Guide. The frequency of
microbiological sampling should be determined according to the level of risk and can vary from more than once
per batch or shift to once every three months or every half year. The topic of microbiological monitoring is
discussed in detail in chapter 11.E Environmental monitoring.
3.J.4 Risks of microbiological monitoring

At today's state-of-the-art microbiological sampling is predominantly performed manually and with procedures
which, strictly speaking, cannot be considered as sterile. As a consequence, such sampling procedures have to
be ranked as process risks! This problem merits attention above all in the context of the new advanced
processing technologies with enhanced sterility assurance levels such as isolator or RABS technology
(see chapter 3.E Barrier systems and isolators).
The topic of microbiological sampling as a process risk is only addressed summarily in Annex 1 of the EU GMP
Guide: with a brief statement that sampling methods used in operation should not interfere with zone protection
(see chapter C.6.1 Annex 1 Manufacture of Sterile Medicinal Products). This issue is, however, addressed more
extensively in the monograph <1116> of the U.S. Pharmacopeia. Here, it is recommended to balance the
frequency of environmental microbiological sampling with the benefits accrued by the results of such monitoring
and to give preference to methods which avoid interference into the process by persons.
Once comprehensive qualification and validation have established the effectiveness of the protection concept in
controlling the microbiological risks, for example in the case of ultra-high safety protection concepts (e.g. isolator
or RABS technology), then a comparatively low frequency of sampling for routine process monitoring can be
adopted. This frequency must, of course, under all circumstances match the batch documentation requirements.
This shift of the determination of the Sterility Assurance Level from monitoring to the upstream qualification and
validation activities is another argument in favour of comprehensive qualification and validation efforts.
3.J.5 Alarm and action limits

In order to ensure early warning against any problems developing during the operation of the HVAC systems,
other utilities and the processing equipment, alarm and action limits (see Figure 3.J-2) should be determined for
the key parameters requiring monitoring. Alerting thus, by means of a two-step approach, to developing
excursions of monitoring data also provides a sound and objective input for trend analyses of process and
cleanroom performance (see alsochapter 11.E.3 Establishment of limits and frequencies).
Figure 3.J-2 Two-step approach alerting to excursions of monitoring data

Two-step approach alerting to excursions of monitoring data
Alert A predetermined value somewhat outside the normally expected tolerance band. If exceeded,
limit intensified supervision according to a pre-determined plan should be triggered.
Action A predetermined value substantially outside the normal tolerance band. If exceeded,
limit immediate formal action according to a predetermined plan specifying the necessary
investigative and corrective actions is to be triggered.
How to establish alert and action limits? Taking the room temperature as example, the following limits could be
selected:
Set point: 22 °C
Control tolerance: 22 °C ± 2 K
Alarm limit: 22 °C ± 4 K
Action limit: 22 °C ± 6 K
Alarms due to exceeding the alarm and action limits of control parameters should be transmitted to the
computerized pharma monitoring system and registered there inextinguishably. Alarms are to be triggered both
for exceeding the alarm and action limits. In addition to these alarms alerting to serious excursions of control
parameters also alarms triggered by incidents like airlock doors being kept open for too long should be
incorporated into the automatic alarm module of the pharma monitoring system.
3.J.6 Operation and maintenance

In order to avoid the infiltration of false air into contamination controlled facilities or premises, the corresponding
HVAC systems should run continuously. This is an absolute must for premises where specified air cleanliness
classes or room grades require to be met. However, it is well feasible to reduce the air flow rate of the HVAC
system outside production hours, for example, in facilities with single-shift utilization. Such a reduction is a potent
saver in energy costs and therefore merits serious consideration in the determination of the operational strategy
for the HVAC system.
Of course, the predetermined pressure differences between rooms as well as the air cleanliness class and air
flow patterns stipulated for the at rest occupancy state must be maintained uninterruptedly during system
operation with reduced air flow rate.
Important guidance for operation and maintenance of pharmaceutical cleanroom systems can be found in the
international standard ISO 14644-5 and in the German guideline VDI 2083 Part 5.1 complementing the ISO
determinations.
Summary:
The purpose of pharma monitoring of the HVAC system is collection, evaluation, recording and long-
time storage of data relevant for the quality of medicinal products. Such data frequently will have to be
incorporated into their batch documentation.
Physical data requiring continuous or frequent recording are, at least in the case of premises for
sophisticated production tasks, collected, processed and stored electronically - and this for an extended
period of time well beyond the expiry dates of the products. Complementary physical and, above all,
microbiological data, on the other hand, are collected and recorded manually.
Both sets of data, i.e. those from computerized monitoring and those obtained through manual data
compilation, should periodically be submitted to a trend analysis. In order to discover excursions from
the specified data range and developing problems at an early stage and to be able to act upon them in
time, alert and action limits should be set. Exceeding these limits should trigger alarms. The automatic
and inextinguishable registration of such alarms is an important additional task of computerized pharma
monitoring systems.
3.K References
Regulatory Requirements Europe
1. EU-GMP-Guide: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary
Use. European Commission, Brussels (seechapter C).
o Annex 1, Manufacture of Sterile Medicinal Products (see chapter C.6.1)

o Annex 11, Computerised Systems (see chapter C.6.11)
o Annex 15, Qualification and Validation (see chapter C.6.15)
2. European Pharmacopoeia, EDQM Council of Europe, Strasbourg.
Regulatory Requirements USA

3. Food and Drug Administration FDA, 21 CFR 210: Current Good Manufacturing Practice in manufacturing,
processing, packing, or holding of drugs, General, Washington DC/USA (see chapter D.1.1).
4. Food and Drug Administration FDA, 21 CFR 211: Current Good Manufacturing Practice for finished
pharmaceuticals, 2008, Washington DC/USA (seechapter D.1.2).
5. Food and Drug Administration FDA, Guidance for Industry: Sterile drug products produced by aseptic
processing - current Good Manufacturing Practice, 2004, Rockville MD/USA (see chapter D.10).
6. Food and Drug Administration FDA, Guidance for Industry - Part 11, Electronic Records, Electronic Signatures
- Scope and Application, Rockville MD/USA, 2003 (see chapter D.12).
7. U.S. Pharmacopeia, Informational Chapter <1116>, Microbiological evaluation of cleanrooms and associated
controlled environments.
ISPE-Guides
8. ISPE, Baseline Pharmaceutical Engineering Guides, especially
Vol. 1: Active pharmaceutical ingredients (2007),
Vol. 2: Oral solid dosage forms (1998),
Vol. 3: Sterile manufacturing facilities (1999),
Vol. 5: Commissioning and Qualification (2001),
Vol. 6: Biopharmaceutical manufacturing facilities (2004),
Tampa FL/USA
9. ISPE, GAMP 5 - A risk-based approach to compliant GxP computerized systems, Tampa FL/USA (2008).
PIC/S-Guides
10. PI 009, Aide Mémoire Inspection of Utilities (see chapter F.6).
International Standards
11. DIN EN 779, Particulate air filters for general ventilation - Determination of the filtration performance, 2002.
12. DIN EN 1822, High efficiency particulate air filters (HEPA and ULPA), part 1-3: 1998, part 4-5: 2001.
13. DIN EN ISO 14644, Cleanroom and associated controlled environments, International Organization for
Standardization ISO, Genf
o Part 1: Classification of air cleanliness (ISO 14644-1:1999)

o Part 2: Specifications for testing and monitoring to prove continued compliance with ISO 14644-1
(ISO 14644-2:2000)
o Part 3: Test methods (ISO 14644-3:2005)
o Part 4: Design, construction and start up (ISO 14644-4:2001)
o Part 5: Operations (ISO 14644-5:2004)
14. DIN EN ISO 14698, Cleanrooms and associated controlled environments - Biocontamination control , Parts 1
and 2, International Organization for Standardization ISO, Genf, 2003.
15. ISO 8573, Compressed air, Parts 1 to 9, 2001-2007.
Publications
16. Coleman L. C.: Cleanroom Ceilings, Floors and Walls. In: Cleanrooms (1995) 12.
17. Sirch E. C.: Construction Materials and Surface Finishes for Cleanrooms. In: W. Whyte (Editor) Cleanroom
Design. Second Edition, J. Willey & Sons, UK Chichester 1999.
18. Mielke R. L.: An update on ISO Technical Committtee 209. In: CleanRooms 20 (2006) 12, p 8-11.
19. Brande D.: Evolving ISO standards serve the global cleanroom market. In: CleanRooms 21 (2007) 8, p 14-15.
20. Neiger J.: European guidelines for sterile manufacture In: Cleanroom Technology 13 (2007) 6, p 14-15.
21. Neiger J.: Cleanroom standards. In: European Pharmaceutical Review 2/2007, p 92-96.
22. Hallworth M.: EU GMP Annex 1 clears the air for sterile manufacturing. In: CleanRooms 22 (2008) 6, p 32-35.
4 Facilities and Equipment
4.A Introduction
Author: Uwe Schwarzat
Co-Author: Dr. Ralph Gomez / Update 06
Apart from the term facility, a range of other designations exist such as "machine", "apparatus" or "equipment".
The EU GMP Guideline and the U.S. CGMP regulations use the term equipment which describes all cases where
individual items, or items that are connected with one another, are used to manufacture, process or package
pharmaceutical products through direct or indirect contact with one another. Equipment may be driven manually
or mechanically. In the EU GMP Guideline, production machines, testing or control devices, as well as supply
and disposal systems for air, water and other utilities, are also included under "equipment". The U.S. CGMP
regulations also use the term for equipment used for control of air pressure, micro-organisms, dust, humidity, and
temperature (21 CFR 211.46 (b)), and automatic, mechanical, electronic or other types of equipment, including
computers (21 CFR 211.68 (a)). The term "instruments" is typically used to describe sophisticated laboratory
equipment.
Information on supply and disposal systems can be found in the chapter on rooms and utilities (see chapter 3
Premises). The following chapters focus on the category of mechanical and automated production and packaging
machines. The specifications and information provided here may partially be applied to simple manual apparatus.
From the start of and throughout their entire service life, rooms and facilities must be designed, organized and
assessed from the standpoint of the quality of medicinal products. To this end all data must be brought together
in a comprehensive technical documentation: starting with the specification followed by the building and design
documents, and then all changes made during production. Calibration (see chapter 4.G Calibration), qualification
(see chapter 6 Qualification) and maintenance (see chapter 4.H Maintenance), can only be effective as quality
assurance functions if up-to-date technical documentation is available (see chapter 4.F Technical documentation).
In addition to the technical performance data, specifications for facilities in the pharmaceutical production and
packaging sectors must always take into account the requirements of the GMP regulations. General
requirements of the EU GMP Guideline for equipment may be found in the guidelines (Article 8) and in chapter
3.34 onwards. In the U.S. CGMP regulations, equipment is described mainly in Subparts C and D, and in
paragraph 211.105 (Figure 4.A-1).
Figure 4.A-1 Requirements for equipment

Requirements for equipment
The equipment ...
... must be suitable for the intended purpose
... must be of appropriate design
... must be of adequate size
... must be suitably located
... must be maintained
... must be qualified
... must be easy to clean
... must not cause any undesirable interaction with the product
... must be properly identified
... must not damage the product
... must be correctly installed
... must be calibrated
Using the above basic rules, individual specifications, known as user requirements, may be derived for all
machines. Together with the technical specification from the supplier and the order documents, these are part of
the design qualification (DQ). (See chapter 4.E.1 Design qualification.)
Apparatus or facilities are constructed using a range of components. In order to be able to assess and quantify
the quality of a facility, its individual components must be initially considered in the installation qualification (IQ)
(see chapter 4.E.2 Installation qualification). The interaction of components is then tested in the operational
qualification (OQ) (see chapter 4.E.3 Operational qualification ) and the effect on the product is tested in the
performance qualification (PQ). As quality cannot be tested in the facility itself afterwards, it is expedient from the
outset to refer to individual components in the specification phase (DQ).
Machines can generally be classified into two main components: a machine essentially consists of the
mechanical part (see chapter 4.B Mechanical components) that is driven electrically or pneumatically, and the
control (see chapter 4.C Control). From the point of view of quality assurance, machine controls have a greater
significance, as their scope and complexity is ever increasing. Special facility designs that are the result of
ongoing further development of GMP ideas (such as Cleaning in Place) are described in chapter 4.D Facility
concepts.
4.B Mechanical components


What must be taken into consideration when configuring facilities?
Which basic specifications exist for facilities?
What is the significance of a facility's specification?
The special characteristics of mechanical, electrical and pneumatic elements are summarized in this chapter. A
number of components are listed that are important for machines and facilities in terms of Good Manufacturing
Practices, and must therefore be specified and subsequently tested during qualification.
4.B.1 Construction and installation materials

Construction and installation materials, particularly those that come into contact with products, must be selected
to ensure that no undesirable interaction with the product occurs during operation or cleaning. To achieve this,
relevant criteria such as operation and cleaning temperatures and pressures must be defined.
Product properties, such as chemical composition, decomposition products and abrasiveness, also influence the
selection of materials and must therefore be described at the outset.
If, for example, halogenides are likely to be produced during the manufacturing process, a
higher-grade of steel (V4A) must be used instead of the usual V2A steel as there is a danger of corrosion.
Granulates may undergo discoloration when coming into contact with aluminum, so contact
between products and aluminum surfaces should therefore be avoided in solids operations.
Standard construction materials that come into contact with products are (Figure 4.B-1):
Figure 4.B-1 Materials used

Materials used
Stainless steels: V2A (1.4301, 1.4304); V4A (1.4401, 1.4404, 1.4571); AISI 304,
304L, 316, 316L; Container materials e.g.: 1.4435; etc.
Plastics: PTFE, polyethylene; silicon etc.
Normal steel: covered with stainless steel, galvanized, powder-coated -
painted steels should be avoided.
Aluminum
V2A and V4A stainless steels according to DIN or AISI (US standard). The alloys selected
depend on the chemical composition of the products being processed and the necessary surface
qualities. The roughness of the surface must also be specified as well as the processing method (cold
rolled, ground, electro-polished, etc.). For critical components, it is recommended that material
certificates be requested from the steel manufacturer (e.g. 31B certificates).
Plastics are mainly used as sealing materials. These must be suitable for use with foodstuffs
and medicinal products. The FDA (21CFR177.2600) in particular has approved a range of plastics for this
purpose. Typical examples are polytetrafluoroethylene (Teflon), polypropylene, polyethylene and silicone.
Glass is used to manufacture reaction vessels and pipes, or to provide visual contact with the
product.
In addition to product contact surfaces, cladding, covers and support braces must be specified
in such a way that they do not have a negative effect on product quality either during operation or
cleaning. This also applies to screws and other fastening elements.
Filters are also important components of a facility. Filters have diverse applications and also have a huge impact
on quality. The specification and qualification of filters should therefore at least include the following:
Technical data: Separation efficiency, mesh/pore size, operating temperatures, pressures, etc.
Filter materials must be asbestos-free - particularly if the filter cake or substrate is subsequently
used in the manufacturing process.
To avoid confusion, it is good practice to record the precise type designation in the qualification
documents.
Filters must not release fibers into products unless it is impossible to manufacture products
without their use (21 CFR 211.72).
4.B.2 GMP-compliant design characteristics

GMP-compliant design characteristics must be specified. In so doing, it must be considered that in practice
detailed designs are often not available for standard machines and are often only available for special machines
in return for a (considerable) additional charge. Though many well known manufacturers have incorporated the
most important GMP requirements into their designs, it is still recommended that all critical areas be precisely
defined, discussed and checked.
Several basic features of GMP-compliant facilities are:
Simple, fast removal of components and facility parts during operation, maintenance and repairs
- without a tool whenever possible - including good accessibility to all components.
No particle, oil or grit-emitting (rotating) parts should be above the areas in which open products
are located. Machine designs are now readily available where the drives, motors and other drive parts
are positioned under or outside the production area. Where this is not possible, these machine
components must be hermetically encapsulated or sealed.
Use of maintenance-free or low-maintenance components. In sterile zones, components
requiring maintenance should be installed outside the clean rooms.
Cross-contamination and mix-ups must be avoided. Slits, holes, corners, cavities and dead
spaces into which products may collect and then subsequently be released into the production process
are not permitted. This particularly applies to screw holes, shaft or pipe bushings, covers made of folded
sheets and screwed cladding. Whenever possible sheets should be (full-penetration) welded, not
screwed or riveted.
It must be possible to completely empty all fixed (CIP/WIP) components and they must be self-
drying (see chapter 4.D.1 CIP (Cleaning in Place)).
Main rings for purified water must be laid in such a manner that they can be completely emptied
at the lowest point and they must be CIP/SIP compatible or scrapable.
Use of lubricants that are compatible with foodstuffs according to FDA/USDA-H1, e.g. white,
silicone or ester oils.
All wear and spare parts must be clearly identified in the technical documentation, e.g. using a
numbering system. This avoids confusion when replacing components.
4.B.3 Electrical and pneumatic components

The following criteria in relation to electrical and pneumatic components should be particularly observed as part
of Good Manufacturing Practices:
Clear, easy-to-follow structure in the design.

Modular concepts to minimize the effort involved in order to qualify subsequent extensions.
Use of a few different standard components rather than a variety of special subassemblies
Systematic, clear use of conductor coloring
Clear labeling of all electrical components including cable
The ventilation of electrical components (control cabinet, motors) in the vicinity of the product
must be avoided. In environments where large quantities of dust are produced (as in the manufacturing
of solid dosage forms) or in sterile zones, separation of the supply and exhaust air is advisable.
Pneumatic components that discharge compressed air must not be installed close to an open
product.
The environmental conditions (temperature and moisture) must be defined for electrical and
pneumatic components including proof of functionality.
Design of appropriate electrical components to make them resistant to splashes or waves of
water (IP 54/IP 64, electrical components according to DIN 40 050).
During qualification the following must be checked:
Installation qualification: completeness of documentation; terminal strips; input/output lists; lists of

components; calibration documentation (seechapter 4.E.2 Installation qualification)
Operational qualification: safety devices, locks (see chapter 4.E.3 Operational qualification )
Summary
To maintain a clear overview, components for facilities are specified individually. In so doing, the
special features of the product must be considered in addition to the machine functions. The
components to be qualified must have been defined in order for them to be taken into account in the
facility specification. When designing the mechanical components of the facility, attention must be paid
to materials that come into contact with the product, effortlessness of cleaning, labeling, and ease of
qualification.
4.C Control

Why do facilities require controls?
Which elementary control features should be specified?
Is the same validation effort required for a microprocessor controlled as for a
computerized system?
"Control is the direction of an operation, e.g. to ensure the proper operation of a machine, [...] as opposed to the
correction of a malfunction - the regulation process."1
The essential function of a control process is the permanent measurement of different process parameters.
The most important prerequisite for achieving the controlled implementation of a process is the measurement of
critical process parameters. Instead of critical process parameters, quality-relevant variables (that influence
product quality) are also referred to. Sensors are used to measure the different variables such as temperature,
pressure, humidity, speed, etc. When selecting the sensors, it is particularly important to specify the following at
the outset (seechapter 4.E.1 Design qualification and Figure 4.C-1).
Figure 4.C-1 Selection of sensors

Selection of sensors
Specification Example
What are the critical process parameters? Product temperature
Within which limits does the process operate? Limits: 20 °C - 60 °C
What degree of precision and which tolerances are Tolerances: +/-5 °C
acceptable for the product? Precision: +/- 5 %
Where is the correct location of the sensor? Positioning in product flow
How should the measurement be processed further? Display, reporting and alarm
The details provided in chapter 4.B Mechanical Dead spaces in which products may collect are
components' apply to sensors that come in direct not permitted. Easy to clean design. Suitable
contact with products. materials.
Quality-relevant measuring points must be calibrated regularly. In addition to the actual measuring sensors,
cables and evaluation units are also integrated into the measuring circuit. All components in the measuring
circuit have built-in tolerances which influence the measurements so the entire measuring circuit must always be
taken into account during calibration. (See chapter 4.G Calibration.) A list of all quality-relevant measuring points
is required for the qualification, and the necessary documentation must be included in the specified delivery
scope of the facility supplier.
Straightforward processes may be controlled manually provided the measured values are visible. Manual control
is no longer feasible as soon as two or more elements influence the process. At this point automatic control
loops take over and keep the parameters within the specified limits. The qualification of critical control loops is an
important part of the function check for control systems in pharmaceutical machines. The most important aspects
of this check are the input/output tests and review of the circuit diagrams.
To enhance product safety, facilities with several control loops are operated via plant controls. In the past
facilities were controlled by contacts. Todaymicroprocessors or programmable logic controls (PLC) are used.
Operating and monitoring systems are used to enable the user to visualize and operate these control systems,
often via a computer.
These cases are referred to as computerized systems, as in: "A system including the input of data, electronic
processing and the output of information to be used either for reporting or automatic control." [EU GMP Guideline,
Glossary] (see chapter 9 Computer Validation).
The FDA's Glossary of Computerized System and Software Development Terminology describes a computer
system as "A functional unit, consisting of one or more computers and associated peripheral input and output
devices, and associated software, that uses common storage for all or part of a program and also for all or part of
the data necessary for the execution of the program; executes user-written or user-designated programs;
performs user-designated data manipulation, including arithmetic operations and logic operations; and that can
execute programs that modify themselves during their execution. A computer system may be a stand-alone unit
or may consist of several interconnected units."
Furthermore, many plant controls are designed for networking with higher-level process control systems. These
kinds of configurations make "paper-free" operations feasible and may be realized in individual cases. However,
the degree of automation should be carefully defined while considering the required validation expenditure.
Considerable costs are generated by the initial validation, and more so for the revalidation of more complex
computerized systems. Moreover, it must be considered that isolated defects may lead to failure of the entire
system with attendant down times and revalidation times.
In practice it is useful to differentiate between plant controls which require a conventional qualification and
computerized systems which require a computer validation.
The EU GMP Guideline, appendix 11.2., grants the following flexibility: "The extent of validation necessary will
depend on a number of factors [...]".
The U.S. guidance, Part 11, Electronic Records; Electronic Signatures - Scope and Application, section C.1
states: "We recommend that you base your [validation] approach on a justified and documented risk assessment
and a determination of the potential of the system to affect product quality and safety, and record integrity".
In the case of standard machines with microprocessors or standard PLC components, a simplified computer
validation should be carried out while considering the cost-benefit equation. The expenditure required for the
validation of computerized systems increases with the degree of software customization, as it does for systems
that are not as widely used. Straightforward standard machines with non-variable microprocessor controls may
be validated with relatively little effort.
Several basic GMP features that should be available with every control are listed in Figure 4.C-2:
Figure 4.C-2 Features of plant controls
Features of plant controls
Hardware and software must be clearly identified

Software version management
Documentation of software and software development
Availability and secure storage of source code
Authorized access for input or data modification
Concept for the handling of emergencies: it must be ensured that valuable data cannot be
lost in the event of a power failure. When restarting, uncontrolled operating sequences must not
take place.
Summary
In order to be able to control a process, quality-relevant process parameters must be measured using
calibrated sensors. Checks are to be carried out as part of the operational qualification to ensure that
parameters are being kept within their limits by automatic control loops. Where microprocessors or
programmable logic control (PLC) is used, this falls within the scope of computer validation
(see chapter 9 Computer Validation).
4.D Facility concepts


Are there facility designs that make GMP economical?
What points must be observed with regard to facility designs such as CIP
(Cleaning in Place), isolator technology and facility chains?
In order to satisfy the special GMP requirements, a range of facility concepts has been developed. These
concepts were developed to provide an economic means of protecting and ensuring the quality of the product.
Several important designs that are applicable for all dosage forms are described as examples.
4.D.1 CIP (Cleaning in Place)

Cleaning in Place was developed for sterile production and represents state-of-the-art technology in this area.
This principle has also been adopted in other areas, e.g. solid dosage forms. CIP refers to the cleaning of
production equipment using stationary attached cleaning nozzles or heads thus dispensing with the time-
consuming process of dismantling the facility (Figure 4.D-1).
Figure 4.D-1 Regulations for CIP systems

Regulations for CIP systems
Observing the requirements for purified water systems
Specification of pipes: dimension, flow rate, permissible length of stubs (3 to 6
x diameter), material, welding seams, surface quality, passivation procedure
Complete emptying capability of all facility parts, particularly pumps, fittings,
valves, pipes, measuring instruments and possibly exhaust devices
Ability to sterilize the entire facility, including all its components
Type of cleaning heads
Cleaning principle (high pressure 10-100 bar, low pressure <2 bar)
Cleansing agent (acid, alkaline)
Final rinse: distilled water
Suitable measuring instruments for purified water: to measure flow rate,
temperature, pressure, pH value, etc.
Possibility of mechanical separation of CIP system from purified water loop
should fast separation be required in the event of reverse microbiological
contamination
Sampling nozzle at representative point
Suitability of control for validation (see chapter 9 Computer Validation)
Controllability of all valves, pumps and actuators for qualification of the
facility
The criteria that must be checked are cleaning effectiveness, contamination of the product with cleansing agent,
and microbiological growth (see chapter 8 Cleaning Validation). The details to which particular attention must be
paid are listed in Figure 4.D-1.
4.D.2 Isolator technology

The significance of isolator technology in the pharmaceutical industry is steadily increasing. Authorities have also
responded positively to this technology as verified by clause 7 onwards in Annex 1 of the EU GMP Guideline:
"The utilization of isolator technology to minimize human interventions in processing areas may result in a
significant decrease in the risk of microbiological contamination of aseptically manufactured products from the
environment"
and in the FDA's Sterile Drug Product Produced by Aseptic Processing guideline, Appendix 1,
"A well-designed positive pressure isolator, supported by adequate procedures for its maintenance, monitoring,
and control, offers tangible advantages over traditional aseptic processing, including fewer opportunities for
microbial contamination during processing."
Figure 4.D-2 Evaluation criteria, isolator

Clean room
Evaluation criteria, isolator Isolator (class A/B)
(class A/B)
Qualitative factors
Product protection ++ +/-
Personnel safety ++ +/-
Sterilization ++ +/-
Availability of facility + ++
Operation of facility - ++
Investment costs
Construction + -
Building services + -
Production machines -- ++
Start-up -- ++
Qualification/validation - +
Operational costs
Air-handling technology ++ --
Personnel requirements +/- +/-
Sterile clothing ++ --
Monitoring ++ --
Sterilization ++ --
Maintenance +/- +/-
Requalification - +
Evaluation: ++ = very good, + = good; +/ = satisfactory; - = poor; - - = very poor
An isolator is a miniaturized self-contained sterile chamber into which the user may reach by means of gloves
integrated in the appliance. The benefits of this room-in-room solution are the protection of persons and products
with a minimum of air-handling effort.
The areas of application range from microbiology (implementation of sterility tests) to aseptic filling through to the
processing of highly potent substances. The investment and operational costs are highly dependent on the
intended purpose. In general, the investment costs for an isolator are higher than for a conventional clean room:
the opposite applies to the operational costs (see Figure 4.D-2).
As this technology is not yet as widespread as the clean rooms which are normally used, special requirements
must be observed, particularly in relation to validation. Critical aspects from the GMP standpoint are listed
in Figure 4.D-3.
Figure 4.D-3 Critical aspects of isolator

Critical aspects of isolator
Docking procedures for the transfer of materials
Integrity of transfer systems, gaskets and seals
Leak-tightness of gloves
Durability of materials of construction
Proper air classification for interior of isolator and the surrounding
environment
Degradation of gloves and other plastics due to decontamination gases (H2O2)
Ease of cleaning and decontamination inside isolator
Frequency of decontamination
Validation: The degree of sterilization is dependent on the duration, the
H2O2 concentration, the flow rate, the temperature and the loading of the isolator,
amongst other factors.
Frequent product or format change
4.D.3 Connected facilities

Connected facilities are used particularly for solid dosage forms, and in this case, for reasons of product and
personnel safety. Ideally, materials are transported between individual facility components installed on different
stories using gravity. This facility concept can even influence the architectural design of a production building.
Details to be considered are: cleanability by CIP or dismantling as well as information flow of product data.
(See chapter 3.B Material flow, personnel flow and layout.)
Summary
A range of facility concepts exist that provide economic GMP-compliant solutions. CIP, isolator
technology and connected facilities are only a few examples of applications for a variety of dosage
forms. Costs are reduced and errors minimized through reduced personnel expenditure and increased
automation. Additional cost savings may be achieved for isolator technology and facility chains by
reducing the room air-handling requirements.
4.E Examples of facility qualification

In this chapter, the various components of facility qualification are illustrated by practical examples. The general
procedure to follow when carrying out qualifications is shown in chapter 6 Qualification.
4.E.1 Design qualification

All essential parameters for the subsequent use of pharmaceutical process equipment are defined in
the specification (also known as user requirements). Together with the technical specification (the approved
supplier specification), this is an important part of the design qualification (DQ). Checks are carried out
throughout the remaining qualification modules (IQ/OQ) to verify whether the facility meets the requirements of
the specification.
Figure 4.E-1 Elements of the facility specification

Elements of the facility specification
Direct references to standards and rules and regulations
Description of facility
Functionality
Procedural description
Accessory
Mechanical components
Version
Dimensions
Materials
Control and process monitoring
Supply of energy and utilities
Constructional prerequisites
Installation, start-up, acceptance tests
Documentation, validation, qualification
Appendix: drawings, internal guidelines
In the following, the specification for a washer is shown as an example:
Preliminary remark
This specification describes the minimum delivery scope for a facility that cleans, disinfects and dries equipment
intended for use in the pharmaceutical industry. This document does not provide a comprehensive or complete
description of the system to be delivered. Instead, it defines a minimum technical standard and refers to
standards and specifications applicable in this case.
Direct references to standards and rules and regulations

The following standards and rules and regulations must be taken into consideration during the design and
construction of automatic washers. This also applies to specifications not stated here that are relevant to the
construction of the facility.
EU GMP Guideline for medicinal products

Current Good Manufacturing Regulations and Guidelines (cGMP) of US Food and Drug
Administration (FDA)
European Pharmacopoeia
United States Pharmacopeia (USP)
DIN standards
VDE guidelines
VDI 2890: scheduled maintenance; instructions for the compilation of maintenance and
inspection plans
Trade association accident prevention regulations
Description of facility
Functionality: automatic cleaning, drying and disinfection of pharmaceutical equipment. Cleaning
is carried out using water of varying qualities to which cleansing agent is added depending on the
program step. The final rinse must be carried out using purified water.
Description of procedure: A standard cleaning procedure as shown in Figure 4.E-2 should be
possible. The tenside-based cleaners are specified. Water and air temperatures must not exceed X °C.
Accessories: washing baskets
Figure 4.E-2 Rinsing program

Rinsing program
Prewash
Main wash with tenside-based cleaner
Repeat main wash cycle, as required
Rinsing in cycle
Clear rinse with purified water in single operation
Drying
Cooling
Mechanical components
Full drainage of machine and pumps; no exposed heating elements; variable partitioning of
internal compartment
Pharma-compliant version characterized by:
o use of material 316L for all surfaces and pipes coming into contact with fluids,
o use of diaphragm valves and tri-clamp connections,
o dead volume-free and fully drainable installation,
o prevention of mixup or reverse contamination and
o use of a validatable process control and machine documentation.
2 programmable liquid metering pumps for cleaning fluids with metering monitoring function.
Drying with high-performance blower; HEPA filter in the drying circuit not required. Suction of
drying air from production room including filtering in accordance with clean room grade D. Discharge of
drying air via roof.
Condensate drainage in venting line to prevent backflow contamination
Dimensions
Materials: washing compartment and inner face of door: 316L (alternatively 1.4401). Cladding
material: 1.4301. The materials used for seals and tubes must correspond with the recommendations of
the US Food and Drug Administration (FDA). Works certificates for the above materials must be included
in the delivery.
Control
Freely programmable control (microprocessor control or PLC). The program should be structured
in a modular fashion. Headings for the individual program modules must be provided.
Plain text display in the relevant language
Display of washing program, current program step, temperature of washing compartment and
remaining running time.
The means to print out the programs and all their parameters (if required, printer to be
connected).
Self-diagnosis, program and malfunction statistics
The control should incorporate a memory that accommodates several (>10) wash programs that
may be called up individually.
The machine must stop if the preset parameters are not complied with. The operator should then
be provided with the reason why the process was canceled. When the machine is restarted, the entire
wash program must be repeated.
Process monitoring
Monitoring of the following process parameters with display option and limit value monitoring with
alarm or machine stop.
Temperature of rinsing water
Pump pressure (circulatory pump)
Drying temperature
The sensors must be readily accessible and removable for calibration purposes (cable length)
and it must be possible to calibrate these with the entire measurement chain.
Dosage monitoring of detergent pumps
Sampling tap for water samples
Error display for important functions and utilities
A connection that enables the machine to be regularly requalified must be provided. For example,
a connection that can be used to log the progress of the relevant parameters during a rinsing cycle via an
on-site chart recorder.
Supply of energy and utilities

Connections for the following water types: purified water, 65 °C, connection to loop provided by
installation location; drinking water both warm and cold.
Drainage via open funnel siphon to prevent backflow contamination
Electrical connection: 400 V/50 Hz
Steam connection
Connection to exhaust line provided by installation location
Constructional prerequisites
The equipment must be installed in a wash room. The particulate and microbiological loading of the room must
correspond with clean room grade D. The nominal room temperature must be 20 °C +5/-2 °C, at 50 % r.h.. Data
on the required limits at the installation location (temperature, relative humidity, electrostatic and magnetic
influencing parameters) must be supplied.
Installation, start-up, acceptance tests

The scope of delivery includes:
Free delivery and placing at site (supervision of placing as minimum)

Complete assembly and start-up including test operation
Instruction of operating personnel
Necessary acceptance tests: the contract giver reserves the right to audit the manufacturing,
programming and quality assurance at the premises of the contract acceptor.
The pre-delivery check, otherwise known as the Factory Acceptance Test (FAT), at the manufacturer's
premises confirms the presence of the necessary manufacturing quality and ensures that the function tests are
carried out.
The final acceptance, otherwise known as the Site Acceptance Test (SAT), by the contract giver takes place at
the installation location once assembly and start-up have been completed and the operating personnel have
been instructed. It must be verified that
the delivery of the facility is complete and correct,

the documentation is complete,
the installation is correct,
the cleaning and auxiliary programs specified by the operator and also the safety devices are
functioning flawlessly,
the locks and alarms are functioning flawlessly,
the installation and function of the measuring equipment is correct and
the initial calibration of the sensors was carried out at the installation location (if carried out by
contract acceptor)
The basis for the pre-delivery check and the site acceptance test is a reference program to be compiled by the
supplier according to the specifications of the contract acceptor containing all elements of the subsequent
cleaning task. This program also serves as the basis for carrying out function tests within the scope of the
operational qualification.
Furthermore, three cleaning cycles with contaminated equipment are to be carried out to assess the success of
the acceptance test using the following criteria:
Visually clean / analytically clean
Visually dry
Surface quality of the materials washed
Analysis of the cleansing agent residues (see chapter 8.E.2 Calculation of cleansing agent
residues)
Documentation, validation, qualification

The technical documentation to be supplied for the purposes of qualifying the facility can be found in the basic
documents table. (see Figure 4.E-3 toFigure 4.E-5).
4.E.2 Installation qualification

The basic structuring and detailed description of an installation qualification are not dealt with here. This
information can be found in the chapter entitled Qualification. (See chapter 6 Qualification.) Only the measures
that must be carried out (partly using forms) during the installation qualification are listed below, using fluid bed
equipment as an example. Computer validation measures are dealt with in chapter 9 Computer Validation.
Technical documentation
To complete the technical documentation, documents concerning the facility or its components must be available.
These are required for the installation, operation and maintenance of the facility and must be checked as part of
the installation qualification and documented in the form (see Figure 4.E-3).
Figure 4.E-3 IQ form - documentation

available yes/no, Responsible for
Date/
Document drawing no. where supplementations, changes,
signature
applicable etc.
Detailed operating instructions
Maintenance manual for entire
facility, partial facility and
components
Operating procedures (SOPs)

The procedures required to operate the facility or its components must be checked (e.g. calibration, operating,
maintenance and cleaning procedures). Attention must be paid to the personnel training documentation
(see chapter 2.C Training). The form provides confirmation that the check has been carried out (see Figure 4.E-
4).
Figure 4.E-4 IQ form - SOP

No. / Rev. Date of Training checked Date/
Title of operating procedure
no. implementation confirmed signature
Operating instructions, fluid bed
equipment
Logs
Preventative maintenance
Risk analysis
The facility and its operating functions are assessed and tested during the risk analysis. Critical areas during
operation, possible errors and causes of the various risks, as well as the steps that must be taken to minimize the
risks, must be defined and recorded. The completed risk analysis must be included alongside the IQ report.
(See chapter 2.C Training.)
Facility components
The technical data of the facility or its components is to be checked against the functional specification and
documented in the form. The available ID numbers of the individual facility components are registered during this
check (Figure 4.E-5).
Figure 4.E-5 IQ form - facility components

Date/signature
Description Exhaust ventilator
Capacity 6000 m3/h
Manufacturer Lima
Type SCL 3 U333
Serial number Determine on-site
ID number Determine on-site
Terminal strip table

The electrical circuit diagram must be used to check whether the wiring of the facility's components is correct. A
random check is sufficient. The circuits to be checked are specified in the form. If no deviations from the
manufacturer's documentation are found during the check, the circuit diagram may be accepted. Where
deviations are found, the circuit diagram must be reviewed. The results must be documented in the form
(see Figure 4.E-6).
Figure 4.E-6 IQ form - terminal strip table

Result
Page no. Checkpoint Terminal strip Terminal no.
Date/ signature
220 Air inlet cover X44 7
340 Product temperature X54 34
675 Exhaust ventilator X27 22
Hardware installation
The system hardware must be checked by inspecting the hardware configuration, the wiring and the electrical
supply. The results are documented in the form (see Figure 4.E-7).
Figure 4.E-7 IQ form - hardware

Date/signature
Description Central device
Manufacturer Siemens
Type 135 U/155 U
Serial number Determine on-site
ID number Determine on-site
Input/output list
Checks must be carried out to verify that the control has been correctly connected to the functional modules and
facility sensors, and this must be documented. If the manufacturer delivers an I/O list, a random check on 15 % of
I/Os will suffice. If no deviations from the manufacturer's documentation are found during the check, the list may
be accepted. If deviations are found, all I/Os must be checked. The results must be documented in the form
(seeFigure 4.E-8).
Figure 4.E-8 IQ form - I/O list
Signal transmitter/ Date/
PLC Input/Output Description
receiver signature
NOMINAL ACTUAL
e7.0 Exhaust ventilator Input is high for electrical exhaust fan
O.K.
a4.7 Steam valve Input is high if supply air steam valve is
open.
Software installation
The software installation must be documented. The designation, type, name and version number (date) of the
software must be noted. Similarly, the manufacturer and/or developer and the back-up system must be recorded.
The results are documented in the form (see Figure 4.E-9).
Figure 4.E-9 IQ form - software

Software no.:
Designation:
Version:
Date:
Programmer:
Back-up copy:
Operating system:
Version:
Initial cleaning
Once installation has been completed for the first time, facilities or their components must be thoroughly cleaned
in accordance with the relevant operating procedures and confirmation provided to show that this has been
carried out.
Inspection of utility connections

The connected loads of all utilities to and from the facility must be compared with the manufacturer's data. The
connections must also be checked to make sure that they have been carried out correctly. The results must be
documented in the form (see Figure 4.E-10).
Figure 4.E-10 IQ form - utilities

Electrical Connection specifications + tolerances, if Connection Date/
connection required (measured) Signature
Operating voltage 3 x 400 V
Control voltage 230 V
Frequency 50 Hz
Safety devices and locks

A list of the safety devices and locks included with the facility or its components must be compiled with reference
to the manufacturer's specifications. When qualifying the installation, checks must be carried out and
documented to verify that all facilities are available. The actual function of the facilities is checked within the
scope of the operational qualification. The results of the installation qualification are documented in the form
(see Figure 4.E-11).
Figure 4.E-11 IQ form - safety

Facility available Date/
No Facility Description
component yes/no signature
1 Emergency Operator The facility halts operation as soon as the button
off button control panel is pressed. All motors and pumps are switched
off and the valves for media supply are no
longer supplied with electricity.
Construction and assembly materials

Materials used in the facilities or any of their components that come into contact with raw materials, intermediate
or final products, must be listed in the form (see Figure 4.E-12).
Figure 4.E-12 IQ form - materials

Component/part Material specified acceptable visually checked date/signature
Spray device stainless steel, 1.4401
Work tower, product contact parts stainless steel, 1.4435
Filter list
A list of the filters required for operation of the facility must be compiled. For sterile filters, copies of the test
reports and the SOP used for implementation are also required. The filters are listed on the form (see Figure 4.E-
13).
Figure 4.E-13 IQ form - filters

Type: Separation efficiency:
Location: Material:
Number of filters: Facility/model no.:
Manufacturer: Serial no.:
Signature: Date:
Measuring and control points (M&C points)

A list must be compiled of the available M&C points that includes the numbers of M&C points, the relevant
manufacturer, the date of the last calibration and the recalibration interval. The documentation of the last
calibration must be included with the IQ report.
IQ - site acceptance test

A summary of the results obtained during the installation check is presented in the IQ site acceptance test. The
results are checked using the form (seeFigure 4.E-14).
Figure 4.E-14 IQ form - site acceptance test

Date/
No. Description
signature
1 Technical documents are complete:
2 The facility supplied is checked to verify completeness and compliance with the
technical specifications (including safety features and equipment).
3 The facility supplied is assembled and connected correctly.
4 The hardware and software for the automated system has been compiled, documented
and installed correctly.
5 The required operating procedures are available: cleaning, operation, maintenance.
6 A log book template has been compiled.
7 Initial cleaning has been carried out.
8 All deficiencies have been rectified.
9 Initial start-up has been successfully carried out.
Comments:
Date/signature:
Deficiency report
Deviations identified during the installation qualification must be documented in the deficiency report. The
operator defines the measures required to rectify the deficiencies or deviations; names the departments or
persons responsible; specifies deadlines by which the deficiency must be rectified; and authorizes
implementation of the measures. Rectification of the deficiencies found must be documented in the form
(see Figure 4.E-14).
It must be ensured that changes made, as a result of rectifying deficiencies that have been identified, are
assessed and documented in accordance with the established change control procedures, and requalification is
carried out as required. The regulations governing requalification are laid down in the relevant operating
procedures. (See chapter 6 Qualification.)
4.E.3 Operational qualification

The basic structuring and detailed description of an operational qualification are not dealt with here. This
information may be found in the chapter entitled Qualification (see chapter 6 Qualification). Only the measures
that must be carried out (partly using forms) during the operational qualification are listed below using fluid bed
equipment for illustration purposes. Computer validation measures are dealt with in chapter 9 Computer
Validation.
Testing equipment required for qualification

The testing equipment required to carry out the operational qualification (OQ) must be listed (see Figure 4.E-15).
It must be ensured that calibration can be traced back to the standards of the NIST (National Institute of
Standards and Technology) or equivalent organizations. It must be checked that the time interval prior to
recalibration has not been exceeded. Copies of the documents from the last calibration of the testing equipment
used must be included with the equipment/qualification documents.
Figure 4.E-15 OQ form - testing equipment

Description
Serial Calibration Date/
of Manufacturer Date of last calibration
number interval signature
equipment
Stopclock Solex
Multimeter Fluke
Calibrations
The quality-relevant MC points (measuring and control points) are identified. A copy of the compiled list is
included in the installation qualification report. The measuring circuits must be calibrated before the operational
qualification is carried out. A copy of the calibration report is filed with the OQ report. (Seechapter 4.G
Calibration.)
Alarms
All alarms that respond to malfunctions in the facility must be checked by simulating the appropriate malfunctions.
The type of simulation must be described in the form and documented. Care must be taken to ensure that only
authorized personnel carry out these simulations.
Safety devices/locks
All safety devices in the facility must be checked to make sure that they are functioning correctly. "Safety devices"
means all equipment that protects the operator from personal injury and the facility from improper handling. The
tests must be documented with the aid of the form (see Figure 4.E-16).
Figure 4.E-16 OQ form - safety

functioning
Date/
No. Facility Description correctly
signature
yes/no
1 Emergency The facility halts operation as soon as the button is pressed.
off button All motors and pumps are switched off and the valves for
media supply are no longer supplied with electricity.
Press the emergency off button when the facility is in
operation:
All motors stop moving
The valves for the utility supply are closed.
Flow rate test

The facility is started with a flow rate of 1000 m3/h without heating output and product (this corresponds to the
minimum capacity). The air velocity is measured and recorded at three different measuring points. This
3 3
measurement is then repeated with a flow rate of 3500 m /h and 6000 m /h. The values determined at the
various measuring points are compared with one another and assessed. The analysis is documented using a
form.
Flow rate control

A check must be carried out to verify that the flow rate is being controlled correctly using three different flow rates.
This involves starting the facility with a flow rate of 1000 m3/h without heating output and product. This setting is
maintained for 15 minutes. The flow rate is then increased to 3500 m3/h for a further 15 minutes and then finally
3
to 6000 m /h for 15 minutes. During this time the control must maintain a stable value that falls within the
specified range. The tolerance values are specified in a form where the results are also documented.
Spray rate
The facility is prepared as if a product cycle was about to be carried out; it is started with a flow rate of 2000 m3/h
without heating and product. The spray medium used is water. Measurements are carried out for 10 minutes with
the minimum, 50 % and the maximum spray rates, respectively. The spray quantity is determined by establishing
the tare weight. The trial must be carried out three times for each spray rate which must not deviate by more
than ±5 %. The tests are documented in the form.
Heat distribution
To check the heat distribution, the facility must be prepared as if a product cycle was about to be carried out and
must be started with a flow rate of 3000 m3/h without a product load. The temperature is set at 50 °C. Following a
five minute warm-up phase, the temperature is measured at 5 different points above the sieve screen for 10
minutes. None of the measured values may deviate by more than ±5 °C from the average value determined
above the screen. The trial is repeated at 80 °C and 110 °C. The tests are documented in a form.
Temperature control
The temperature control is checked without a product with a flow rate of 5000 m3/ h, at 50 °C, 80 °C and 110 °C,
respectively. After the five minute warm-up phase the temperature must settle down to a constant level which is
maintained for 10 minutes. The same procedure is then carried out for temperatures of 80 °C and 110 °C,
respectively and the control checked. The deviations must not be more than ±5 °C from the preset value. The
results must be documented. A printout of the plot must be included with the OQ report.
Screen masks
Checks must be carried out to verify whether the screen masks perform the functions they have been assigned. It
must be ensured that the operational parameters can be modified within their assigned limits. It must be possible
to store new formulations with the programmed operational parameters and call these up again. The temperature,
humidity and pressure values displayed are checked during calibration. A hardcopy of each screen mask must be
made and included with the form.
Equipment functions
This involves testing specific functions of the facility such as the "on/off" or "raise/ lower" operator control
elements. The decision as to which tests should be carried out is influenced by insights gained from the risk
analysis (see chapter 6.B.6 Risk analysis). The tests are documented in a form.
Product cycle
To check the entire sequence of functions in context, a trial run is carried out with the product. The manufacturing
instructions for the product must be used as the basis for the trial run.
Figure 4.E-17 OQ form - product cycle

Results
Product cycle correct:
yes/no
The product cycle was implemented in accordance with the manufacturing instructions.
The product cycle was implemented without interruption.
The prescription steps were processed correctly.
The step enabling conditions were achieved and identified.
No process-related malfunctions occurred.
The preset process parameters were complied with.
The product was checked in accordance with existing guidelines and complies with the
specifications.
Comments:
Date/signature:
The final product is checked in accordance with the relevant test procedure. The implementation and the test
results must be documented (see Figure 4.E-17). The product cycle data may be used for the performance
qualification and validation.
Batch record
The recording of a batch starts when the process begins and ends when the container is lowered. It must be
ensured that the process data entered and the measured values gathered are reproduced correctly in the batch
record. To check this, the batch record for the test run described above must be recorded manually in the form.
Once the trial has ended, the batch record which is generated automatically is compared with the manually
recorded data. There must not be any deviations.
Data backup
Checks must be carried out to determine how the system responds in the event of a power/utilities failure. It must
be ensured that the operating data that has accumulated up to this point is not lost in the event of a sudden
power/utilities failure. The facility must also be capable of continuing with the last process status following
restoration of the power/utilities and final confirmation. There must not be any deviations in the parameters set or
the process data. The test is documented using the form.
Access protection
It must be demonstrated that unauthorized individuals cannot access the system and manipulate data. A check
must be carried out to determine whether operational parameters can only be modified by authorized personnel.
The analysis is documented using the form.
Deficiency report
Deviations identified during the operational qualification must be documented in the deficiency report. The
operator defines the measures required to rectify the deficiencies or deviations; names the departments and/or
persons responsible; specifies deadlines by which the deficiency must be rectified at the latest and authorizes
implementation of the measures. Rectification of the deficiencies identified must be documented.
It must be ensured that changes made, as a result of rectifying deficiencies that have been identified, are
assessed and documented in accordance with the established change control procedures, and a requalification
carried out as required.
4.F Technical documentation


What does technical documentation have to do with GMP?
Which components make up the technical documentation in the GMP context?
How can extensive technical documentation be handled?
4.F.1 Necessity
Technical documentation comprises the recording, organization, and archiving of technically-relevant documents
and data, as well as their provision for information purposes (dtv, 1984). It is used to present procedural
sequences and general technical conditions in a reproducible and up-to-date form. What does technical
documentation have to do with GMP?
Chapters 4.26 and 4.27 of the EU GMP Guideline state: "There should be written procedures and the associated
records of actions taken or conclusions reached, where appropriate, for:[...], equipment assembly and calibration,
maintenance, [...]. "Clear operating procedures should be available for major items of manufacturing and test
equipment.
The U.S. CGMP Regulations state: "Written procedures shall be established and followed for cleaning and
maintenance of equipment, including utensils... These procedures shall include ... A description in sufficient detail
of the methods, equipment, and materials used in cleaning and maintenance operations, and the methods of
disassembling and reassembling equipment as necessary to assure proper cleaning and maintenance" (21 CFR
211.67).
"Automatic, mechanical, or electronic equipment or other types of equipment ... shall be routinely calibrated,
inspected, or checked according to a written program designed to assure proper performance. Written records of
those calibration checks and inspections shall be maintained" (21 CFR 211.68).
In order to satisfy the requirements of the EU GMP Guideline and U.S. CGMP Regulations, the technical
documentation is just as necessary as the qualification of rooms and facilities. Analogous to the basic principles
of the documentation contained in chapter 4 of the EU GMP Guideline and subparts D and J of the U.S. CGMP
Regulations, the technical documentation is also a part of the quality assurance. If no technical documentation
exists, it will not be possible to install, qualify and operate facilities or calibrate, repair or maintain them. Important
prerequisites for the usefulness of the technical documentation include being error free, relevant to the current
situation, clear, understandable, logical and complete.
The technical documentation is for the most part compiled by the machine suppliers. Incomplete, incorrect or
flawed documentation should not be accepted. To avoid this situation, the manufacturer of the machine should
have the documentation checked, approved and released by competent authorized personnel prior to delivery.
For more extensive documentation, it may be expedient for the users to receive instruction from the supplier, e.g.
as part of training courses. Due to the dissimilarities of potential users, it should be strongly requested that
overseas manufacturers provide the most important sections of the documentation in the local language in order
to eliminate misunderstanding and confusion.
4.F.2 Scope and content

The documents in Figure 4.F-1 are an important part of the technical documentation (also see general
requirements, chapter 4 EU GMP Guideline and subparts D and J of the U.S. CGMP Regulations).
Figure 4.F-1 Contents of the technical documentation

[EU Guideline]
Content of the technical documentation
Technical specifications
Process descriptions
Operating and assembly instructions
Wiring diagrams and construction drawings
Test protocols
Maintenance, cleaning and sanitizing procedures
Maintenance, cleaning and sanitizing schedules
Calibration documents
Machine log books
In the interests of clarity, ease of handling, and reduced search times, all technical documents should be
structured in a similar fashion. Figure 4.F-2contains an example of this.
Figure 4.F-2 Possible organizational system for technical documentation
A good way of standardizing the technical documentation is to develop checklists (see Figure 4.F-3, Figure 4.F-
4, Figure 4.F-5). These lists are helpful when specifying new facilities and they simplify the review of the technical
documentation during qualification.
A great deal of information, usually drawings, but also increasingly operating instructions, bills of materials, etc. is
being stored on data media. In order to ensure that the available documents are compatible and therefore useful,
the supplier and customer must agree on which data medium and data formats should be used. The Internet
provides an interesting option in this case as online access to the supplier's server means that the necessary up-
to-date information can be downloaded directly with little or no administrative effort.
Figure 4.F-3 Checklist - technical documentation (part 1)

Basic documents for the mechanical part of a facility (section 1 of 2)
Available
Document
yes/no
Documents requiring authorization after construction
Technical specification
General description of facility with drawings and function diagrams, abridged form
List of components of a facility, machine, equipment or system
Assembly and layout plans that explain interaction with existing facilities/equipment (on-site
requirements, connection requirements).
Equipment drawings including data for on-site connections (energy, utilities, drainage) and
other on-site equipment as necessary (platform, stair, balustrade, etc.)
Instructions for bringing in large components (into building)
(*) Facility documentation upon delivery
Installation plans, layout plans and electrical plans must be available both in paper form
and on data media (DWG or DXF file formats).
Detailed list of the energy and utilities supplied in accordance with the equipment
specification
List of operational parameters/tolerances of these components; data on limits (pressure,
temperature, variation limits)
List of components and equipment used, structured according to assemblies, including
full description (model number, material, type, size, manufacturer, etc.) and schematic
drawing of installation location (overview of assemblies)
Comprehensive documentation (materials used, requirements for materials, etc.) of parts
in the facility that come into contact with products, auxiliary modules and the controls
Machine drawings/equipment drawings
Contractual documents with technical specification to subcontractor
List of all parts that come into contact with the product
Clearance certificate for parts that come into contact with products
List of operating instructions and instruction manuals
Detailed operating instructions
Condensed version of operating instructions, maximum 1-2 pages
Maintenance manual for entire facility, partial facilities and components
Spare/wear parts list
Bill of materials with original manufacturer's specification
List of preventative maintenance and repair measures
TÜV (technical inspection authority in Germany)/other certificates (certification of
construction and water pressure inspection; final acceptance of safety equipment;
certificate of compliance for cryogenic plant, liquefier, etc.)
Documentation of pressure and leak tests for components, chambers, condensers,
intermediate valves, cryogenic systems, etc.
Record of function tests (factory acceptance test, FAT) at manufacturer's premises
Characteristic diagrams (e.g. of circulatory pumps)
(*) In the first column, the documents requested by the suppliers must be ticked.
Basic documents for the electrical and control element of a facility (section 1 of 2)
Available
Document
yes/no
Documents requiring authorization after construction

Technical specification (e.g. following ISO/DIN 3694 and in conjunction with
mechanical element)
Block circuit diagram/diagram of facility with designation of utilities
P&ID (piping & instrumentation diagram)
Front panel views, to scale
Equipment layout plans, to scale
Schematic or operating circuit diagrams
List of measuring points including definition of quality-relevant measuring points by
contract giver/list of sensors
Measuring point sheets
Terminal diagrams
Cable lists
Equipment parts lists
(*) Facility documentation upon delivery
Installation plans (strip maps) for decentralized assembly, requirements for strip
maps
Application software on specified medium
Documentation of process control with comments on steps (in relevant language)
Functional description of user software
Detailed documentation of PC and visualization application programming
Version status of firmware (PLC)
Description of development environment/development tool - data on system and
name of programming system
Commented source code (in relevant language) or viewing rights
Storage of source code in a neutral location
Assignment list (PLC only)
Version number of software in the code
In the event of a user change: notification to supplier
Input/output memory map for PLC
Interface specifications
Alarm list with structure: effect, cause, remedy
Operating manual/function description (hardware)/original documentation of
supplier
List of equipment parameters
Qualification of measuring circuits
Operating instructions/start-up instructions
Maintenance instructions (calibration instructions, if required)
Spare parts list
Electrical acceptance report at manufacturer responsible for production of facility
parts (sub-contractor)
EMC test protocols for equipment and facilities (electromagnetic compatibility)
CE certificate for facility
Instrument manuals
Installation certifications (e.g. according to VDE)
Installation instructions, software
Installation instructions, hardware
Additional documents for qualification of facilities
Available
Document
yes/no
(*) Mechanical element
List of machine, equipment and system drawings, with confirmation that these
correspond with the actual installation
Test procedures and results of the review to determine completeness and correct
assembly
Installation certificate (certifying correct assembly and on-site wiring between
control cabinet and machine including plan and checklists)
Special inspection reports on the quality of workmanship (e.g. weld seam protocols)
Certification of surface quality (e.g. surface roughness measurements)
Certification of correct installation of sterile filters (check for leakage flow)
Descriptions of materials used (e.g. raw material, condensers, adjusting plates,
reinforcement profiles, auxiliary welding materials)
Electrical and control element
Input/output diagram of software modules

Confirmation that completeness check on documents delivered by sub-contractors
has been carried out
Detailed description of utilities used
4.F.3 Administration of the technical documentation

Due in part to ISO certification (see chapter 1 Pharmaceutical Quality System (PQS)), there is widespread
acceptance amongst manufacturers of machines that equipment is incomplete where appropriate documentation
is lacking. If the manufacturers would provide complete and accurate documentation, then questions and
differences of opinion concerning the functioning, performance and acceptability of the machines would be
avoided. The extent and scale of the technical documentation continues to increase with the complexity of the
machines. Nowadays, it is not unusual for as many as twenty folders of equipment documentation to be required,
and so the necessity to administer and tend to this mass of paperwork and data as well as develop suitable
systems to deal with it, is unavoidable.
A system for technical documentation is characterized by established archiving modalities (see Figure 4.F-6).
Figure 4.F-6 Archiving modalities

Archiving modalities
Uniform structure
Clear identification
Change control
Version management
Access control
Defined responsibilities
Established in a SOP and training of staff
An example of uniform structuring is shown in Figure 4.F-2.
The definition of an identification system (e.g. using code numbers) is particularly important, especially in the
case of centrally archived systems. However, defined numbering is also highly recommended where
decentralized storage systems are used and where the document administration is to be carried out electronically.
For engineering drawings, the introduction of a "descriptive" numbering system is recommended.
Figure 4.F-7 Change control

9Change control: (see chapter 19.C Change control). The effort required to keep documentation for
implemented changes up-to-date on an ongoing basis cannot be underestimated and a pragmatic approach
should be employed. For example, the frequency of the updates can be linked to the quality relevance of the
technical change. If the change affects the quality of the product, the revised technical documentation must be
prepared and approved immediately, irrespective of whether the change is planned or is made as a result of a
malfunction. However, non-quality related, secondary and "nice to have" changes, which do not have to be
implemented immediately, can be collected and, when there is a sufficient number, the technical documentation
can be updated, approved and the changes implemented at that time. This process can contribute to the
efficiency and cost effectiveness of the change control process.Figure 4.F-7 shows the relationship between the
cyclical updates and changes that are subject to mandatory requalification for qualification, technical and
calibration documentation and maintenance schedules.
It must be kept in mind that the technical documentation for minor changes must be approved before
implementation. It may be tempting to document only major changes at the time of their implementation and to
implement what are considered minor or secondary changes and document and approve these periodically at a
later date (e.g., once or twice per year).
Although this practice may save on costs, resources and administrative effort, it is in violation of the US CGMP
Regulations, section 21 CFR 211.100 (a), which reads: "There shall be written procedures for production and
process control designed to assure that the drug products have the identity, strength, quality, and purity they
purport or are represented to possess...These written procedures, including any changes, [bolding added] shall
be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the
quality control unit".
The statement that written procedures have to include any changes is interpreted to mean that all changes have
to be documented and approved.
Figure 4.F-8 Administration sheet for working copies
In addition to being in violation of the US CGMP regulations, there are sensible reasons for documenting and
approving changes prior to implementation. One is that there is a risk that the change will be forgotten or some
details of the change will be overlooked and not properly documented. More importantly, records that will be used
to manufacture product may not reflect the latest approved procedure. It is also important to have all changes
documented to insure that the periodic review of changes to a piece of equipment is accurate and meaningful. All
changes to individual equipment should be reviewed periodically to determine if the sum of all of the changes
implemented is significant enough to trigger a requalification or revalidation. A single change may be deemed
insignificant and not require a requalification or revalidation. However, several insignificant changes over a period
of time may, in the aggregate, be significant enough to prompt a requalification or revalidation. If minor changes
are not documented when they are implemented, the conclusion from the periodic review as to whether the
equipment or process continues to be in a qualified or validated state will be flawed because the review will not
include all of the data.
For technical documentation, version management is a prerequisite for the availability of clear and up-to-date
information. For documentation stored on data media, particularly software documentation, this is essential.
Clear arrangements regarding access control and responsible persons must be made. To prevent copies being
made that are uncontrollable and therefore not subject to updates, the original documentation must be accessible
only to authorized individuals and any lending/borrowing must be documented (seeFigure 4.F-8). In practice it is
recommended that one or several working copies, subject to updates, are handed out (see chapter 15.D.8
Administration).
Figure 4.F-8 shows an example of an administration sheet that can be used for the control of working copies.
This manual sheet can be very easily and effectively used in a facility where the number of documents and the
staff that uses them is small. However, in a much larger facility, with many documents to control and a large staff,
the establishment of a more comprehensive electronic system with a low administrative burden should be
considered. This system would allow any authorized individual to obtain a copy of a document through a
computer or terminal. An audit trail would be created which would include the title of the document, version
number, to whom it was provided and the date and time. The system should also be capable of clearly identifying
copies of documents by imprinting each page with the word "COPY", or other suitable wording, and a clearly
visible expiration date. The expiration date should be kept as short as possible and can be based on the needed
usage of the document. A recall step should also be included in the system, which would automatically notify
holders of the copies that a new version of the document has been issued and that the copies of the older version
must be returned to the administrator. The implementation of an electronic system of this type would provide
further assurance that obsolete working copies would not be used after the issuance of a new version of a
document which would serve to enhance control and compliance.
4.F.4 Log book

"Log books should be kept for major or critical equipment recording, as appropriate, any validations, calibrations,
maintenance, cleaning or repair operations, including the dates and identity of people who carried these
operations out." (EU GMP Guideline, chapter 4.28)
Chapter 4.29 of the EU GMP Guideline additionally states that "Log books should also record in chronological
order the use of major or critical equipment and the areas where the products have been processed."
The U.S. CGMP Regulations do not specifically mention the use of a log book but refer to the need to keep
equipment logs, which do not necessarily have to be a book. However, many U.S. companies do maintain log
books. 21 CFR 211.183 states that "A written record of major equipment cleaning, maintenance ... and use shall
be included in individual equipment logs that show the date, time, product, and lot number of each batch
processed.... The persons performing and double-checking the cleaning and maintenance shall date and sign or
initial the log indicating that the work was performed. Entries in the log shall be in chronological order".
Log books must be kept and stored on-site, i.e. in the room or at the facility. Following CFR 211.180, records,
which includes log books, must be retained for at least 1 year after the expiration date of the batch manufactured
on the facility. However, to reduce administrative effort it is recommended that a standardretention time for log
books be defined, e.g. 6 years (expiration date of the medicinal product batch manufactured: 3 years, plus safety
margin: 3 years). If batches have expiration periods longer then 3 years, then the retention period should be
increased accordingly. This ensures that log books will still be retained once the machines and rooms have been
decommissioned.
Figure 4.F-9 Contents of log book

Contents of log book
Documenting log books in chronological Operation and use
sequence: Cleaning and sterilization
Maintenance, repair, changeover
Changes, conversion
Qualification, calibration, validation
Log books must be kept for: Equipment, machines, facilities
Ventilation systems, purified water
systems
Rooms
Entries must be made on-site in chronological order by the person carrying out the task(s). The entries must be
confirmed by the signature of another person who is overseeing the task and must be made promptly, i.e. when
the current task is being carried out; the signing may be done immediately after completion of the task. Entries
and changes in the documentation must be performed in accordance with the requirements of the EU GMP
Guideline or the U.S. CGMP Regulations. (See chapter 15 Documentation and chapter 15.B GMP-conforming
documentation).
In the interests of simple handling, it is recommended that a standard log book be compiled for use in all the
necessary areas. The assignment of log books to facilities or rooms must be facilitated through clear labeling.
The individual pages of the log book must be consecutively numbered. An example of a general purpose log
book can be found in Figure 4.F-10. Special features of an area may be recorded in the log books using the
"facility-specific area" column.
Figure 4.F-10 Log book (example)
Summary
If no technical documentation exists, it will not be possible to install, qualify and operate machines and
facilities or to calibrate, repair or maintain them.
It is recommended that the same standards that apply for pharmaceutical documentation are adopted for
the handling of technical documentation.
There is no cost-free solution for a technical documentation system.
It is not sufficient simply to introduce systems and expect them to take care of themselves. The
technical documentation must be updated during change control procedures. The success (or failure) of
the system depends on how well the organization embraces it, lives with it and develops it further.
Log books for machines, rooms and systems must be used to document all work in chronological order.
4.G Calibration

What do the terms calibration, adjustment and gauging mean?
What measuring points must be calibrated and how often?
How should calibration be documented?
"Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by
appropriate methods. Adequate records of such tests should be maintained." [EU GMP Guideline, chapter 3.41]
"Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related
systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and
holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked
according to a written program designed to assure proper performance. Written records of those calibration
checks and inspections shall be maintained." [21 CFR 211.68 (a)]
4.G.1 Definitions
According to DIN 31051, calibration is the determination and documentation of the difference between the
displayed value and the correct applicable value without technical intervention.
According to DIN 1319/Part 1, in measuring technology, adjustment involves the setting and balancing of a
measuring instrument to prevent deviations in measurements exceeding the margin of error. Adjustment
therefore requires intervention on the part of the measuring instrument, normally by making a permanent change.
Figure 4.G-1 Calibration variables
Gauging: The gauging of a balance involves testing and stamping by the relevant gauging authority in
accordance with the regulations. Gauging and calibration do not mean the same thing. A balance must be
calibrated but not always gauged. According to gauging legislation, mandatory gauging applies, e.g. for balances
that are used or are available "to determine weight for the purposes of business transactions" or "to test finished
batches or medicinal products". Additional balances that are subject to mandatory gauging are defined in the
legislation.
Following DIN 1319 Part 2, the measuring area is the display range specified by the manufacturer in which the
guaranteed margin of error will not be exceeded.
Measuring point: The unit delivering a measurement result is known as a measuring point. The measuring point
consists of a measuring circuit.
The sum of all the elements required to produce the measurement results is known as the measuring
chain or measuring circuit, which consists of at a minimum, a sensor, signal converter, display unit and
connecting cables.
Operating range is the interval between measured values in which the measuring instrument is operated. The
operating range must be defined in relation to the process parameters.
The calibration range normally includes the operating range as a minimum. In order to avoid limitations, it may
be expedient to calibrate the entire measuring range, particularly if the facility is used to carry out different
processes with a variety of operating ranges. The calibration must be carried out at a minimum of three test
points (start, middle, end of operating range). Five or more test points may be practical for a large operating
range (see Figure 4.G-1).
Alert/tolerance range: If the calibrated values are inside the tolerance limits, the calibration has been
successful; if not, the measuring instrument must be adjusted until the values are within the tolerance limits.
Upper and lower tolerance limits exist. If a deviation that is outside the tolerance limit is found, sometimes
referred to as an "as found" deviation, the persons responsible must assess the effect of this on the batches
already produced and introduce measures as required. The details of the deviation, data analysis and
conclusions reached should be documented in an official investigation report. With some measuring equipment it
may be expedient to introduce alert limits in addition to the tolerance limits. If the alert limits are exceeded the
equipment may be adjusted accordingly. The advantage of introducing alert limits is that the so-called "drifting" of
measuring instruments will be detected.
Calibrators are calibrating equipment, test pieces or testing devices that are used for calibration. Reference
measurement standards are more precise standards used to calibrate calibrators. Reference measurement
standards are in turn calibrated using a more precise reference standard. The national measurement standard
is at the very top of this chain. It must be possible, as evidenced by certificates, to trace all hierarchy levels back
to the national measurement standard. The traceability of calibrators to the reference measurement standard
may be achieved by calibration at the company itself. Reference measurement standards must be calibrated by a
national authority.
4.G.2 Procedure
The calibration procedure must be described in an SOP. A prerequisite for the calibration of measuring points is
that they all must be evident in the facility documentation. From the GMP perspective it is sufficient if the quality-
relevant measuring points are calibrated, but in addition to these, there are also many other measuring points
that are relevant to safety or are necessary for plant control. The person responsible for the calibration of the
facility must differentiate between the quality-relevant measuring points and those for which calibration is required
for other reasons. In so doing, it is expedient to assign priorities to the various measuring points, so ensuring that
quality-relevant measuring points have the highest priority.
Before the actual calibration of the measuring points can begin, the environment of the measuring instrument
must be checked. This is referred to asqualification of the measuring circuit by calculating the margins of
error and must be carried out in order to be able to assess the compatibility of the measuring circuit with the
measuring point. For this, the total statistical error of the measuring chain is calculated according to VDI 2620
(propagation of margins of error during measurements) by calculating the square root of the sum of squared
individual errors for all components (see Figure 4.G-2).
Figure 4.G-2 Calculation of margin of error according to VDI 2620
A complete technical documentation of individual components is required to qualify a measuring circuit. Error
calculation is often not possible in the case of old facilities that are not sufficiently documented but it is still
possible to define the facility as "qualified" provided that it has been successfully calibrated three times. This
procedure must be documented accordingly.
The actual calibration is carried out at intervals to be defined individually by comparing the required values of the
calibrator with the actual values of the measuring point at a minimum of three test points. To ensure a uniform
approach, the exact procedure for each individual measuring circuit type (temperature, pressure, volume, etc.)
should be defined in operating procedures. A successful calibration must be documented in what is known as
thecalibration report. If the tolerance limits are exceeded, the calibration must be repeated once the
adjustment has been successfully made.
This adjustment must be documented. If the tolerance limits are exceeded, the persons responsible must be
informed (ideally in writing) before adjustment and recalibration is carried out. An investigation must be performed
which evaluates any possible impact of the out of tolerance limits on batches manufactured since the previous
acceptable calibration. In addition to the paper documentation, the calibration status of the entire facility must
also be visible on-site, e.g. by using an adhesive label (Figure 4.G-3). Furthermore, it is recommended that each
individual calibrated sensor be labeled (Figure 4.G-4).
to to enlarge,
enlar click here!
ge,
click
here!
Figure 4.G-3 Facility status Figure 4.G-4 Labeling of sensors
4.G.3 Documentation
The documentation for the calibration must at least contain the following documents:
Figure 4.G-5 Calibration documentation

Calibration documentation
1. List of all measuring points. At least the following information must be available on each measuring
point:
1.1 Clear identification of facility (name, location, facility number, etc.)
1.2 Clear identification of measuring point (designation according to DIN and numbering)
1.3 Measuring range
1.4 Operating range
1.5 Alert/tolerance range
1.6 Calibration interval
2. Flow diagram of facility with exact location of measuring points
3. Calibration report (separate documentation per measuring point for the calibration performed)
4.G.4 Administration of scheduled calibration dates/ times

Compliance with the scheduled calibration dates/times is even more important than preventative maintenance, as
doubts about the quality of the products may be raised if defective measuring points are found. This is the reason
why it is becoming increasingly important to define the intervals for calibration cycles. Intervals that are too short
are uneconomical and intervals that are too long may put the quality at risk. In practice, an iterative progression
from short to long cycle times developed based on the quality and consistency of the calibration results has
proven to be effective.
For larger facilities, the many measuring points must be kept correctly calibrated without causing excessive
downtime. Calibration intervals of 6 or 12 months are practical. To increase flexibility, it is recommended that
the calibration deadlines be expressed in months and years (calibrate by end of 04/2010) and not dates
(24.4.2010). When only the month and year are given as the calibration due date, it should be specified in the
general calibration sop and made clear on each label that the calibration is valid until the last day of the month.
For critical measured variables, such as humidity, much shorter intervals may be necessary. Weighing systems in
the analytical laboratory or central weighing areas, for example, must be checked on a daily basis and/or before
every weighing operation. (See chapter 14.E Calibration in the lab.)
Figure 4.G-6 Procedure for a computer-supported calibration

(Boehringer Ingelheim Pharma KG, function description, 1995)
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here!
To cover busy periods and also to carry out special calibrations in the base load range, the services of certified
companies may be used. In these cases, timely authorization and planning of facility assignment is important in
order to be able to carry out the calibration on time, i.e. before the calibration deadline expires. If the calibration
date is exceeded, a sign must be posted indicating that the equipment is past its calibration date and can not be
used.
Thorough training of the third party personnel in the general company calibration requirements must be provided
before they are allowed to begin work. For example, if an "as found" calibration is outside of the acceptance
range, third party personnel must be trained to notify the designated company individuals and not to continue with
the calibration until given further instructions. The training program for third party personnel must be described in
an sop and the actual training documented.
The greater the number of quality-relevant measuring points, the more beneficial it becomes to consider
automatic deadline monitoring and assignment generation systems. Deadline tracking, generation of
assignments and production planning can be adopted by higher-level systems such as SAP. Laptops may be
used to call up calibration instructions from a database at the machine. Invoicing, documentation and calculation
of the next due date are carried out automatically following completed confirmation of the assignment.
Summary
Calibration is the identification and documentation of the difference between a displayed value and a
measurement standard.
From the GMP point of view, only quality-relevant measuring points must be calibrated.
Shorter calibration intervals must be selected where the measurement is more critical for the quality of
the product and where the measurement method is less known.
Equipment must not be used if the calibration deadline has passed. A sign must be posted stating that
the equipment is past its calibration date and can not be used.
The calibration status should be identifiable at each measuring point.
It is recommended that automatic systems be used to monitor calibration intervals.
4.H Maintenance

What does maintenance have to do with GMP?
Can preventative maintenance improve the product quality and be cost-
effective at the same time?
How can maintenance be optimized?
The EU GMP Guideline gives fairly unspecific requirements on the subject of maintenance or servicing. The
following passages are found in chapter 3:
3.34 Manufacturing equipment should be designed, located and maintained to suit its intended purpose.
3.35 Repair and maintenance operations should not present any hazard to the quality of the products.
The FDA, on the other hand, makes very specific requirements which are certainly not to be disregarded in light
of globalization and mutual recognition of inspections. Thus, the 21 Code of Federal Regulations (CFR) Part 211,
Subpart D, § 211.67 states:
a) Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent
malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product
beyond the official or other established requirements.
(b) Written procedures shall be established and followed for cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing, or holding of a drug product.
Further references to equipment maintenance are included in
211.63 Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of
appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its
cleaning and maintenance and
211.182 A written record of major equipment cleaning, maintenance (except routine maintenance such as
lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time,
product, and lot number of each batch processed.
The complaints frequently listed in the FDA's inspection records (FDA-483) regarding "non-existent or only
averagely executed maintenance" are evidence that, at least for the FDA, maintenance is not of secondary
importance.
4.H.1 Types of maintenance

The terms servicing and maintenance are often used as synonyms in practice, but are differentiated in the
literature.
In accordance with DIN 31051, maintenance is the entirety of all measures carried out to preserve and restore
the required status and to ascertain and assess the actual status of a system's technical means. Maintenance
includes measures such as inspection, repair and servicing. Servicing (care) is used to preserve the required
status. Inspection is used to ascertain and assess the current status of a component. Repair eliminates a fault
and thus restores the required status. A distinction is also made between preventative and fault-based repair
(Figure 4.H-1).
Figure 4.H-1 Definition of maintenance in accordance with DIN 31051
4.H.2 GMP-conforming maintenance

"The aim of GMP-conform maintenance is to minimize the number of malfunctions that occur and to stabilize the
sequences of the production and packaging processes so that a consistently high product quality is guaranteed."
(Excerpt of an industry SOP)
To assure operation of the process equipment with few malfunctions, preventative maintenance in particular is
required. Maintenance is preventative when the inspection and servicing of a facility is systematically carried out
in an established scope and time interval, i.e. it is planned (Lang, 1996). Maintenance measures are carried out
without prior inspection and without a malfunction having occurred. Preventative maintenance can be limited to
qualified equipment, or equipment that requires qualification, but can also be used for all other facilities.
Initially, maintenance without a malfunction having stopped the production process appears to be in competition
with valuable production times. When facilities are faced with particularly high production loads, it is often
tempting to give in to the pressure of production and postpone or cancel servicing and inspection. It is forgotten
that gradual wear and tear can negatively influence the product quality just as much as a malfunction. However,
studies have concluded that in many cases preventative maintenance can be carried out more cost-effectively
than fault-based maintenance, due to the prevention of damage and the associated more economic personnel
planning. The enormous costs of defective batches, which include the cost of the batch itself, time and effort to
conduct internal investigations and possibly experiencing an out of stock situation, are not taken into account in
these studies.
4.H.3 Systems for maintenance

A preventative maintenance system should be described in an SOP. For the above-mentioned reasons, it should
be scheduled on a machine with the same high priority as a production batch. The synchronization of servicing
deadlines with calibration deadlines should be planned, to avoid additional downtimes of the facilities. Even if this
is usually carried out via data processing systems, it is recommended that the implementation of preventative
maintenance be started with "manual" procedures, due to the high level of complexity.
Figure 4.H-2 Procedure for preventative maintenance
Figure 4.H-3 Maintenance instruction

The following procedure can be used to automate execution of preventative maintenance:
1. Compilation of an (adaptive) paper-based system for preventative maintenance (Excel, etc.)

2. "Manual" coordination and test runs of the maintenance
3. "Manual" scheduling of maintenance in the production planning
4. Transfer of paper systems to database systems (Access, Oracle, etc.)
5. Linking of database systems with the production planning system.
Figure 4.H-4 Automatic maintenance system
When introducing a "paper system" for preventative servicing and maintenance, proceed as described
in Figure 4.H-2.
Selection of the facilities and equipment in question

Stocktaking of all required activities: Collection of all required activities that are required to
maintain operation of the facility. The manufacturer's documentation is assessed by means of a risk
analysis and supplemented with the historical operating data. It is helpful to structure the facility into
individual facility components using the technical documentation (chapter 4.F Technical documentation).
Compilation of maintenance instructions: For each individual piece of equipment or for entire
facilities, a form is compiled with the inspection and servicing activities in question (see Figure 4.H-3).
Initiating and carrying out maintenance: All maintenance measures to be carried out regularly are
to be entered in a maintenance calendar. Maintenance must be commissioned and its execution
controlled.
Documentation: The maintenance measures that have been carried out must be documented. In
the above-mentioned example, this can be carried out directly in the form. The form can also be
supplemented with any additional required measures and thus be continuously improved, i.e. "learn".
The developed paper system forms the basis for implementation in the automatic maintenance
systems. A possible configuration is shown inFigure 4.H-4.
The order request for a maintenance measure is made from the production planning system (PPS). The
maintenance instructions, possibly with current information from the Internet, are loaded onto laptops from the
database. These laptops are used to document the maintenance measures on-site. Additional technical
information from the archives can be called up on-site via interfaces. Confirmation of the maintenance results is
incorporated into the maintenance forms and in the production planning. There, the maintenance request is
cleared and stored in the archive.
With automatic systems, it is worth considering that uniform procedures and the periodic upgrading of electronic
systems must be compared against the costs of procurement and maintenance and the costs of validation. The
potential improvement in GMP compliance must also be included in the comparison. It must also be kept in mind
that older data may not be readable after the software version is changed. Plans must be put in place to insure
that systems that can read older data are available and maintained in working order.
Summary
Maintenance includes measures such as inspection, repair and servicing.
"The aim of GMP-conforming maintenance is to minimize the number of malfunctions that occur and to
stabilize the sequences of the production and packaging processes so that a consistently high product
quality is guaranteed."
Preventative maintenance is profitable, not only from a GMP perspective.
The possibilities of "online maintenance" via the Internet and other electronic systems must be pursued
taking the costs/benefits relationship into account.
4.I CIP (Cleaning in Place)
Author: Thomas Kamm

How does a CIP facility work?
What is required of the components (pipes, seals, pumps, valves)?
What kinds of nozzle heads can be used?
What parameters are recorded continuously and for qualification?
What is to be taken into account when undertaking cleaning projects?
4.I.1 Introduction
The increasing expansion of production capacities and increasingly detailed quality management require
extensive automation in the production of pharmaceutical and cosmetic products. This means that production
must be carried out in closed systems, which minimizes the manual influence of operating personnel on
controlling the processes and significantly reduces operating errors. For compliance with the quality guidelines,
this not only applies to the actual production process of the pharmaceutical products, but increasingly also to the
associated cleaning processes. Economic aspects as well as specific cleaning validation requirements must be
considered.
Standing times, for whatever reason, are unproductive. With a continuously increasing focus on cost containment,
the personnel-intensive and time-intensive manual cleaning process is being compared critically against
automatic cleaning processes. Also, with closed facilities, fundamentally more aggressive cleaning conditions -
type and concentration of the cleansing agent, temperatures, pressures, etc. - can be applied than with the
customary methods (seechapter 8.B.3 Validating manual and automated cleaning procedures).
4.I.1.1 Definition
The quality of the product depends on the cleaning of the process equipment. Cleaning is the first and last step in
any production.
DIN 11483 defines "Cleaning-In-Place" as: "CIP is the cleaning of systems without having to dismantle them and
without making significant changes to the usage status of the system."
In order to be able to carry out this type of cleaning effectively and safely, it is absolutely necessary that
cleanability by means of a CIP process be considered when planning the process equipment.
4.I.1.2 Cleaning mechanisms

There are four essential influencing factors, which exert a crucial influence on the cleaning results and should be
taken into account for cleaning process equipment (see also Figure 8.B-1):
Temperature of the cleansing solution: The temperature range required for cleaning is based on
the technical possibilities, the obstinacy of the contamination/product residue to be removed and the
chemical composition of the cleansing agent
Mechanical effect of the pumped cleansing solution: The physical conditions required for
cleaning, such as pressure, volume flow and flow rate are considered. To achieve turbulent flow ratios,
the flow rate should be at least 2 m/s (or Re > 8000).
Chemical activity of the cleansing solution: The composition, concentration, surface tension and
dispersion ability are the parameters that influence the cleaning process. The type and concentration of
the cleansing agent to be used depends highly on the type of contamination. In addition, the sequence
and combination of different cleaning steps play an important role (see Figure 4.I-1).
Total duration of effect of the cleansing solution: The chemical processes for dissolving dirt (e.g.
dissolving stone with acid), dirt accumulation (e.g. dried-on starch and protein residues), saponification
(e.g. for fats), dispersion and rinsing are subject to time constraints.
Not all parameters must be constant during the cleaning process. The cleaning process can be
optimized by making special changes to individual parameters.
Taking into account the type and level of contamination or product residues anticipated, a decision must be made
on the deployment parameters of these influencing factors during the planning phase for a CIP facility.
Figure 4.I-1 Possible cleaning programs for a CIP facility
4.I.2 CIP systems

In systems engineering, a distinction is generally made between two types of CIP systems which have specific
advantages and disadvantages depending on the intended use.
4.I.2.1 CIP facility for stack cleaning

The main feature of stack cleaning is the repeated usage of the rinsing water and the cleansing solutions.
Depending on the cleaning plan, the facility usually consists of a pre-rinse container, an alkaline solution
container and/or an acid container with cleansing solution in the concentration required for use, and possibly a
disinfectant container, i.e. so-called stacking tanks (see Figure 4.I-2). The required container sizes are
determined by the volume of the largest cleaning cycle.
Figure 4.I-2 Stacking CIP facility
Cleaning begins with a pre-rinse step in which the relatively clean final rinse water from the last cleaning cycle,
which has been collected in the container for pre-rinse water, is used. The cleansing solution is conveyed through
the process equipment via a supply and reverse flow pump, with the stacking tanks often being included in the
circuit.
This is followed either by pure alkaline cleaning or an alkaline/acid cleaning process, possibly with intermediate
rinsing steps. Using a suitable measuring technique (see chapter 4.I.3.6 Requirements for measuring
instruments) the phases of the individual cleansing solutions are separated in the reverse flow to the stacking
tanks, e.g. water - alkaline solution or alkaline solution - acid, and the cleansing solutions are conveyed to the
respective tanks. In addition, an initially dirty part of the cleansing solution can be rejected specifically into the
waste water. The last rinsing step is always carried out with the water quality that is required in the production
process, e.g. drinking water in acc. with DVGW, purified water or WFI (see chapter 5 Pharmaceutical Water).
Advantages of stack cleaning

Minimized water and cleansing agent consumption and reduced energy costs through multiple
use of the solutions/rinsing water
Short-term availability of the cleansing facility through the stacked cleansing solutions; only the
final rinse water is taken directly from the operating network
Shorter cleaning times through more highly concentrated cleansing solutions
Disadvantages of stack cleaning

Residue particles from previous cleaning processes can accumulate in the stacking tanks ®
Hazard of cross-contamination if several items from process facilities are cleaned with a CIP facility
Higher effort required for systems engineering on the CIP facility
Validation takes longer and results in higher costs
4.I.2.2 CIP facility for lost cleaning

Disposable cleaning is characterized by the fact that a fresh solution is used for each cleaning step. The
cleansing solution is pumped into the process equipment in a short circuit, i.e. not using the stacking container,
and rejected into the waste water system after cleaning.
There are two versions of disposable cleaning that can be installed,
with containers in which the ready-to-use cleansing solution is stored (see Figure 4.I-3),
Figure 4.I-3 Disposable CIP with stacking containers
or without containers, where the solution is generated "online" by dosing the cleaning
concentrate directly into the circulation line (see Figure 4.I-4).

Figure 4.I-4 Disposable CIP with online dosage
Advantages of lost cleaning

The cleansing solutions are not burdened by the residue particles from previous cleaning
processes and have a constantly consistent cleaning effect.
Each cleaning step can be optimized for specific cleaning requirements (e.g. concentration,
temperature).
Especially with the "online" variant, there are reduced system engineering costs.
Validation is easier to carry out.
Disadvantages of lost cleaning

The consumption of water and cleansing agents and the energy costs are high due to the one-off
use of the solutions/rinsing water.
Cleaning times are increased due to the lower concentration of the cleansing solutions required
by the procedure.
The cleaning duration, especially with the "online" version, depends on the availability of the
waters used.
In the pharmaceutical industry, lost CIP cleaning is in practice preferred to stacked cleaning, as the risks of cross-
contamination are minimized and the cleaning processes are easier to validate.
Through an in-depth analysis and consideration of the requirements of a cleaning system, and taking into
account the needs of the production process, it is possible to achieve the optimum product safety, quality,
investment and operational costs.
4.I.3 GMP-conforming design of CIP facilities

As CIP facilities are directly connected to the process equipment, at least during cleaning, it goes without saying
that the same execution requirements apply to these as to the process equipment itself. (See chapter 4.B
Mechanical components.)
The technical design of the facilities is described in many bodies of rules, including the EU GMP Guideline and
U.S. CGMP Regulations. These stipulate detailed hygiene requirements for premises and equipment, and also
for components and facilities. Specific reference is made to the fact that they must be easy to clean [EU GMP
Guideline, chapter 3.36 and U.S. GMP Regulations 21CFR 211.42 (c) (10) (i)]. They must be designed,
constructed and used with a view to minimizing risks and achieving thorough cleanability so that any
contamination, cross-contamination or quality impairment of the product is prevented.
The principles of hygiene-compliant construction are given in the guidelines on QHD qualification (Qualified
Hygienic Design). This deals with a test system developed for hygiene-compliant construction [QHD Manual] by
the VDMA's Department for Sterile Process Technology.
The test system is split into 2 test phases:
Phase I: Theoretical proof of hygiene-compliant construction

Phase II: Proof of the practical cleanability via a standard test
4.I.3.1 Influences of the surfaces

The main effects that lead to hygienic problems can be avoided through the knowledge of the behavior of
microorganisms and microsubstances in facilities and components. A significant cause is the extremely large
adhesive power that is exerted between small substances or microorganisms and surfaces. If the surface
rawness is less than the size of the particle, the cleansing agent can directly wet and destroy the microbiological
contamination during cleaning. If the surface rawness is larger than the particles, the microorganisms are
affected only after the cleansing agent has been given a sufficiently long diffusion time. If the cleaning times are
too short, contamination is left behind. This problem is even more critical for narrow slits (e.g. seals), where the
cleaning effect is difficult to achieve and microorganisms find ideal conditions for reproduction.
From these considerations, it is easy to deduce the most important requirements for the different facility
components, although only the most important components are specified here, as these requirements can also
be easily transferred to other facility components.
4.I.3.2 Requirements for pipes and tanks

Pipes and containers in pharmaceutical process equipment take up the biggest percentage of surface area and
are therefore particularly critical in terms of their technical design. Surfaces should cause little mechanical
damage to the product and should have a low bonding capacity for external particles. Their roughness, as a living
space for microorganisms and sediments for substrates should be as low as possible and the contours should be
rounded. (Seechapter 4.B.1 Construction and installation materials.) Figure 4.I-5 gives an overview of the
requirements.
Figure 4.I-5 Requirements for pipes and tanks

Requirements for pipes and tanks
Surface rawness of pipe interior and tank interior wall Ra < 0.8 μm
Minimization of the surface rawness on welding seams through orbital welding
technology Ra < 1.6 μm
So-called "dead legs" are to be avoided;
the l < 3 x d rule applies (see Figure 4.I-6)
Pipe systems and containers are to be self-emptying
The pipe material should preferably be stainless steel of AISI 316L quality
Solid connections are to be preferred to detachable connections, where
possible
The length of the tank connection nipple is to be kept to a minimum
Even with CIP tanks, a nozzle head for self-cleaning is to be provided
Figure 4.I-6 Dead legs, flow ratios in pipes/reductions, bends
4.I.3.3 Requirements for bonding elements and seals

Seals present a particular source of hazards. On the one hand, this is caused by the materials themselves, and
on the other hand, standard construction is often used to manufacture the equipment, without taking into account
the associated infection hazards. Therefore, the requirements specified in Figure 4.I-7apply in particular.
Figure 4.I-7 Requirements for bonding elements and seals

Requirements for bonding elements and seals
Reduction or prevention of bonding elements where technically possible
Use of hygienic screw fittings and flange connections in accordance with DIN
11864 with defined compressed sealing rings (see Figure 4.I-8) or use of clamp
connections in accordance with ISO 2853
Use of FDA-approved sealing materials (e.g. EPDM, PTFE)
Defined compression of sealing elements
Figure 4.I-8 Screw fitting in accordance with DIN 11864
4.I.3.4 Requirements for pumps

In the field of pumps, the draft of "DIN EN 12462 Biotechnology" laid down the first precise definitions of the
cleaning and sterilization capability, the tightness of the materials and their surfaces and constructive details in
terms of the CIP/SIP capability (see Figure 4.I-9).
Figure 4.I-9 Requirements for pumps
Requirements for pumps
Surface rawness of pump housing, shaft and wheel should be <0.8 μm.
Slit-free design of all inner parts, e.g. slits that cannot be reached by the
cleaning flow.
If unavoidable, the length to width ratio for slits should be <1.5.
It must be possible to empty the pump completely.
Figure 4.I-10 shows a cross-section of a hygiene-compliant pump.
Figure 4.I-10 Cross-section of a hygiene pump
4.I.3.5 Requirement for valves

Special requirements are made for valves in automated pipe networks. Often, the main task of such fittings is to
act as switch modules to interrupt or release the flow in pipes, in order to separate or connect facility areas from
or with each other.
In order to be able to safely separate mutual contact of a product or cleansing agent in a pipe network, for
example, the principle of double sealing with a leakage cut-out is today state-of-the-art for valves. In addition to
safeguarding contact between the different products, the mechanics of the valve are also separated from the
liquid by bellows and are thus easy to clean.
Parallel to this complex valve technology, diaphragm valves are also increasingly being used in systems
engineering. The diaphragm valves are very easy to clean due to their design, and can be used for almost any
task.
Examples of hygienic valves are shown in Figure 4.I-11.
Figure 4.I-11 Hygienic valve types using the example of a diaphragm valve (left)
and aseptic valve (right)
4.I.3.6 Requirements for measuring instruments

Control equipment and sensors are fitted in the facilities to control and regulate the production process and to
keep it externally transparent. Cleanability and sterilizability in the CIP/SIP procedure is just as important as the
regulated function of the equipment, i.e. it must be possible to clean and sterilize the measuring equipment with
no residue. Given this premise, the recording fitting of the measuring instrument is given special importance. In
particular, the points in Figure 4.I-12 must be taken into consideration.
Figure 4.I-12 Requirements for measuring instruments

Requirements for measuring instruments
The fitting should, if technically possible, be welded into the facility.
A slit-free and dead volume-free installation must be achievable.
The thermal isolation of the sensor must be ensured.
It must be possible to calibrate the equipment.
Programmable measuring instruments must have system software that can be
validated.
4.I.4 Nozzle heads for container cleaning

Nozzle heads are generally used to apply the cleansing solutions to the container walls when cleaning facilities,
especially containers. Their design and version differ according to the required purpose. The type, shape,
performance, positioning and number of nozzle heads must be selected from an engineering perspective and
take into consideration the points specified in Figure 4.I-13, as the hydraulics, consisting of the nozzle head and
cleaning pumps, are an important factor for successful cleaning.
Figure 4.I-13 Factors for successful cleaning

Factors for successful cleaning
Tank shape (up-right, horizontal, rectangular, conical, cylindrical, etc.)
Tank dimensions
Position, size and shape of connection nipples, stirrers, baffle plates, etc.
Size of the outlet nipple
Type of contamination and estimate of the difficulty of removal using
chemicals
The nozzle heads are installed so that a sufficient flow volume reaches the upper and lateral tank walls. While
nozzle heads that are too low will not achieve a sufficient upwards spray width of the spray jet, if the nozzles are
positioned too high, the spray will be so strongly deflected by the unfavorable angle of deflection that the falling
cleansing solution could spoil the entire spray pattern of the nozzle head.
However, the aim is to achieve the best possible cleaning with all types of nozzle heads, specifically in very
contaminated areas. The lower area is usually etched and removed by the receding cleansing solution.
A distinction is made between the following kinds of nozzle heads:
4.I.4.1 Spray ball

Low pressure cleaning principle
Fixed nozzle head
Variable spray patterns through different bore patterns in the head
For readily soluble dirt residues
High flow with low pressure
For an illustration of the spray pattern, see Figure 4.I-14.
4.I.4.2 Rotating nozzle head

Low pressure cleaning principle
A targeted, rotating fanned jet in one level, driven by a flow gear
Individual nozzle layout on the nozzle head
Higher cleaning effect with lower water consumption compared with the spray ball, due to lower
overall outlet area
For an illustration of the spray pattern, see Figure 4.I-15
4.I.4.3 Targeted jet/orbital cleaner

Low and high pressure cleaning principle
Rotating, sharply bundled cleaning jet in two levels, usually driven by an electric motor
Special outlet cross-sections prevent vaporization of the cleansing solution
Defined friction tolerances achieve a self-cleaning effect of the nozzle head.
High cleaning effect with minimized consumption of cleansing solution
To achieve overall coverage of the container walls, a minimum running time must be adhered to.
Function monitoring possible -> Validation
For an illustration of the spray pattern, see Figure 4.I-16.
Figure 4.I-14 Figure 4.I-15 Figure 4.I-16

Spray ball and spray Rotating nozzle head and spray Targeted jet cleaner and spray
pattern pattern pattern
4.I.5 Measuring technology

From a qualification and validation perspective, the reproducibility of automatic cleaning has advantages over a
manual cleaning process that depends on people. Cleaning-related parameters can be recorded and
documented sooner and more easily and are thus more readily accessible for validation. To this end, the
following parameters are usually measured and documented online in modern CIP facilities.
Measuring value:
Flow Q
Pressure p
Temperature T
Conductivity k
4.I.5.1 Flow measurement

The flow is typically used as the supply value for the CIP pump control in the supply and reverse flow in order to
assure that there will always be a sufficient flow rate (v > 2 m/s, Re > 8000) in the pipes.
Measuring instruments with a magnetic inductive measuring principle and mass flow measuring instruments with
the Coriolis measuring principle are suitable for measuring the flow. It must be ensured that a minimum
conductivity of at least k > 4 μS is given for magnetic inductive measuring procedures. If demineralized water is
used in a CIP procedure, this measurement type cannot be used. A further measuring method, though far below
the aforementioned methods in terms of precision, is flow measurement by ultrasound. However, this does offer
the advantage that it can be applied to the pipe from outside and thus, from a GMP perspective, is the most
hygienic volume measurement.
If the flow measurement is defined as a critical measuring instrument for qualification or validation, the mass flow
measuring instrument should be given priority due to the precision of the measurement. For calibration of the
measuring instrument, it must be ensured that not only the measurement transmitter itself, but also the output
signal for control (pulse signal, flow signal) is checked.
4.I.5.2 Pressure measurement

The pressure measurement in CIP systems is used both as a critical measuring instrument for process
monitoring and as a safety measuring instrument. In particular for nozzle heads, compliance with a defined
pressure range must be ensured, both minimum and maximum, in order to attain the desired spray pattern for
optimal cleaning of a container. The pressure measurement is often used to monitor and measure the level in
pressurized containers, as a safety precaution.
The main type of pressure measuring instruments used are measurement recorders with diaphragm pressure
gauges, which are filled with different utilities depending on the requirement (temperature and pressure range).
They are installed in hygienic screw fittings or clamp connections and follow the GMP Guidelines. If the
measuring values are not only used for display, but are also evaluated in the CIP control, then electrical
measurement recorders are used. These are coupled in the process in the same way as manometers with the
diaphragm pressure gauge. Recently, electrical pressure transmitters with ceramic surfaces have also been used,
which do not require diaphragm pressure gauges.
If a pressure measurement is classified as a critical value, it is recommended that the pressure measurement be
carried out electronically in order to be able to record and evaluate the values in the control. Long before cleaning
is no longer adequate due to a falling pressure level, trend analyses of measurement values often have exposed
this condition as a fault.
4.I.5.3 Temperature measurement

For effective cleaning, but more so for steam sterilization, compliance with the required temperature at specific
points in the cleaning facility is a quality-related criterion and is usually also classified as a critical measurement
value.
Temperature is now measured almost exclusively with PT-100 thermocouples which are installed in special fitted
sleeves or immersion sleeves. The speed of the temperature changes in the process and the associated need to
measure the temperature just as quickly is crucial for the design of the immersion sleeves. The immersion
sleeves are welded into the pipe or container and are thus installed with no slits or leaks.
To measure the temperature to ensure a correctly executed sterilization, the temperature sensor must be
positioned at the coldest spot of the facility.
4.I.5.4 Conductivity measurement

Measurement of the conductivity of liquids is used in CIP procedures to satisfy several requirements of plant
control. On the one hand, it is used to determine the concentration of cleaning solutions, as the conductivity
changes with variation in concentration, and on the other hand, it is used to separate the phases of the individual
cleaning steps (see chapter 4.I.1 Introduction). In particular, the measurement of the final rinse conductivity after
cleaning, i.e falling below a minimum conductivity level (usually k < 1 to 3 μS), is most important for the
subsequent production process.
A distinction is made between conductive and inductive measuring procedures. As the cell constant can be
relatively easily minimized in conductive conductivity measuring instruments due to their structural design, these
instruments are preferred for the lower measuring range, e.g. demineralized or WFI water. Inductive instruments,
due to their design, are almost maintenance-free, can be easily calibrated and, due to the inductive measuring
procedure, are insensitive to electrode abrasion and build-up of deposits.
4.I.6 Realization of cleaning systems

To ensure realization of a GMP-conforming cleaning program, the exact cleaning target must first be defined. The
cleaning target gives a required value to be achieved for the later qualification and validation (see chapter 8.E
Acceptance criteria and limit calculation).
In order to achieve a cleaning target, exact knowledge and analyses of the objects and production residues to be
cleaned are required. The cleaning selection is based on the prescribed products and procedures from a GMP
perspective (Figure 4.I-17).
Figure 4.I-17 Interaction between production and cleaning process
Only detailed knowledge of the production processes allow selection of the chemical cleansing agent and
cleaning process. Checklists for querying the conditions (see Figure 4.I-18) help in the selection of the best
cleaning variants while maintaining the economic perspective.
Figure 4.I-18 Checklist for realization of cleaning projects

Checklist for realization of cleaning projects
What should be cleaned?
Tanks (diameter, height, number, cleaning frequency)
Pipes (cross-section, length, number of bends, height difference, cleaning
frequency)
Facility objects (type, volume or performance, cleaning frequency)
What production residues, contamination are present?
What cleaning steps must be provided for? (see Figure 4.I-1)
Alkaline solution (cold, hot)
Acid (cold, hot)
Disinfection
Steam
How should cleaning be carried out?
Automatically
Semi-automatically
Manually
Visualization of the process (CIP validation by PC)
Is the CIP system working to full capacity for the intended project plan?
What time is available for cleaning?
Should cleaning processes be carried out simultaneously?
What disassembly stages are planned in production, for which the CIP system should also be used?
Is there a plant standard for components?
Valves
Pumps
Other components
Is there a flow chart of the objects and/or paths to be cleaned?
What utilities supply is necessary?
Fresh water (DN, position in the room)
Demineralized water (DN, position in the room)
Water for injection (DN, position in the room)
Steam (DN, position in the room)
Air/sterile air (DN, position in the room)
Cleansing concentrates (DN, position in the room, container size used)
Summary
Knowledge of the different kinds of procedures and functionalities is necessary to realize a GMP-
conforming CIP facility. Procedures, chemicals and spraying steps, through to the measuring and
control technique, are selected. For CIP systems, a distinction is made between stacked cleaning (re-use
of the cleansing solution) and disposable cleaning (one-off use of the cleansing solution).
The same requirements apply to the design of CIP facilities as to the process equipment: dead volume-
free design of the components, smooth surfaces and turbulent flow in the pipes.
The type, shape, performance, positioning and number of nozzle heads determine the level of success of
the cleaning.
The advantage over manual cleaning is that cleaning-related parameters such as flow, pressure,
temperature and conductivity can be measured and included in qualification and validation.
4.J Containment (personnel protection)

in solids handling
Author: Richard Denk

Why are containment systems important for users?
What does the term containment mean?
What different categorization systems are there for containment?
Where can weak points occur in process engineering?
What are the different containment systems?
4.J.1 Significance
The significance of containment in the pharmaceutical and API area is understood as health protection
for operators and as product protection. Drugs or APIs can be dispensed in liquid or solid dosage forms. This
chapter will not address liquids, as closed systems are better used in this area. In the API area, there are starting
materials, intermediate products from the centrifuges or powders after drying. All have in common that dust is
released in varying concentrations and particle sizes during production. If handled without special protection, this
dust is inhaled by the operator and can enter the bloodstream via the respiratory tract. Products can also be
absorbed via the eyes or skin. Particularly with highly potent drug substances, the inhalation of this dust can lead
to short-term or long-term damage to the employee's health or can damage the genetic material. For this reason
in particular, it is important to contain the product where it is manufactured - from the first step of the process
through to the final packaging.
Extra attention is paid to full protection of the operator during the production of highly active APIs and drugs
(see Figure 4.J-1) or the facilities are installed in isolators or laminar flow units (secondary containment).
4.J.1.1 Use of laminar flow units
The use of systems engineering in laminar flow units results in the undesired contamination of the interior of the
laminar flow unit. When the product or batch is changed, the laminar flow unit must be cleaned, which in turn can
be problematic for the health of the operator if the laminar flow unit has to be dismantled or opened for cleaning.
Furthermore, each container discharged from the unit, as well as the personnel, must be cleaned
(decontaminated). It is recommended that swab tests be carried out on the operator, in addition to regular particle
monitoring, in order to ensure that the operator's clothing has not become contaminated.
4.J.1.2 Working in the full protection suit
to enlarge, click here!If the entire work process is set up without containment systems, work
must be performed in a full protection suit, depending on the potency of the medicinal
product or API. The working area must be isolated accordingly. Access by the operator
must be via special locks.
Putting on a protective suit is a time-consuming procedure for the user. The operator must
leave the room for a break after two hours which entails going through a decontamination
procedure to prevent transfer of the product from the isolated area, and then putting on the
suit again when he returns to the room. For health and safety reasons, there must always
be two people in the room, which means increased personnel costs. Additionally, a third
person is located in the neighboring room to complete the records. To enable
communications between the two rooms, the operators have radio links with each other
and must confirm the values with each other to avoid errors. If an electronic system is
established and validated, the records can be filled in by the personnel in the room, thus
eliminating the need for a third person.
When using protective suits, the following legal principle should be considered, in
accordance with EU Directive 89/391 EEC,Introduction of measures to encourage
improvements in the safety and health of workers at work. This directive explicitly refers to containment systems
with the following wording: "Giving collective protective measures priority over individual protective measures."
The reason for this is that most personal protection measures have failed, either through small tears in the suits,
which go unnoticed, or through incorrect wearing of the protective suits. To counteract this, systems have been
developed, and successfully implemented, which contain the product in a continually closed process - even
during transportation in intermediate containers, such as containers(IBC - Intermediate Bulk Container), Big
Bags (FIBC - Flexible Intermediate Bulk Container) and drums. This has the advantage of allowing the operator
to move without taking particular precautions, and it also eliminates cross contamination.
4.J.2 Definition of terms

Containment: Process of enclosing a biological agent or other material within a defined space.
Primary containment: A containment system that prevents the escape of a biological agent into the immediate
working environment. This includes the use of closed containers or biological safety workstations together with
safe working procedures.
Secondary containment: A containment system that prevents the escape of a biological agent externally or into
other working environments. This includes the use of premises with special ventilation and the availability of locks
and/or sterilizers for removing materials together with safe working procedures. In numerous cases, this can
increase the efficacy of the primary containment.
Containment area: An area designed and operated (and equipped with suitable ventilation and filtration
systems) in such a way as to prevent the contamination of the environment by biological agents from the area.
4.J.3 Containment grades of products

The containment requirements are specific for each individual product, and must therefore be defined for each
product. Different grading systems exist. In Germany, the residue limits are defined by the AGW (workplace limit
value). Internationally, grades are recognized in accordance with the OEL (Occupational Exposure Limit). The
pharmaceutical industry classifies its products and active ingredients according to different bands
(OEBs, Occupational Exposure Bands).
OEBs (Occupational Exposure Bands): These bands consider the toxicology of the pure substance. The aim is to
provide a system categorization that can be used to select a suitable production facility and working procedure
for a product.
The OEL (Occupational Exposure Limit) defines an average concentration load of a drug or API measured over a
particular time (TWA - Time Weighted Average). The measurement is carried out in the employee's breathing
area over a period of eight hours (40 hour week). The term OEL comes from the pharmaceutical industry, where
internal occupational exposure limits have been calculated for a long time without being regulated by the
authorities.
Figure 4.J-2 The OEL (Occupational Exposure Limit) grade means the limit for the
particular place of work.
Grading in accordance with the table from OEL1 to OEL5 (see Figure 4.J-2) must be defined according to the
toxicity and the potency of the product. While open systems with local aspiration are used in the OEL1 area, the
systems must become increasingly closed higher up the pyramid. OEL5 products can only be processed using
special equipment (see chapter 4.J.7 Containment systems for filling and emptying drums).
The following special feature should also be noted when selecting the facilities: The containment grade deals with
the particles in the air, not the product build-up on the surfaces. It is absolutely possible for a system to be graded
as a containment system and yet still have product caking on the external surfaces at the containment interfaces
after system separation. (This refers to the separation from one unit to a different unit, with the containment
system being separated in between.) Compliance with OEL4 or higher can still be achieved nonetheless.
Provided the product remains on the surface or only a small number of particles escape into the air when the
product falls, the required value is, on average, not exceeded. This is permissible but not desirable, as the
cleanliness of the facility in this case is highly user-dependent. It is recommended to perform swab tests at
interfaces and on surfaces in order to determine the level of product residue on the surfaces.
The residue limits are defined using company-specific calculations provided by manufacturers of active
pharmaceutical ingredients and medicinal products. Among other factors, this calculation takes into account the
toxicity, carcinogenicity, mutagenic properties or fertility-damaging effects of the substances. If the residues
exceed the residue limit, the surfaces must be cleaned with appropriate methods before leaving the room in order
to prevent carry-over or cross-contamination.
Figure 4.J-3 Technical protective measures depending on material group G1- G4 according
to the German Chemical Industry Association
The following categorization systems should also be mentioned:
In the U.S., the Occupational Safety and Health Administration (OSHA) establishes PELs
(Permissible Exposure Limits), which place limits on the amount or concentration of a substance in the air.
PELs are legally enforceable. In 29 CFR 1910.1000, a tabulation can be found which contains
approximately 500 PELs covering some 300 chemicals, many of which are used in industry.
Also in the U.S., NIOSH (National Institute for Occupational Safety and Health) establishes
Recommended Exposure Levels (RELs) to protect workers. However, unlike OSHA, NIOSH's RELs are
not legally enforceable. NIOSH makes recommendations to OSHA for the establishment of limits for
hazardous substances.
There are other organizations in the United States that publish exposure limits. These
organizations include the American Industrial Hygiene Association (AIHA), the American National
Standards Institute (ANSI), the Mine Safety and Health Administration (MSHA), and the U.S. Navy.
Technical protective measures depending on the material group G1-G4 according to the German
Chemical Industry Association (BG Chemie /1/) (Figure 4.J-3)
TRGS 900: German technical guidelines for hazardous materials (new Ordinance on Hazardous
Substances), available under www.baua.de. In the Ordinance on Hazardous Substances (German
Gefahrstoffverordnung, valid from 31.12.2004), closed systems are also required for CMR substances
(carcinogenic, mutagenic and toxic to reproduction substances).
4.J.4 Measurement of the residue limits (OEL)
to enlarge, click here!The OEL value is measured over eight hours, which corresponds to
one working day. The average value must not exceed the required value during the
measuring period. This value is measured with special measuring instruments (e.g. laser
spectroscopy by the company rapID) or with filter systems which are then analytically
evaluated in certified laboratories. It must be ensured that measurements are taken at the
critical points, such as when docking on to and off from the containment system.
Measuring instruments and filter systems should be installed close to the operator's respiratory tract
(see Figure 4.J-4) and at critical points in the room, for example at personnel and product locks.
It is difficult for suppliers of containment systems to guarantee a required value, as this can be influenced by
several factors.
In particular the frequency of changing the container should be mentioned here. If only one drum is filled during
a shift, the average value can be much lower than if 20 drums are filled every hour. Other factors for achieving a
very high level of containment are the particle size, air exchange, and air pressure.
During measurements, intermediate evaluations should be performed in addition to reporting the overall result
across the day. These intermediate values are indispensable for recognizing peaks in critical working steps. With
each OEL grade, limits should be defined for the peaks, which must not be exceeded (Figure 4.J-5).
Figure 4.J-5 The required OEL value is an average value - measured over eight hours.
All systems are subject to wear and tear, which is why regular monitoring is important. It is advisable to perform a
measurement in accordance withSMEPAC (Standardized Measurement of Equipment Particulate Containment).
The SMEPAC recommendation was compiled by a working group involving representatives from the industry,
engineering and consulting firms, and suppliers. The ISPE (International Standards for Pharmaceutical
Engineers) has published the Good Practice Guide Assessing The Particulate Containment Performance Of
Pharmaceutical Equipment, which is available from the ISPE website (www.ispe.org). This Good Practice
Guide is intended to enable unification of the measurement procedures so that containment systems can be
compared more easily.
4.J.5 Example of containment facility planning

Before planning a containment system in an API or pharmaceutical facility, the residue limits of the required level
of containment should be defined (seeFigure 4.J-2). The OEL value (Occupational Exposure Level) defined
ultimately determines the selection of the containment system.
In the following example, an OEL of less than 740 nanograms/m3 TWA (Time Weighted Average) is required. In
order to ensure compliance with this value, aDEL (Design Exposure Level) of 370 nanograms/m3 TWA has been
defined. The DEL is the value that the containment system must meet, and is usually a certain defined
percentage below the OEL value. Determination of the DEL value varies depending on the pharmaceutical or API
manufacturer. In this example, the required OEL value has been divided by two in order to guarantee compliance
with the required OEL value. Since this example deals with a system for discharging and filling highly-active APIs
from containers such as Big Bags, and a comparable installation with this high level of containment did not yet
exist anywhere in the world, an increased degree of qualification was required in the design phase. For this
reason, a pre-DQ was carried out, which also incorporated safety aspects into the design with regard to
personnel safety during the risk assessment. A feasibility study (mock up) was also executed during the pre-DQ,
to assess whether the design of the facility was suitable for the requirements. An OEL measurement should be
performed during the FAT (Factory Acceptance Test), to ensure that the technology in the facility complies with
user requirements (user requirements, Figure 4.J-6).
Figure 4.J-6 Qualification of containment systems

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A measurement reference and a suitable reference product for measuring the containment should also be
selected. In this example, the ISPE baselineAssessing The Particulate Containment Performance Of
Pharmaceutical Equipment was determined. Lactose was used as a reference product in accordance with the
ISPE baseline.
Further requirements of the containment system were:
Flexibility in size
Easy to empty
(also if the products to be manufactured have poor flow properties)
Disposable containment system
(i.e. no time-consuming cleaning validation of containers)
Maximum container filling quantity of 350 kg
In particular, the disposable container and its design should have the following characteristics:
Suitable for products with different flow properties

The geometry of the container should allow self-discharging or emptying using suitable
discharging aids
Approved for use with hazardous materials, in order to enable transport of the products outside
the building without outer packaging
Approved for the following modes of transport: ship, HGV and rail
The costs of the disposable packaging system also played an important role, since a large number of containers
is to be filled and emptied each year.
4.J.5.1 The FIBC (Flexible Intermediate Bulk Container) as a

containment system
A suitable containment system should be selected with regard to fulfillment of the requirements based on a risk
assessment. In this example, the FIBC (e.g. Big Bag) is the suitable packaging medium.
When connecting the FIBC inlet or outlet, in addition to the desired containment value, the product to be
processed, and in particular its flow properties should also be taken into account. This determines the required
connection diameter. Here a connection using an isolator was selected, since this was able to achieve the
required containment of less than 370 nanograms/m3 with a connection diameter of 250 mm.
In order to achieve this high level of containment, the FIBC must be equipped with two inner film bags (inliners) at
the inlet neck and the outlet neck. The internal inliner is filled with the product, and the outer inliner is required for
double protection and for connection to the isolator.
Both inliners are protected by the external shell of the FIBC during transport (Figure 4.J-7).
Figure 4.J-7 Big Bag with inliners

4.J.5.2 Isolators as a containment system

To ensure that containment is maintained at a constant level, the isolator is operated at a constant negative
pressure (-50 to -70 Pascal) and with 20x air exchange. The negative pressure is controlled by a frequency
converter on the vacuum system, which increases the capacity if a leak is detected in the isolator, so that no
particles are allowed to escape, even in the case of a fault (Figure 4.J-8).
Figure 4.J-8 Total containment system with Big Bags

During the risk assessment, each individual work step was precisely defined and its implementation recorded in
the requirements specification for the design (Figure 4.J-9).
Figure 4.J-9 Requirements and implementation for isolator connection

Work step Requirement Implementation
Connection of the Adapt the outlet neck of the inliner to Connection system that achieves a dust-
external inliner to the (still closed) isolator tight stable connection, with easy and
the isolator fault-free operation
Check outlet neck Leak test is required before isolators can Leak test system in the connection
for tightness be opened for attaching the internal system for the external inliner, which is
inliner (with product) via the RTP verified and released by the control.
(Rapid Transport Port).
Attach the internal Open the RTP (figure 4.J-10). The
inliner with product negative pressure in the isolator means
to the isolator that the inliner with product is pulled
into the isolator.
Connect the internal Prevention of any dust formation/open Additional connection system in the
inliner product handling isolator to enable safe and closed
connection of the inliner.
Figure 4.J-10 RTP (Rapid Transfer Port)
4.J.5.3 Transport and docking system for the FIBC

Because the FIBC is a flexible packaging material, it is recommended that it be always transported in a frame.
This frame has the advantage of fixing the FIBC in the frame and also permitting transportation by pallet lifting
trucks. The frame is also required for transporting the FIBC into the filling or discharging position using a lifting
column.
The lifting column fixes and centers the transport frame of the FIBC. As an additional element, the lifting column
includes a discharge unit for the product in the FIBC. The height of the discharge unit can be adjusted, so that
once the FIBC frame is attached, this can be moved to the FIBC outlet to contact the cone on the FIBC. This
stimulates the product flow. The lifting, lowering and rotation of the FIBC frame by the lifting column has been
equipped with special safety features to protect the user and the Big Bag during the lifting and transport
movements.
4.J.5.4 Feasibility study (mock-up)

Before the completion of the design and release for manufacturing, all components are constructed for the mock-
up using dummies (e.g. adjustable frame with gloves to represent the isolator). This enables the operator to test
the individual steps. This has the advantage of allowing the operator to feel integrated in the decision process,
which leads to acceptance of the new system. The cleaning procedures and the exclusion of components for
cleaning can also be tested in this way. The mock-up is part of the mechanical pre-DQ (Figure 4.J-11).
Figure 4.J-11 Mock-up

4.J.5.5 Particle measurement of facilities in accordance with SMEPAC

Due to the new technology, during the Factory Acceptance Test (FAT), a particle measurement should also be
carried out on the facility components. For this measurement, a concept is developed that includes the core
points of the ISPE baseline (replacement material lactose for measurement, air exchange, alignment of filter
system IOMs, closed housing around the containment system).
First, the facility components were structured at the customer site in accordance with the planned installation. To
enable this, all the facility technology was constructed in a frame, in order to adjust the range of measurements to
suit the final facility installation at the customer site. The inside of the frame was covered with film. All cable ducts
for controlling the components were tightly closed (Figure 4.J-12).
Figure 4.J-12 Wooden frame construction
to enlarge, click
here!
One area was designated for entry of personnel through the lock into the contained room. Lactose was used as a
surrogate product. To avoid contamination during entry of personnel through the lock, a lactose-free zone was
also set up outside the measuring area. A sign bearing the information "Lactose-free zone - Access for
authorized personnel only" was attached to the doors to the relevant area. The lactose transport via a vacuum
conveying system from the discharge container (big bag) outside the hall into the area was also hermetically
segregated. The lactose was transported into a bin above the contained room via a pneumatic conveying system.
The bin was designed to simulate the dryer that empties its contents into the FIBC during the measurement. At
the same time, the room in which the measurement was to take place was flushed with purified air
by HEPA filters (three air exchanges per hour). The system components were cleaned with purified water,
because wipe tests were performed as well as the particle measurements (see Figure 4.J-13).
Figure 4.J-13 Wipe test split valve /isolator

The IOM sampler (so named because the sampler was developed at the Institute of Occupational Medicine (IOM)
in Scotland) was attached in a similar way to the SMEPAC. In the SMEPAC, the position is defined precisely on
or, if applicable, above the interface. The samplers were installed under the docking station while the FIBC was
filled. This meant that in the event of dust escaping, the particles, which are guided downwards by the air flow,
would be collected in the filter.
Two samplers were therefore positioned approximately 10 centimeters below the docking station and two more
were positioned immediately adjacent to the docking station, in accordance with SMEPAC. The other samplers
were attached according to SMEPAC at the glove ports on the isolator, on the filters, close to the operator's
breathing area, and in the room. Persons who were present during the measurement had to put on
uncontaminated protective clothing, gloves, and head coverings before entering the room.
The measurement was documented using video monitoring. This enabled individual work steps to be followed
and suggestions for improvements to be defined, even after the tests. The video documentation also makes the
subsequent compilation of the SOPs (Standard Operating Procedures) easier. Before start-up, the video
recording can be used to explain and discuss each individual movement with the operating personnel.
After the particle measurements (one background measurement to measure the basic load of lactose in the room,
and three measurements with the products), wipe tests were performed on critical surfaces, in order to determine
the level of surface contamination. Each discharging and filling process was repeated and recorded three times.
The samples were evaluated in a laboratory in the USA recruited by the end customer, since there there were no
labs in Europe capable of evaluating concentrations in the low nanogram range.
4.J.5.6 Documentation and results

The results fulfilled and confirmed expectations in all areas. The background measurement (how much lactose
was present in the room before the measurement) and the results of three consecutive measurements were
recorded in the measurement log (see figure 4.J-14). A result of less than 100 nanograms/m3 was achieved in
nearly all cases.
Figure 4.J-14 Measurement log for the example described
to enlarge,
click here!
4.J.6 Containment weak points
The points in the process where containers are emptied or filled should not be the only ones graded as critical. All
points where leadthroughs from the closed process are applied from the inside to the outside must be taken into
consideration. This includes, for example, shaft leadthroughs on stirrers, dosing systems and shut-off flaps, etc.
Other weak points are the exhaust systems and filter facilities for filling or emptying solid materials. Here, it is
necessary to use systems in which the dust collection pot and the filter medium can be disposed of when closed.
For ex-protection reasons, it may be the case that facility components have to be inertised. Inertisation means
excess pressure in the system. The excess pressure, even if it is in the mbar range, stresses flexible connections
such as tri-clamp and flange connections. When testing the tightness, the possible maximum pressure value
must also be tested to account for pressure fluctuations.
Figure 4.J-15 Open manhole Figure 4.J-16 Shaft feedthrough as a possible weak point
Note that Atex (Atmosphere Explosible Directive 94/ 9/EC - Use of facilities in an explosive environment) and
containment can also contradict one another. Atex recommends inertisation for dust explosive products or if seals
are used, which should themselves be electrically conductive, but FDA or food conformity is required for a
particular reason. (Seals that are food conformant or FDA conformant are usually white and not conductive.)
Containment as operator protection requires negative pressure inside equipment and containers.
Even when cleaning the facility, freedom from dust must be ensured. The best solution is CIP (Cleaning in
Place) and DIP (Drying in Place). With this solution, the facility is not opened and contamination is not possible.
For containers and simple equipment, this can also be easily installed and validated. For complex facility
components such as a drum filling with buffer hopper, dosing system and other additional equipment, CIP is
difficult to implement. Critical points often have to be cleaned manually afterwards. With manual cleaning,
contamination must be prevented before opening the system. For this reason, a placebo product should be used
the first few times the system is cleaned in order to validate and, if necessary, optimize the cleanability. The use
of a placebo instead of the critical API ensures that no contamination occurs if the system has to be opened at
critical points.
4.J.7 Containment systems for filling and emptying drums

Suitable systems must be selected for this, according to the required OEL or OEB.
4.J.7.1 Drum filling with endless liner

A primary containment system for filling drums is the endless liner system. This system includes a drum filler
head which is designed to receive a liner cassette. This liner cassette can be made from hard cardboard, plastic
or stainless steel. All cassettes are equipped with a certain quantity of liner. In most cases, this is approximately
30 to 50 m. A special feature is the mounting of the liner so that a closed system is ensured when the end of the
liner is reached. It must also be possible to change the liner cassette without contamination. The already sealed
liner end is pulled out to a sufficient length before filling the liner bag, and sealed to the liner bag with an
expanded clamp. After filling, the liner can be separated using various systems. The liner inlet and the new liner
floor must always be sealed automatically after separation.
The following systems are feasible:
Welding of the liner: The weld should be at least 1 cm wide and automatically be separated in the
middle so that there are no open points.
Another variant is applying adhesive tape at the separating point. The separating point is cut in
the center with a pair of scissors. Both ends are then sealed with adhesive tape. With this version,
containment of less than 1 μg/m3 can be achieved.
Clipping with subsequent separation between the clips is less effective: There could be material
in the space between the two clips. In any case, the ends should be sealed and local aspiration applied.
The advantage of endless liner systems is that no containment can take place outside the inliner,
such as during filling in isolators.
4.J.7.2 Drum filling and emptying with DCS (Drum Containment System)
Another primary containment system is a special adapter head for emptying and filling drums with inliners.
When filling a drum, the inliner is connected to the filler head using a special connection technique and the drum
edge (with just one inliner) is pressed against a gasket on the bottom part. If filling with two inliners, the second
inliner is again specifically connected to the filler head. With this version, primary containment of less than
1 μg/m3 can be achieved. With this system too, the inliners are sealed with an adhesive tape and separated in
the middle after filling. The inliner is sealed onto the filler head with the gloves. The remaining liner on the filler
head and the remaining liner on the outer filler head mean that the system is kept completely leak-tight after
filling (Figure 4.J-17).
Figure 4.J-17 Drum Containment System for drum filling, by Hecht
Additional equipment: Locks for bringing parts into the filling head (e.g. sampling), exhaust filter with push-
through filters (contamination-free filter change), for inertising and rinsing the filler head before
filling, cleaning drum for Cleaning in Place of the filling or emptying head (Figure 4.J-18).
Figure 4.J-18 Drum emptying with conveying in a reactor

An almost identical system with similar function is also used for emptying drums. In this case, however, a suction
lance is required, which sucks the product out of the barrel. With a Powder Transfer System (PTS), the product
can, for example, be safely and inertly emptied into a reactor (Figure 4.J-19).
Figure 4.J-19 Measuring for recording containment in a DCS system

Especially when filling reactors, a material lock should be used as product transfer in accordance with Atex.
Direct coupling of an unpressurized container or pack to a pressurized container should be avoided. It is
advisable to use a Powder Transfer System (PTS) to fulfill this function. With the PTS system, a product quantity
from the container to be emptied is sucked into a lock with a vacuum. The lock outlet to the reactor is secured.
The lock inlet is sealed after filling the PTS body and kept under vacuum until the lock does not contain any
more oxygen. The lock is then inertised with nitrogen and the product is discharged into the reactor by opening
the outlet flap. The PTS is designed with the same pressure as the reactor (3 bar or 6 bar).
With the combination of the Drum Containment System (DCS) and the associated Powder Transfer System
(PTS), toxic, highly potent and sensitive products can be emptied safely. An important advantage is that the
operator can view the product via a borosilicate disc, despite the closed system. With the gloves and suction
lance, it is possible to empty even lumped products or products that do not flow easily. The suction lance is also
available in combination with an integrated lump breaker. Access to the product via the glove on the DCS system
offers a significant advantage over other closed systems.
Cleaning in Place is possible during both filling and emptying.
4.J.7.3 Big Bag emptying and filling with a protective liner system
This system is also a primary protection system for emptying and filling Big Bags (Figure 4.J-20 ).
Figure 4.J-20 Big Bag emptying system by Hecht

Emptying of Big Bags via closed double ring systems has already prevailed in the industry. The only
disadvantage is that before connecting and after emptying, the Big Bag outlet neck is open. This weak point was
solved by a protective liner connection system. With this, the Big Bag inlet is connected to a protective liner
before it is opened. At the same time, the protective liner seals the system connection so that no contamination
can occur. Both inliners (1x inliner in the Big Bag, 1x inliner protective liner system) are connected to each other
via a hardboard ring and clamped together so that they are dust-tight. The hardboard ring is removed after
emptying and disposed of with the empty Big Bag. If the Big Bag is emptied, the inliners above and below the
hardboard ring are sealed. The seals below the hardboard ring are separated in the middle. The Big Bag outlet
and the inlet into the filling system remain sealed.
The same system with a similar procedure is also used to fill Big Bags. With this system, OEL values between 1-
10 μg/m3 can be achieved. With additional equipment, this can even be less than 1 μg/m3 (Figure 4.J-21).
Figure 4.J-21 Protective liner emptying system by Hecht

The Big Bag has advantages over other systems in terms of storage, the possibility of emptying, and production
costs. The Big Bag also does not have to be cleaned after emptying if it is used as single-use packaging. A
further advantage of the protective liner system is the ability to empty and fill different types of containers without
changing the system. The protective liner system can be used, for example, to fill and empty Big Bags,
containers, Mini Bags (Mini Bag systems instead of drums) and small bags. Cleaning in Place is possible
during both filling and emptying.
Figure 4.J-22 Total containment system in API production

4.J.8 Container systems
Containers are classic systems for internal transport and for storage of intermediate products and final products.
Container systems have been used successfully in the containment area for a long time. A distinction is made
between the following container systems (Figure 4.J-23).
Figure 4.J-23 Cone system at the container outlet
4.J.8.1 Container with outlet cone for discharging

Execution: In the container outlet, there is a closure cone which is paired with a flexible counter-cone at the
discharging station. The container is emptied by lifting the cone.
The cone not only performs the function of discharging the product but also the function of a containment system.
Through an automatic lifting adjustment of the cone to different positions, a predetermined volume can be
emptied from the container. The cone can be used as a dosing system. The emptying station is then either set on
weighing cells (withdrawal weighing) or the next process is weighed (gain in weight). The different height
adjustments of the cone also make it easier to empty for different materials. Partial emptying of the container is
possible.
Another advantage is that the large discharge cross-section also makes it possible to discharge products that do
not flow easily. The sealed cone systemis also available for emptying Big Bags. The benefit of this system is
that the Big Bag is used as a single-use system. This means that time-consuming cleaning of the container is not
required. The purchase price is more favorable compared to a similar container-based system. A further
advantage is the better suitability of a flexible container rather than a stiff container for products that do not flow
easily (see Figure 4.J-24).
Figure 4.J-24 Cone discharge system with Big Bags

4.J.8.2 Containment Transfer Unit at the container inlet for filling
Execution: A special containment lid is attached to the container inlet. When closed, the lid is securely positioned
over the filler head and removed from the container inlet. The container lid is so neatly fixed through the
incorporation in the filler head, that the filler head and container lid are largely free from product accumulations
after the system has been filled.
Figure 4.J-25 System for container filling

Figure 4.J-26 Containment installation with split cone system in pharmaceutical formulation
The filler head is located above the container filling station and is docked to the container inlet via a lifting device
(Figure 4.J-25).
Containment in mechanical systems such as the cone system or the Containment Transfer Unit greatly depends
on accuracy during manufacturing and maintenance. In this system, visible freedom from dust is only possible to
a limited extent.
A safe system for filling a container is the cone system. As described under cone discharge, this system is also
suitable for filling flexible containers such as Big Bags. Examples for the use of a cone discharge and filling
system in formulation/packaging are shown in Figure 4.J-26.
4.J.8.3 Split valve systems

Execution: A shut-off flap is virtually separated in the middle. The two separations are now applied to the
systems separately. One system is called the active flap and is equipped with the drives. It is attached to the
discharging or filling position. The passive part is found on the container inlet and outlet. During filling and
discharging, the two parts are connected as with the cone system, and are then opened. The discharge opening
in this system, however, is designed for "small" cross-sections and is only of limited suitability for emptying
products that do not flow easily without additional discharge aids.
Figure 4.J-27 Split valve system

Figure 4.J-28 Split valve by Buck
With a standard version, containment of between 10-100 μg/m3 is achieved. In order to achieve containment of 1-
10 μg/m3, a special version is required in which the space between the flap halves is rinsed and dried before
docking. It must be ensured that the flap seals are always in perfect condition, so that no liquid can enter the
product space and then cause the product to bake off during the next filling process. This system, like the cone
system, should only be considered a closed system if it is maintained regularly and the seals replaced.
Cleaning in Place is possible for container systems to a limited extent. The level of automation is also a plus point
in the use of containers. Container systems can be transported completely via AGVs (Automatic Guided
Vehicles) and automatically emptied, filled and cleaned.
4.J.8.4 Laminar flow, Glove box systems (isolators)

Laminar flow systems are used for protection of the product, person and room. The working area of the laminar
flow system is supplied with clean air from above through H14 filters. Aspiration takes place opposite the user
position or the working area through high-performance HEPA filters. These systems are particularly suitable, for
example, for separating the manual weigh-in area for small quantities. Other possible uses are the emptying of
sacks, drums, Big Bags and containers, if these do not already have a primary containment system or cannot be
emptied by a containment system. The dust load inside a laminar flow system can usually be improved a
thousand-fold compared with the exterior. However, an exact specification of the OEL value to be achieved
cannot be established. Laminar flow systems only reduce the risk of cross-contamination to a certain extent.
Figure 4.J-29 Glove box system

Comprehensive cleaning when changing between different products and contamination-free clothing of the
operators must be ensured.
Glove box systems (Figure 4.J-29) and isolators are mainly used for personnel safety. Compared with the laminar
flow systems, in which the operator intervenes in the system via an air curtain or, in bigger systems, even finds
himself inside the laminar flow, this is not possible with a glove box or isolator system. If manual intervention or a
manual operation is necessary within the system, this is either executed via a manipulator within the system or by
the operator wearing gloves.
Glove box systems and isolators are used for hazardous and highly potent materials. As these systems are also
used for secondary containment, the inner area of the glove box or the isolator is contaminated. It is therefore
important to ensure that contaminated parts are first isolated, particularly when discharging parts from inside. An
OEL value of less than 1 μg/m3 can be achieved.
4.J.9 Filter systems

Filter systems are often forgotten in the consideration of containment systems. But especially here, the system
must meet the same requirements as the entire production process. This means contamination-free changing of
the filter medium and of the dust collection pot. Washing and subsequent cleaning must be carried out before
inserting the new filter.
Recommended additional equipment is a monitoring system on the clean gas side, in order to prevent carry
over or cross-contamination (Figure 4.J-30).
Figure 4.J-30 Filter system

4.J.10 Sampling
Samples must be taken for in-process controls and for the release of manufactured products. Sampling must
be representative of the manufacturing batch. The installation location of the sampling system must be precisely
selected, especially for hazardous and highly-active substances. With the sampling system, a defined volume is
taken from a closed system over a period of time and filled into a container. The container must then be closed,
removed, and transported to the analytical laboratory for analysis. It must also be possible to open the container
for subsequent analysis. The sampling system must be completely closed to the outside. Below are two
examples of suitable systems:
4.J.10.1 System 1: Sampling via a withdrawal screw fitted in the

production area
The screw can be fitted in a downpipe or buffer container. The worm screw continuously withdraws a
representative sample across the entire cross-section.
Figure 4.J-31 Screw sampling by Hecht
The sample is filled into a container. This container is connected to the sampling system via a split valve system.
The split valve must be closed for withdrawal of the sample container. The half of the valve with the sample
container is uncoupled and removed by the operator (Figure 4.J-31).
Advantages of this system:
Withdrawal of a representative sample

Simple integration into an existing facility
Disadvantage:
Only WIP (Washing in Place) is possible. The system must then be opened and cleaned
manually.
4.J.10.2 System 2: Sampling via a micro Powder Transfer System (MPTS)

This system withdraws the product using a suction lance integrated in the process. The suction lance can be
installed statically or dynamically. The product is sucked into a bottle located in the glove box by vacuum. With
this system, samples can be taken from different positions. It must be assured that there is a product collection
that can be aspirated (Figure 4.J-32).The sampling container can be installed at a position far from the process.
Figure 4.J-32 Micro Powder Transfer System (MPTS)
Advantages of this system:
Withdraws a representative sample.

Can be easily integrated in an existing facility.
WIP (Washing in Place) is possible.
4.J.11 Containment on equipment

Two further examples show that containment must also be ensured within processing steps.
4.J.11.1 Example 1: Shaft leadthroughs
This area must be considered as particularly critical. In a closed

system, there is penetration from the inside to the outside. The shaft leadthrough is usually fitted with special
seals and air or nitrogen rinsing. For containers that are pressurized with excess pressure, a leak test is
particularly important. In consideration of containment, these points should be measured separately, for even the
smallest leaks that cannot be detected by a monitoring system cause the OEL4 or OEL5 value to be exceeded.
The stored air rinsing should also be purified when changing the product (Figure 4.J-33).
4.J.11.2 Example 2: Filling and discharging cone dryers

Usually, process equipment is permanently closed together. Cone dryers are an exception as the inlet and outlet
must be uncoupled. This should be executed with split valves, as described above for containers (see chapter
4.J.8 Container systems), as with this system, the active flap can be docked on the cone dryer inlet and outlet via
a lifting device (Figure 4.J-34).
Figure 4.J-34 Cone dryer

!
4.J.11.3 Practical example of a containment API plant

Figure 4.J-35 Practical example:
1. PTS - Powder Transfer System, 2. DCS - Drum Containment System, 3. PTS - Mobile
Powder Transfer System (mobile PTS), 4. LBSL - Lump Breaker Suction Lance, 5. MPTS -
Micro Powder Transfer System (micro PTS), 6. TBFS - Transbatch Feeder System, 7. SCC -
Single Change Container
Summary:
There are now a number of possibilities for achieving primary and secondary containment. For each
type of use, the optimal variant should be selected in terms of:
Containment (value to be achieved)
Flow behaviour of the product
Dedicated or multi-purpose facility
Level of automation of the facility
Spatial circumstances
In any case, risk analysis should be carried out before selecting a containment system and during the
DQ (design qualification). The system should be qualified. Cleaning of the containment system should
also be validated. Regular revalidation is recommended at shorter intervals straight after the PQ
(performance qualification), in order to obtain information on the safety of the system.
4.K Process control systems

Author: Andreas Rösch

What tasks are performed by process control systems?
What different kinds of process control systems exist?
What are the differences between them?
How can the functionalities of process control systems be delimited from those
of other systems? What are they?
What must be taken into consideration during project processing and
qualification?
4.K.1 Definitions
Process control systems are identified by the fact that, " ... they take into account the entirety of all tasks
(functions) that are required for controlling a process. ... in addition to the functions of the respective automatic
procedures that are established in its programing, all decision processes of the person who monitors the process
are also taken into account, including his resulting direct intervention in the process". [J. Heidepriem,
Prozessrechnertechnik und Automatisierungssysteme, Volume 1& 2, Oldenburgverlag, 2001]
This definition clarifies that the person plays an important role in a process control system, in contrast to the
control or automation technology. While control or automation technology deals exclusively with technically
known and logical contexts, a process control system takes into account the decisions of a person (facility
operator). Process control systems are further distinguished by the fact that the data basis to which the person or
automatic procedure reacts is constantly changing and cannot be restored. chapter 9 Computer
Validation distinguishes between monitoring systems and transaction-based systems. According to this, process
control systems are to be classified as monitoring systems.
Process control systems offer a multitude of possible uses. The scope of function of process control systems is
just as multifarious. This chapter deals with general functions and problems (chapter 4.K.3 How to use process
control systems).
Process control systems are used to monitor and control the production process across facility components. In
order to correctly classify the tasks of a process control system, a few further definitions of terms are required:
Process Data Acquisition system (PDA) PDA systems record various measurable values from
production. These can be the temperature flow, counter statuses, revolutions, etc. Depending on the
relevance of the value, a relationship can be established between the measuring point (sensor, balance,
etc.) and the order or batch number.
Enterprise Resource Planning Systems (ERP) ERP systems belong to the company
management levels with strategic, commercial tasks with a longer-term time frame. The most widely used
ERP system is SAP.
Laboratory Information Management Systems (LIMS) LIMS, like MES, belong to the plant
management levels. They are used to record and document quality-related values e.g. for inspection of
incoming goods or so-called In-Process Controls (IPC) for the process running time.
Manufacturing Execution Systems (MES) MES belong to the plant management level. They
produce the connection between the process control level and the company management level. On the
one hand, this includes functions such as production planning, requirements determination within a mid-
term time frame and, on the other hand, it includes extensive search options for batch tracing or fault
analysis.
Batch systems Batch systems map procedural sequences in the process control system. They
manage formulations which produce the connection between the manufacturer's instructions from the
ERP system and the technical equipment of the process facility. Likewise, the MES provides parameters
based on the raw materials.
Process visualization and control These systems show the current status of each individual
element of the technical equipment and make it possible to control these elements. A drive can, for
example, be activated or deactivated, and at the same time the operating hours of the drive and the
storage temperatures of heavily burdened gear parts can be recorded.
The limits shown here between the systems are in no way to be viewed as strict limits. They can fluctuate
significantly depending on the company size, plant organization and the systems used.
Figure 4.K-1 Schematic illustration of the control levels
4.K.2 Features of process control systems

Process control systems differ essentially through the hardware used. While some manufacturers use their own
hardware components which are specially tailored to the software supplied (system-specific hardware), other
manufacturers use commercially available, usually widely used and proven hardware components. In the latter
case, so-called PLC-based process control systems are usually used, which use PLC as process-near
components (PNC). However, display and operating components (DOC) of the process control systems, i.e.
servers and client stations are becoming increasingly similar, as industry PCs (IPC) are increasingly being used
with the usual operating systems. Widespread technologies such as the Ethernet with TCP/IP protocol are also
becoming increasingly important for networks. Proprietary protocols are becoming rarer. Both variants have their
pros and cons, which are illustrated below.
System-specific hardware with its tailored software offers uniform parameterization and programing tools for
project planners and for users alike. However, such systems require special knowledge which is not usually very
widespread. From a GMP perspective, these systems offer the advantages that all programing and
parameterization changes are logged, provided they have an Audit Trail. It may be a disadvantage that such
systems do not support all current interfaces. As the example of the facility configuration shows, Figure 4.K-2,
this can play an important role.
Figure 4.K-2 Example of a facility configuration
PLC-based process control systems, on the other hand, use widely available programmable logic
controls (PLC). The use of the equipment is tested in a wide range of areas. The purchase price and the spare
parts storage are relatively inexpensive. In addition, spare parts availability and procurement are guaranteed for
years (>10 years). Special knowledge is not usually necessary as PLC exists in every company at machine level
and the knowledge is thus already available. Often, the opinion prevails that PLCs and PCs exchange
unstructured data and thus parameterization of the process control system is not possible from the PC level.
Through the increasing efficiency of PLCs in recent years, the PLCs can be incorporated as "real" process control
system components, i.e. the process control system can be parameterized completely from the PC level (the
difference between programing and parameterization is dealt with in more detail in chapter 4.K.5 Qualification of
process control systems). From a GMP perspective, changing programs is associated with a higher
organizational effort in the context of change management (see chapter 9 Computer Validation).
The use of industry suitable PCs is also relatively inexpensive in terms of purchase costs. Here, the availability
and procurement of spare parts is more problematic. The short innovation cycles, both for hardware components
and operating systems, mean that in some cases, individual components are no longer available after five years.
As the operating systems and programing languages used in the company are often also used in other areas, the
company has sufficient technical knowledge available and specialist knowledge is not required. However, for
exactly this reason, the following note is particularly important.
Please note: Although the hardware and network components of EDP workstations and PCS workstations are
increasingly similar, you are strongly discouraged from operating process control components as EDP
components. For as already shown, process control systems are monitoring systems for constantly changing
process variables.
Failure of a hardware component or network connection leads to a non-reconstructible loss of information, in

contrast to transaction-based systems. This means:
The process bus is to be separated from an EDP network.

Servers should be accommodated near the facility. Dependencies between network components
of superordinate departments, e.g. backbones of IT departments and multi-site components are to be
avoided.
Software not released by the process control system vendor should not be installed, or only by
agreement with the vendor.
4.K.3 How to use process control systems

Ideally, the process control system should form a standardized interface along the entire production process
(value added chain), both for users and for superordinate systems.
To this end, the PCS records the status of all equipment involved in the process (drives, valves, controllers, etc.)
and all kinds of measuring values (levels, temperatures, pressures, humidity, flows, masses, conductivity, etc.)
and, possibly, machine runtimes and operating cycles which can be used for the next maintenance.
This recorded information is
forwarded to superordinate systems,

displayed to the user,
evaluated by automatically running processing steps.
Forwarding to superordinate system is generally used for logging and archiving and for production planning. This
task is the same as that of a PDA system.
Through the visualization of the facility, the operator obtains an overview of the entire facility. The process
images are structured so that an overview of the facility can be obtained as quickly as possible. Therefore, the
level of detail of the process images varies significantly.
It is crucial that the user can make decisions based on the visualized information and can intervene in the
production process. This corresponds to process visualization and control.
The control of automatically running processing steps is undertaken by batch systems, for example. A batch
system offers the possibility of merging defined basic functions into a prescription, so that the entire process can
take place automatically. Automatic can also mean that the process control system issues operator instructions,
e.g. via radio terminals and waits for inputs by the facility operator. Furthermore, this forms the basis for
later batch tracking1.
4.K.4 Carrying out a process control system project
In most cases, this will be the extension or introduction of a process control system in an existing facility, which
has often developed over many years, i.e. a heterogeneous control or automation landscape will already be in
place.
At the control level, this can be simple control cabinets or PLC-controlled facility parts, DOS computer-based
controls through to PC-based visualizations (Microsoft Windows, Linux, Unix).
Often, the introduction of a PCS project is motivated by the fact that the process data is to be forwarded directly
to the company management level or that all data is to be stored centrally. This means it is necessary to provide
PCS interfaces to ERP systems (SAP), MES systems and/or LIMS systems. Figure 4.K-2shows an example of a
facility configuration.
As the example of a facility configuration shows, not only production-like operating areas can be affected in a
company by the introduction of a PCS, but also operating areas such as storage, requirements planning and
laboratory.
This heterogeneous system landscape usually requires a number of interfaces to be created. Typically, the
establishment of these interfaces is technically challenging, but can easily be realized by interface converters that
are available on the market. However, this does not give any specifics on whether the information that can be
acquired from the exchanged data is sufficient. This problem usually occurs if autarkic facility component controls
(e.g. reactors, coaters, batch production facilities) are to be connected, which contain formulation administrations
that are specific to the facility vendor. In such cases, practice has shown that it is best to replace facility
component controls and integrate the functionalities directly into the control system.
This procedure is particularly advantageous in the GMP environment:
Maintenance of the formulations is simplified as they are compiled and maintained on the PC
and not in the control. This means that the formulations are included in the data backup concept. A
further positive side-effect is that modern process control systems provide version tracking of the
formulations so that all changes are documented in full.
Operation of the facility parts is thus subject to access authorizations through the user
administration of the process control system, or dual maintenance of the user administration is dispensed
with, whose organizational costs are not to be underestimated. Operating actions by users are thus
entered in the central audit trail and can then be easily copied into the batch documentation.
By contrast, this procedure is to be avoided for machines that are configured and do not allow for any manual
intervention during production (e.g. packaging lines, tablet presses, etc.). This is because the runtimes for such
machine controls are optimized by the manufacturers, and this cannot be achieved with process control
components. Checking of the packaging material and product feed should, however, be monitored by the PCS.
4.K.5 Qualification of process control systems

At this stage, it must first be stipulated that, through the use of a process control system, the process equipment
must be considered as a "computerized system" in accordance with chapter 9 Computer Validation and is
therefore subject to computer validation as described in detail in chapter 9 Computer Validation.
However, an often underestimated yet very important requirement for successful and timely processing of such a
project is of a non-technical nature. The close collaboration of the facility operator and process control system
supplier over the entire project runtime is particularly important. This is not only because the process control
system ultimately has to be validated by the facility operator together with the technical facilities and procedure,
but also to achieve the highest possible acceptance of the system by the users.
For qualification of process control systems, it is important to distinguish between programing and
parameterization. Programming means software modules are compiled in a programing language, and are then
translated. The logic is saved in the source code and cannot be changed during the running time. As described
in chapter 9 Computer Validation , this is individual software which must be qualified in the context of the project.
Parameterization means that a standard software system, in this case the process control system, is configured
specific to the application (see chapter 9 Computer Validation). In this case, it is sufficient to document the
version used and, if relevant, carry out a supplier audit.
From a GMP perspective, parameterization of a standard software product is recommended. However, in many
cases this is not possible or is not desired for plant organization reasons. In particular, process equipment that
has developed over many years often contains technical and organizational features which make it necessary to
supplement the selected process control system with modules or entire applications. Examples of this are
container management or software for interfaces to upstream or downstream programs/machines, which were
developed by the facility operator himself. Interfaces to current systems, such as SAP or standardized PDA
interfaces can be parameterized in modern process control systems.
To achieve the best possible qualification documentation (see here), the following points should be taken into
consideration during the technical specifications phase:
Program modules, or functions and functional units should be defined and named.
On the basis of these defined modules, etc. the structure of the documentation of the process
control system should be drafted.
Change management and versioning should be defined.
According to experience, this is initially a painstaking undertaking which takes some time and does not initially
show any visible project progress. Given the usually tight schedule, this frequently leads to intense discussions
between the project team and the QM-/validation managers. However, this pays for itself many times over during
the course of the project. (Author's note: Unfortunately, nobody notices as the subject of documentation barely
stands out any more.)
In this way, a good basis both for the compilation of the specifications and test plans at module level, and for the
documentation and testing schedules for IQ, OQ and PQ phases can be created at the start of the DQ phase.
Once the required technical specifications are completed, the agreed qualification documents, i.e. specifications
and test plans for the individual modules, must be compiled and released during the DQ phase. After
implementation, i.e. programing or parameterization, the test plans must be worked through and the modules
must be released during IQ. Ideally, this is carried out in several stages in the presence of a representative of the
facility operator. Each of these appointments can be seen as part of the FAT (Factory Acceptance Test). This
procedure ensures that the facility operator's employees become familiar with the PCS at an early stage and can
indicate that processes can be designed in an ergonomically improved manner.
The qualification documentation to be compiled should be established at the latest as part of the technical
specifications compilation, i.e. very early in the DQ phase. This must, of course, agree with the facility
operator's validation protocol, if already defined therein. The persons/functions who will release the individual
documents should also be established. This depends on the composition of the project team and the plant
hierarchy (see below.).
Usually these specifications are based on theoretical requirements, so that it must be checked if this can be
implemented as such in practice. This applies both for the specifications and test plans at module level and for
the documentation and testing schedules for IQ, OQ and PQ.
The following reasons could speak in favor of deviation from the theoretical requirements:
The software structure requires a deeper nested documentation.

Parallel work by several employees must be divided across several documents, both for the
compilation of the software and also in the further qualification phases.
The schedule provides for parts being started earlier so that release must also take place
correspondingly early.
Resources that must release documents are only available to a limited extent
For a large software module, different knowledge is required, meaning that it is advisable to split
this software module into several work packages
To avoid repetitions, requirements that relate to several modules are to be grouped together in a
separate document to ensure that the documentation can be maintained
The last point carries a certain amount of risk: During the project phases, i.e. from DQ to OQ/PQ, the
documentation is compiled and thus has a foreseeable end. However, it is not usually taken into account that this
documentation must be revised during the entire life cycle of the facility if changes are made. This means that if
the same content appears in several documents, all these documents must be revised and released again in a
new version. However, parts of the text can be easily overlooked and the documentation will thus no longer be
identical.
The level of detail of the contents of the documents varies and is directed towards different groups of
people/functions. Experience shows that this not only depends on the type of document, but also on the group of
people involved, on the size of the project and on the level of detail of the requirements, e.g. in the form of user
requirements, but also on the size of the company of the facility operator.
Finally Figure 4.K-3 contains a few more questions that must be asked from time to time at the end of the
technical specifications phase, e.g. with final acceptance of the IQ or OQ, and whose answers should be
reviewed. The questions may appear to some to be trivial or even unnecessary, but experience has shown that
reviewing these questions has helped develop a clear and uniform vision by all those involved, both of software
structures and of documentation structures, across all qualification phases.
Figure 4.K-3 Questions at the end of the technical specifications phase

Are the responsibilities for the release of documents and software modules regulated in the technical
specifications?
Are functionalities, interfaces, applications and software modules defined, named and clearly
separated from each other in the technical specifications? Is there a diagram that contains the above-
mentioned elements and roughly illustrates the dependencies/links?
Are the interfaces between the standard software system and individual software known?
Can the above-mentioned elements be mapped in the documentation structure?
Can the defined documents be compiled on time by those involved? Can the defined documents be
checked on time by those involved? Can the defined documents be approved on time by those
involved?
Is the change management process defined?
Is there a description of which version number must be increased for which changes?
How are the documents distributed?
Are those involved familiar with the project documentation?
For more information and examples of qualification documentation, see chapter 9 Computer Validation.
Good qualification documentation means that the entire documentation is clearly structured and oriented to
the target groups. Even if the documentation is viewed by investigators, and contributes essentially to
qualification, the target groups are nonetheless all the roles of the plant employees, such as operating staff,
maintenance staff, plant managers, and employees of suppliers as well as project managers and programmers,
i.e. the documentation must fully and completely reflect the installed process control system for the
corresponding target group.
Summary
Process control systems are used to monitor and control the production process across facility parts. A
distinction can be made between system-specific and mostly PLC-based hardware, which have different
advantages and disadvantages. The challenge when introducing a PCS is the many interfaces that must
be integrated, which must be taken into account for project execution, qualification and documentation.
Solution approaches for this problem are illustrated.
4.L Hygienic (sanitary) design when using solids
Author: Richard Denk

What does hygienic design mean for solids facilities?
Does the surface finish of facilities influence the product quality?
What must be taken into account when installing solids facilities in a
controlled room?
What metering systems are available in hygienic designs?
To what end are quick connections and flexible connections required?
4.L.1 Introduction
Hygienic (sanitary) design means easy-to-clean, self-contained facilities with little dead space.
In the event of improper and open handling, solids, unlike liquids, can be distributed throughout the entire building
through the ventilation system or by being carried on surfaces or by personnel. Subsequent removal of
contamination from all surfaces in order to avoid cross contamination can be very expensive and time-consuming
or even impossible, depending on the room and facility planning. Therefore, the facility design to be used is of the
utmost importance and should be taken into consideration during the early stages of planning.
The internal parts must be dead-volume-free (dead legs) and easy to clean. There should preferably be no
attachments on the equipment components, as these only reduce the ease of cleaning. But in the solids area in
particular, this is difficult to implement. For example, when filling an API after drying, it may be necessary to crush
agglomerates, which requires the installation of a crusher with a screen.
Representative samples of the products are drawn with a sampler. The product is then filled into a temporary
container or sales container via a metering system, at times with an extremely high degree of accuracy. This all
means a significant number of mechanical facility components are required, which also have many attachments
in the product flow.
Cleaning is not always possible with CIP (chapter 4.I CIP (Cleaning in Place)). WIP (Washing in Place) is more
realistic with subsequent dismantling of the critical facility components for manual cleaning. These critical
parameters must be taken into consideration before and during cleaning validation and documented in the SOP.
If the facilities and equipment are to be opened, hygienic design also plays a key role in the external area. In
particular in clean rooms, where special requirements exist for cleaning the facilities and surfaces, there must be
as few attachments, cable ducts, etc. as possible. But also outside clean rooms, the facility design is important
for emptying or filling, as this is in the immediate vicinity of the product and an increased level of cross
contamination can occur. In addition, it must be considered whether or not the facility is a mono-purpose or
multipurpose facility and, for clean rooms, the clean room category is important, e.g. A, B, C and D. Each area
requires its own facility design, which must be defined and documented in the user requirements during the early
planning stages.
Examples:
External surfaces ground to a required surface finish
No open cable ducts
Cladding of attachments such as drives should be routed from the clean room area to the
services area. (This also makes maintenance and repair of the facility easier).
4.L.1.1 Weaknesses in facility planning

During facility planning, the area of solids supply and removal is often taken into consideration after the room or
building planning has been completed. Often rooms or buildings are under construction before the supply and
filling of solids is considered. Take, for example, the field of API Production: the reactors and crystallizers are
usually accommodated in the upper stories, the centrifuges in the middle stories and the dryers in the lower
stories. Equipment inlet and outlet heights for the solids feed must be taken into consideration, as the raw
materials are sometimes delivered in large containers. This is similar for facility planning in drug product
production, except that the solid already plays a key role and is usually taken into account from the outset.
In cases in which the solids feed is not taken into consideration, the solids can not be supplied or emptied by
gravity. They must be supplied to the facilities through transport systems (e.g. power transport system - PTS,
see chapter 4.J.11 Containment on equipment), in order to feed the solid to the reactors or to load a tablet press,
for example. When emptying dryers, centrifuges in API production and blenders in formulation, a pneumatic
converging system must be used if the room is not high enough.
Another weakness is the facility design. Most APIs are filled in a classified room after drying, but the room
design is often inadequate. The wall design and room planning with GMP conforming passages often have weak
points. The solids facility design is often given too little attention during planning. Open pipes, open cable ducts
and unfavorable facility design of the surfaces are not rare occurrences, and cleaning of the solids facility is often
impossible.
4.L.2 Surfaces
4.L.2.1 Product-contact surfaces
The definition of the required surface finish plays a key role in the quality and hygienic design of a solids system.
A high quality surface on the product-contact and non-product-contact parts significantly diminishes the sediment
of products (solids) and also the growth of micro-organisms. A guide value of Ra ≤ 0.8 μm has prevailed for
product-contact surfaces (Figure 4.L-1).
Figure 4.L-1 Arithmetic average surface finish

Ra: arithmetic average surface finish of the absolute amounts of distance y of the surface
profile from the centre line within the measurement section. This is equivalent to the height
of a rectangle whose length is the same as the total length lm and whose area is the same as
the total area between the surface profile and centre line.
But values of less than 0.8 μm are not rare. On the contrary, the frequency of installations for which a value
of ≤0.5 μm is required is constantly increasing. The reason for this is certainly that the size of bacteria has
become a basic criterion for this assessment. The size of bacteria is between ≤0.5 and 5 μm. Yeast and fungi are
bigger than bacteria. Only viruses have sizes in the nanometer range. It is only possible to manufacture surfaces
in the nm range by using very expensive technologies and this has not been economically feasible to date. In
addition, the growth of viruses in a facility is improbable as only a small minority of viruses can multiply or survive
outside a host.
A surface finish of Ra 0.8 μm can be manufactured up to a thickness of 6 mm by using cold rolled sheets
(see Figure 4.L-2), without having to post-process the surface with grinding or polishing. Mechanical post-
processing would only deteriorate the surface finish of a cold rolled sheet.
Figure 4.L-2 Protective film on cold rolled sheets
should only be removed where necessary for
processing.
During processing (such as welding) of cold rolled sheets, it is important, during the production steps, to leave
the sheets in the double-sided protective films applied after they leave the roller. The protective films should only
be removed in the areas in which mechanical processing takes place or where a welded seam has to be
produced. To polish the processed surfaces, the film ends are reinforced with an adhesive tape. This prevents
the sheet underneath the film from being polished too (Figure 4.L-2).
For hot rolled sheets or welding seams, a surface finish of Ra ≤ 0.8 μm can only be achieved through
mechanical polishing with grinders. During final grinding of the area to be processed with a grain size of 240, the
required surface finish of Ra ≤ 0.8 μm is achieved.
Another type of surface finishing is electropolishing (electrolytical polishing, anodic polishing).

Electropolishing is the smoothing of metallic surfaces through galvanic abrasion of the peak-to-valley height in an
electrolyte. Electropolishing has the effect of improving the surface finish through the abrasion of surface peaks
and lends the metal a glossy appearance. The procedures for electrochemical polishing and deburring are, in
principle, a reversal of the galvanic process. Under the effect of direct current, metal is removed from the anodic
wired work piece surface into a special electrolyte. The abrasion is carried out with no load and preferably
extends to the micro-roughnesses. The surface is smooth and glossy in the micro-range. This is therefore called
"electropolishing". Structures in the macro-range are retained, but their surface is smoothed and rounded,
depending on their shape. Edges and corners face tougher abrasion, which causes a reliable fine deburring of
the entire surface area (electrochemical deburring).
Yet the use of this procedure has dropped sharply in the pharmaceutical and API production industry in recent
years, and there are only a few applications remaining which use this additional type of surface treatment. The
reason: Some products tend to adhere to electrolytically produced surfaces. This means that the simple
emptying and easy cleaning remains elusive in very expensively processed parts. Another disadvantage: Not all
materials can be electropolished (see chapter 4.L.3 Material: stainless steel and Figure 4.L-3 to Figure 4.L-9).
The surface finish is measured and documented by a stylus instrument.
Figure 4.L-3 Surface of a filter sheet - Figure 4.L-4 Ground to achieve rough deburring
starting status
Figure 4.L-5 10 min electropolished Figure 4.L-6 CrNi-steel surface (1000 times
enlarged) blasted with aluminium oxide
Figure 4.L-7 Ground grain size 180 Figure 4.L-8 Surfaces (IIIc)
Figure 4.L-9 Electropolished
(Source: Poligrat GmbH, Germany)
4.L.2.2 Non-product-contact surfaces

The external surfaces of facilities and equipment (the surface facing away from the solid) are dealt with in a
slightly different manner than the internal surfaces. If the solids facility uses a closed process, no particular
significance is generally placed on the external surface. If the room in which the facility has been set up has
platforms and steel beams made from coated carbon steel, the non-product-contact stainless steel parts remain
mechanically untreated with a roughness of Ra > 3.2 μm. In this environment, coated carbon steel parts can be
used, provided they are not welded to parts that are in contact with the product. Welding carbon steel parts and
stainless steel parts directly together should be avoided, as this causes the stainless steel to mingle with the
carbon steel. This can lead to rust within the product-contact area.
If the facilities and equipment are set up in a controlled area (e.g. clean room), the following implementation
options are available:
Untreated external surfaces Ra > 3.2 μm, untreated, pickled and passivated welds
(see chapter 4.L.3.2 Welds and Figure 4.L-13): This variant is very rarely used in controlled areas. The
surface finish of Ra > 3.2 μm should only be used if the filling or emptying process is completely closed
and no external contamination can take place. This external surface treatment can also be used if the
product is an intermediate stage and the same product is always produced in the facility (mono
production).
Exterior surface with grinding pattern grain 180, pickled and passivated welds: This variant is
frequently used in API production and also partly in drug production. The grinding pattern on the external
parts means the facility already achieves a fine surface. The unprocessed welds are adapted to the
grinding pattern with a brush.
External surface with grinding pattern 180, welds subsequently leveled or ground around the
radius, if they are fillet welds (parts welded in the corner joints). This implementation is a very elaborate
facility finish in the external area, which also enables simple surface cleaning.
The highest quality variant is grinding (polishing) of the external surfaces to a specific surface
finish. This concerns surfaces and welds. Usually, the surface quality is slightly lower for welding seams.
In general, on such a high quality facility, the surfaces are ground to a surface finish of Ra < 1.2 μm and
the welds to a surface finish of Ra < 1.6 μm. This surface finish is usually implemented in controlled
areas of multipurpose facilities, in order to be able to clean the facilities more easily, even in the external
area. If highly toxic or highly hazardous APIs and carcinogenic, mutagenic or reproduction-toxic APIs or
medicinal products (CMR substances) are produced in a facility, the external surfaces, including welds,
are produced up to Ra < 0.8 μm, in order to be able to clean them more efficiently in the event of
contamination with the API.
4.L.3 Material: stainless steel

While stainless steel has been used for many years as a material for product-contact and non-product-contact
surfaces in the pharmaceuticals industry, this trend has only recently been recognized in API production. One
exception is the last synthesis step for the production of the pure API where the facility technology is produced
completely in stainless steel, even in the filling area. The stainless steel material used is available in various
compositions and qualities. The different material qualities start with the lowest quality stainless steel (1.4301)
and extend to titanium, a material that is extremely expensive and also very difficult to process. For this reason,
we will consider materials up to Hastelloy here. This material is also expensive, but is now used in the solids area
where aggressive solvents are used.
Figure 4.L-10 gives an overview of the most frequently used stainless steels.
Figure 4.L-10 Overview of the most frequently used stainless steels
When processing the selected material, please note the following:
Absolute black-white separation in the processing and storage of materials (stainless steels).
This means that only materials made of stainless steel are processed in the stainless steel processing
area. Normal steel parts may only be found in this area if they are not mechanically processed there. This
area must not contain any normal steel parts that have rust on their surface. The risk that the rust will be
transferred from the normal steel parts to the stainless steel parts is too high. On the rolls, for example,
(for sheet processing) no material mixture of normal steel and stainless steel may be used.
With welding it must be ensured that the welding fillers, such as electrodes or welding rods, are
made of the same quality of stainless steel (material quality) as the materials to be welded. This means
that, when welding two stainless steel parts with quality 1.4435, the welding filler must also be of material
quality 1.4435. The welding fillers are labeled with the material number on the end of the welding rod.
The welding fillers must also be documented if 3.1.B certificates are required.
3.1.B certificates: With very high quality stainless steel, such as 1.4435 or even Hastelloy,
certificates from production of the material are usually required. This certificate must be supplied with the
material. In the storage area, the materials must be stored separately along with the material certificate,
so that there is no confusion. If different shapes and sheets are welded together, this must be codified in
the material and welding filler documentation, including copies of the 3.1.B certificates supplied by the
manufacturing plant. Subsequent delivery of 3.1.B certificates is not acceptable: An easier way of
confirming the materials is a 2.2 certificate. Here, the manufacturer confirms that it used the required
material, without also having to document or prove it. This also means that the manufacturer has an
orderly material warehouse, in order to be able to guarantee use of the right material
4.L.3.1 Coating of stainless steel surfaces
PTFE (polytetrafluorethylene)
PTFE is a fluorinated hydrocarbon with a highly molecular, partly crystalline structure, which is resistant to nearly
all chemicals. The coating system consists of two layers, the primer and the top coat. PTFE offers the highest
usage temperature range of all fluorpolymers of -200 to +290 °C. The surface is not adhesive. The slip properties
and the electrical insulation strength are better than those of FEP and PFA.
E-CTFE (ethylene chlortrifluorethylene), Halar

E-CTFE is a thermo-plastic fluorinated plastic. Due to its chemical structure - a 1:1 alternating copolymer of
ethylene and chlortrifluorethylene - it offers the following properties (Figure 4.L-11).
Figure 4.L-11 Properties of E-CTFE

Properties of E-CTFE, Halar
Chemical resistance
Use at temperatures from cryogenic to 150 °C
Rigid material with excellent impact resistance
Good frictional resistance
Thermo-plastic
10 to 100 times better barrier properties than PTFE or FEP vis-à-vis oxygen,
carbon monoxide, chloric gas or hydrochloric acid
Resistant to solvents made of organic chemicals including concentrated acid,
chlorine and sodium hydroxide solution
Low and stable permittivity
Very pure and suitable for use with ultra pure water
4.L.3.2 Welds
Inert gas welding procedures are the most frequently used methods of welding stainless steel parts together.
With inert gas welding, a light arc burns between a non-melting tungsten electrode or a melting wire electrode
and the work piece. In the process, an inert gas surrounds the weld point, deflects the ambient air and thus
prevents chemical changes, such as oxidation in the pool crater. A distinction is made between tungsten inert
gas (TIG) welding, metal inert gas (MIG) welding and metal active gas (MAG) welding (see Figure 4.L-12).
Figure 4.L-12 Welding procedures

Welding procedures
TIG (tungsten inert gas)

Argon and helium or a mixture of the two are used as the inert gas. These
gases do not create any chemical compounds with the liquid weld material at the
high temperatures of the light arc.
For stainless steel, DC welding is predominantly used.
A further development is the pulsing of the weld current - finely dosable heat
application - special welding facility required.
MIG (metal inert gas)
Argon is used as the inert gas.
Fine drops, short circuit free material transition
Average and large sheet thicknesses
MAG (metal active gas)
Use of active gases such as CO2, mixed gases of CO2 and Argon or even O2.
These gases are cheap but have disadvantageous influences on the welding process,
such as combustion of alloy elements, or reduction of the mechanical quality. The
corresponding composition of the wire electrodes can compensate for these
disadvantages. Good welding is therefore dependent on the correct combination of
the wire electrode and the inert gas.
With MAG welding, thin sheets or wide welding gaps are welded with the short
light arc - large sheet thicknesses with the long or spray light arc.
The difference between TIG and MIG/MAG is that with TIG welding, the welding gun contains a tungsten rod
surrounded by inert gas, with the result that there is no scaling or fusion penetration on the welding seam. The
welder applies the welding filler to the weld seam manually. TIG welding is mostly used in thinner walled areas up
to a sheet thickness of 8 mm. An experienced welder can create a very clean and fine welding seam with this
procedure. With MIG/MAG welding, the welding filler is also surrounded with gas. This time it is active gas. With
MIG/ MAG welding, in contrast to TIG welding, the welding filler is supplied automatically. Depending on the
selected strength of the welding filler, the welds are also larger and thus rougher. MAG welding is recommended
for sheet thicknesses of 10 mm and more.
Processing of welding seams

Welds within the product-contact parts are always ground flush with the material to the same surface quality
specifications as the required surface finish (see also chapter 4.L.2 Surfaces).
The simplest way to process external welds (non-product-contact) is untreated, pickled and passivated. With
chemical pickling, the parts to be pickled are dipped in pickling baths, depending on requirements, or the pickling
agent is applied to the metal surfaces. At room temperature, the pickling agents act for a few minutes to a few
hours and are then rinsed off with water. In order to give the welds a slightly neater appearance from the surface,
they can be polished with a brush. The welds can be ground to obtain neat and easy to clean surfaces. This
means that the butt welds are leveled to the level of the surrounding surface.Fillet welds are ground in the
radius R > 3 mm. With fillet welds, more welding material must be applied when grinding bearing parts, so that
there is sufficient material available after grinding to meet the required load bearing capacity.
The tendency to also grind the external welds is constantly increasing, in order to assure easy cleanability of the
facility (Figure 4.L-13 and Figure 4.L-14).
Figure 4.L-13 Untreated welding seam Figure 4.L-14 Ground welding seam
In addition, it must be ensured that the welds on external welding seams are always completely welded through.
Partial seams are not permitted, as organisms can settle in the gaps and multiply (Figure 4.L-15 and Figure 4.L-
16).
Figure 4.L-15 Continuous welding seam Figure 4.L-16 Partial seams
4.L.4 Connections
4.L.4.1 Flange and quick release connections
The connection of pipes and adapters, and any method of connecting two components rigidly, is usually carried
out through flange or quick release connections (Tri-Clamp connections). Bayonet connections are also possible,
though these have largely been replaced with Tri-Clamp connections for hygienic reasons. The reason for this is
that Tri-Clamp connections have prevailed due to the easier dismantling and improved hygienic design compared
with bayonet connections.
Flange connections
Composition:
2 flange halves
1 flexible flat seal
Screws, nuts and washers for connecting the flange halves
Figure 4.L-17 Flange Figure 4.L-18 Aseptic flange connection as per DIN
connection 11864, Form A
However, a flange connection does not necessarily have to be produced as per DIN (Deutsches Institut für
Normung), the German industry standard. In the hygienic area in particular, flange connections are preferable for
depressurized connections, with thinner flange thicknesses and fewer screw connections (number of screws
distributed around the circumference) than with a comparable DIN implementation. The flexible connection
between the flange halves often deviates slightly from the DIN standard of an injected flat seal. In the connection
space between the two flange halves, either a flat seal is fitted flush with the inner tube, or O-ring connections,
which also match with the inner tube diameter, are used.
The flange connections also deviate from the DIN connections in another respect. They usually have a
mechanical centering device for the flange halves, in order to make it easier to fit the seal and to prevent damage
to the seal during fitting in the flange connection.
Pressing the flange halves together by tightening the screws anchors the flexible seal securely in its seat and
deflects it slightly into the product space, which results in a streamlined hygienic connection. There is also leeway
for expansion of the seal in the event of temperature fluctuations. Flange connections without flexible seals can
also be used up to a pipe diameter of 100 mm. These connections are called metallically sealing (Figure 4.L-19)..
Figure 4.L-19
Connect-S flange connection
Difference between flange and quick release connections

(Tri-Clamp connection)
The difference between a flange and a quick release connection is essentially that a flange connection usually
involves a rigid connection with screws and nuts as established in a DIN. Such flange connections are available
for various pressure stages. Accordingly, they can be very large and clumsy. A soft, flexible seal firmly connects
the two halves of the flange to each other at the ribbed connection surfaces when the screws are tightened. This
variant aims primarily to guarantee pressures.
The Tri-Clamp connection also joins together two connection halves as a rigid connection. The difference
between it and the flange connection is that there is a more flexible connection between the two connection
halves. These quick release connections are available in a range of implementations and materials. In recent
years, various manufacturers have worked very intensively and successfully on an optimal dead-volume-free
quick release connection. The only disadvantage is that the sizes were designed primarily for pipes that transport
liquids. Most of the Tri-Clamp connections shown below are available up to a size of 150 mm (Figure 4.L-
20 and Figure 4.L-21).
Figure 4.L-20 Figure 4.L-21

BioConnect clamp connection BioConnect clamp connection
Larger quick release connections are rarer and can now extend to a maximum diameter of 300 mm. Quick
release connections too can now be implemented in line with DIN standards. However, deviations may occur
depending on the manufacturer. Therefore, it is important not to define the quick release connection as an
interface between suppliers but to always order these quick release connections from one supplier and adapt
them to the connection pipe of the connector.
Composition of a Tri-Clamp connection

Tri-Clamp connection halves with pipe set for welding onto the connection pipe
Seal as shaped part or O-ring
Clamp
The Tri-Clamp connection halves are usually not form fitting connections, but are provided with a groove for the
molded flat seal or O-ring seal. Due to the lack of a form fitting connection between the two connection halves, it
is very difficult to assemble large quick release connections without additional assistance by one or two helpers
(Figure 4.L-22).
Figure 4.L-22
Central O-ring connection (not dead-volume-free implementation)
Assembly
During assembly, one person holds the part to be assembled, while a second helper, if necessary, checks that
the seal is sitting securely and then closes the clamp securely around the connection. When tightening, it must be
ensured that the seal does not slip and is not damaged during assembly. Unfortunately, improper installation of
the seal is only ascertained during production, when dust escapes through the connection or liquid leaks during
cleaning.
Installation of the seal is made all the more difficult if the flat seal used is made of silicone. In this case,
installation with a diameter of >200 mm is only possible if more than two people are involved, as the very flexible
flat seal must repeatedly be pushed back into the position prescribed for the seal before the clamp can be
secured.
A very soft and flexible seal is, however, a prerequisite for a closed and leak-tight connection. There are also
PTFE (Polytetrafluorethylene - Teflon) seals with a soft core. These are easier to fit and are not easily damaged
during installation. However, they have the disadvantage that the connection is not dust-tight or liquid-tight during
cleaning. With PTFE seals, the choice of clamp must be given particular attention.
Clamps
Here, two half clamps should be used, which can be tensioned on both sides with a tool in order to produce a
more secure connection (Figure 4.L-23).
Figure 4.L-23 Cast clamp
The following must be noted for quick release connection halves:
Quick release connection halves usually have a weld-on pipe for connection with an extension
tube or another connection. It must be ensured that the welding pipe is long enough not to transfer too
high a heat influence around the sealing surfaces during connection welding, because warping caused
by the welding heat will make it impossible to achieve tightness in the connection.
Materials: Quick release connections are nearly exclusively made from stainless steel material
1.4435 or even 1.4404 or in accordance with USA standard (ASTM 316L) (see also chapter 4.L.3
Material: stainless steel). It is also possible to obtain the entire item made of Hastelloy C22, which is
significantly more expensive.
Note: In part, the product-contact surfaces (product-contact surfaces come into direct contact with the product or
the solvent to be cleaned) are Halar or PTFE coated, in order to save costs over the more expensive Hastelloy.
Halar and PTFE are very resistant plastic surfaces (see also chapter 4.L.3 Material: stainless steel), which are
applied to the stainless steel surfaces. In this case, it must be ensured that around 0.2-0.5 mm of material is
applied. Sharp edges must be avoided on the connection parts and replaced with radii before application. In the
end, making a coated quick release connection leak-tight is so time-consuming that there is no price advantage
over Hastelloy.
Seals
When selecting the seal between the connection halves to be connected, please note the following:
Differences in the shape: the following examples show different shapes of seal. The best
connection has proven to be an O-ring connection which is flush with the inner tube. This is, however,
only available up to a size of DN 100. For anything bigger than DN 100, many quick release connections
have an O-ring connection in the center of the connection halves, which means an absolute GMP
deficiency in terms of hygiene (Figure 4.L-22). A positive-fitting flat seal is better in this case (Figure 4.L-
24).
Figure 4.L-24 Flat seal
Material of the seal: the most frequently used selection criterion for the sealant is its resistance
to solvents, be it because a product contains solvents (e.g. after the centrifuge) or because solvents are
used for cleaning. The second most frequent reason is FDA-compliant (see extract from the material list,
(Figure 4.L-25)) or electrically conductive material. Another selection criterion might be flexibility, in order
to realize more leak-tight connections, for example..
Figure 4.L-25 Extract from a list of resistances against solvents (source: ESSKA
Maschinen Vertriebs GmbH)
The most flexible connection is a seal made of silicone, followed by EPDM (ethylene-propylene dien rubber) and
Viton, which are still flexible and are also more resistant to solvents. A very high resistance to most solvents can
also be achieved with a PTFE seal (polytetrafluorethylene) on flat or shaped connections. With PTFE seals, it
should be ensured that the sheath is made of PTFE and the core of a flexible material (e.g. silicone), in order to
achieve better tightness of the connection. For connections with an O-ring seal, O-rings coated in PEP
(perfluorethylenepropylene) are often used. These also consist of a soft core and a thin FEP sheath, which is
resistant to the most frequently used solvents. Another material with the best resistance to nearly all solvents is
Kalretz. However, Kalretz is a very rigid sealant material and can therefore only be used in certain cases. It is
also barely economical due to its high manufacturing costs.
4.L.4.2 Flexible connections

In addition to rigid connections, flexible connections are also used. Flexible connections are required for
uncoupling a balance, for example, or for uncoupling moving, vibrating parts from their rigid connections. Flexible
connections can be produced in a wide range of shapes and materials. However, it must be ensured that the
connections to the rigid connection are either easy to undo for cleaning or are suitable for CIP in a hygienic
design (chapter 4.I CIP (Cleaning in Place)). There are also different implementations for the materials. The most
frequently used material is silicone because it is so flexible compared with the other materials. It is therefore
used for uncoupling balances. Other materials include EPDM, NBR, Viton, PTFE and Kalretz. While EPDM,
NBR and Viton are still considered to be flexible and can be used for balance uncoupling in certain conditions,
PTFE and Kalretz are more rigid. With PTFE, more flexible materials like silicone can be coated in a thin layer of
PTFE or thin PTFE films can be used, which in turn creates a flexible connection. EPDM, NBR, Viton, PTFE and
Kalretz are resistant to current solvents such as acetone and toluene.
The above-mentioned materials are available in food or FDA-compliant implementations in light quality. If the
plastics come into contact with solids which have a risk of exploding dust, the plastics must have additives that
make them conductive. The color of this plastic ranges from grey to black and it is only available in a food or
FDA-compliant quality with limitations. To guarantee the use of light plastics when handling critical products, the
product-contact side should be made inert in a closed process with nitrogen.
Examples of different flexible connections

Collar for adaptation of the same or different containers to one connection piece. This variant is an open pipe with
a collar or tension band. Both systems shown fit flush with the connection container. With variant 1 (Figure 4.L-
26), a connection pipe penetrates the flexible collar. The connection is dust and water-tight.
Figure 4.L-26 Pressed on, flexible collar Figure 4.L-27 Pressed on, flexible collar
With variant 2 (Figure 4.L-27), a connection flange, which is secured to the container outlet, is pressed onto the
flexible collar. This connection enables quick and easy connection of very large containers. However, it usually
only has limited dust and water-tightness. Slight unevenness on the connection flange results in small gaps
through which product can escape.
Flexible collar with two connection ends (Figure 4.L-28).

Figure 4.L-28 Flexible collar with two Figure 4.L-29 Flexible collar with balance
connection ends uncoupling
This specially produced collar for connecting two pipes is set apart by its material offset on the connection pipe.
This means the collar is nearly flush with the material in the product-contact area. The interior of the connection
can therefore be cleaned more easily. The collar is secured with tension bands at the inlet and outlet. This
guarantees a dust-free connection. Disadvantages: The bulge in the collar means product can become trapped in
the trough.
Flexible collar with Tri-Clamp connections

This specially produced collar can be very easily integrated as an intermediate piece in a quick release
connection (Tri-Clamp connection, see screw connection and quick release connection in chapter 4.L.4
Connections). The connection is CIP (Cleaning in Place) capable and is extremely hygienic due to its dead-
volume-free implementation.
Flexible collar for balance uncoupling (Figure 4.L-29)

When uncoupling a balance via a flexible collar, the design of the collar is crucial. The collar shown in Figure 4.L-
29 is distinguished on the one hand by its optimal balance uncoupling via a horizontal and vertical connection,
and on the other hand by the fact that it is easy to clean.
4.L.4.3 Screw connections

In contrast to a welded connection, a screw connection is a fixed but detachable connection. This type of
connection is required if it is necessary to be able to disassemble parts for maintenance and repair or if the parts
are very large and can only be brought into the room when dismantled. The parts are reassembled in the room
and connected to each other via a fixed screw connection. A screw connection can also bear very high forces
and torques.
Another reason for using a screw connection is the safety of the connection. In the pharmaceuticals and API
areas in particular, quick connections are often used for easy cleaning of the facility (see also Quick release
connections in chapter 4.L.4 Connections). In many cases, a quick release connection can be opened without a
tool. The operator can therefore access the inside of a container or other systems at any time. This is not always
desirable and can also be hazardous if, for example, there is a moving part inside. To protect this area from
undesired access, a quick connection is sometimes implemented as a screw connection at a certain position.
This single screw connection is quicker to release with a tool than if the operator had to disassemble an entire
flange with screw connections. The remaining connection is opened via the quick release connection.
A screw connection is therefore not a quick release connection. A tool is required to open a screw connection
and close it again. A screw connection consists of two connection components that are connected with a screw,
washer and nut. The classic screw connection consists of a screw specified in accordance with DIN. Depending
on the requirements, various strengths, lengths and designs of screw can be used. The connection is tightened
by turning the screw in a thread. The thread is located either in the counterplate or in a nut. This is used if the
connection is made through two fastening elements without a thread.
The following designs are suitable as sanitation connections (Figure 4.L-30 to Figure 4.L-33).
Figure 4.L-34 and Figure 4.L-35, however, are unsuitable as they contain dead space and protruding threads,
which cannot be cleaned, or can only be cleaned with difficulty.
If the screw connection is to be seldom unscrewed, it is recommended to seal the transitions from one connection
part to the other with a flexible connection (Figure 4.L-36), which can also be removed.
In particular, it must be ensured that a screw connection to a pipe (square, round, rectangular pipe, etc.), does
not enter the inside of the pipe. When undoing the screw connection, this would create an open system from a
contaminated area within the pipe to the clean area outside the pipe. Therefore, a plate or reinforcement should
be welded onto the pipe in order to be able to attach a blind hole with a thread, so that the contaminated area
within the pipe remains unopened (Figure 4.L-37).
It should also be ensured that the washers between the screw head and the connection plate have a flexible
surface. This flexible surface seals the space inside the screw connection so that no contamination can occur.
Figure 4.L-30
Raised head with slit
!
Figure 4.L-31
Hexagon head screw
Figure 4.L-32
Screw fitting with cover nut
Figure 4.L-33
Screw fitting with through boring
Figure 4.L-34
Countersunk screw with hexagon
socket
Figure 4.L-35
Unfavourable screw
fitting
Figure 4.L-36
Screw fitting with plate
Figure 4.L-37
Screw fitting on pipe
4.L.5 Hoists and roller conveyors

4.L.5.1 Hoists
Lifting columns have become established in the hygienic area, as alternative hoists, such as chain hoists, fork-lift
trucks or caterpillars can only be encapsulated with limitation.
But there are also different designs of lifting columns. In general, all lifting columns in the external area are
covered in stainless steel sheets or have stainless steel profiles.
A hygienic lifting column is distinguished by its inner guide and the sealing of the centring slide as well as the
cable duct for the components to be actuated. The centring guides for the centring slide should always be inside
the lifting column. Particular attention should be paid to the sealing of the centring slide on the lifting column, as
this seals the lifting movement of the centring slide. The reason for this is the different variants that also protect
the inner workings of a lifting column against contamination from the environment. In most cases, a plastic or
stainless steel band is used as the cover, which is pulled through the back of the centring slide during the lifting
movement of the lifting slide.
The design is superficially very good, but is not tight through to the inside of the lifting column. The plastic band
can be removed by hand and intervention in the inside of the lifting column is possible. Nor does the cover band
rule out contamination of the inner parts. A much more elegant and better design involves stainless steel cover
bands or rollers, which close off the centring slide from the inside of the lifting column. These stainless steel
rollers can be sealed in integrated guides, so that the lifting column can also be installed on the clean room wall.
In the event of installation in a clean room (wall installation), the back wall can be opened at the rear of the lifting
column (in the services area outside the clean room) for maintenance and repair work, via quick-flange
connections as on electrical switch cabinets (safety locks with special tool). This reduces the interruption to the
use of the facility during maintenance work compared with the disruption caused by work that would have to be
carried out inside the clean room.
General requirements: A lifting column should always be designed so that the external parts are smooth and
easy to clean. The electrical cables and pneumatic tubes should be routed inside the lifting column.
It is easier to lay the cables inside the lifting column and this also ensures that the outside of the lifting column
has a better design. If the cables are to be installed externally, it must be ensured that they are routed in an
enclosed tube, the outer surface of which must be cleaned.
If the lifting column is set up in an area that is classified as at high risk of explosion, the closed tube must also be
permitted for this area. This is an absolute requirement in accordance with ATEX (Atmosphere Explosible
Directive a4/9/EC - Use of facilities in explosive environment).
External and internal surfaces: In most installations, the external surfaces of lifting columns are made of
stainless steel and the inner parts are partially or totally of carbon steel. As there are moving parts inside the
lifting column or an aggressive atmosphere in the environment which can cause temporary or permanent use of
solvents, rust may start to form inside the lifting column. A better design is a lifting column made completely of
stainless steel, even if this means a higher investment.
Part of the lifting column must not only execute a lifting movement, but must also pivot the lifting column from one
to several other positions. The cover of the wheel flange must also be closed. The wheel flange is located near
the floor where wet cleaning is often carried out. The wheel flange cover should be sealed to avoid the entry of
spray water.
4.L.5.2 Roller conveyors

Roller conveyors are usually used as a delivery transport system or removal transport system for drums, fiber
drums and other containers. A prerequisite is that the containers can be transported on rollers. A roller conveyor
may also be necessary to make the operator's work easier, as they would otherwise have to transport the full and
empty containers by hand. With the supply transport system, the empty containers are stacked up and moved
under the filling system. In the filling position, there is usually also a short roller conveyor section. The removal
transport system for the full containers buffers them before the containers are palletized. Roller conveyors are
available in various implementations.
Manual roller conveyor

The simplest variant is a roller conveyor without a drive. With this type of design, the containers must be moved
by hand or are transported by gravity. (The roller conveyor has a slight slope of around 5°.) With a manual roller
conveyor, the facility's performance does not play a significant role. The advantage of this system is the design of
the roller conveyor. It can be simple, which also makes the conveyor easier to clean. The side walls can be made
of vertical plates which are connected by round tubes. The feet are also of a closed square tube construction,
which slope at the top end and are closed. The roller conveyor support is designed so that the rollers are easy to
remove for cleaning purposes (Figure 4.L-38).
Figure 4.L-38 Design of a roller conveyor
Driven roller conveyor

The other variant of the roller conveyor is the driven roller conveyor. The driven roller conveyors have the
advantage over manual roller conveyors that performance is increased through the automation. However,
automatic roller conveyors lose the advantage of easy cleaning. On driven roller conveyors, the walls are fitted in
a sandwich construction, in order to accommodate the roller to roller drive elements in the spaces. The drive
elements can be chain wheels with chains or a V-belt connection.
Figure 4.L-39 Space saving fibre drum stacking
The V-belt connection is always preferred to the connection chain, as the V-belt does not have to be lubricated
and is also easier to clean. The arrangement of the roller conveyors and their accessories depends on the task.
For example, to save space, the containers can be stacked one on top of the other as shown inFigure 4.L-39.
The empty containers are buffered in the top area and transported to the bottom area as required, via a lifting
device, where they are then automatically brought to the filling position. If the roller conveyors are in a controlled
area (in a clean room), the empty and full containers must be brought through a material lock.
In the locks, there may also be an air nozzle to clean the containers before they enter the clean room. Other
additional equipment includes systems for palletizing the containers, as well as vacuum lifters which lift the
containers via suckers and allow an operator to then set them on pallets. A pallet robot automatically sets the
cover on the container, positions the container on the pallet and wraps the entire pallet in film. A fully automatic
conveyor and palletizing system is only worthwhile with high performance rates (more than 40 barrels per hour).
4.L.6 Pneumatic conveyor system

The use of pneumatic conveyor systems requires particular attention to the cleanability of the system. As a
general rule, pneumatic conveyor systems are used wherever filling or emptying of a product is not possible via
gravity. This can be the case if there is only limited space above the container or process system to be filled or
below the container process system to be emptied. A pneumatic conveyor system may also be used for filling a
reactor during API production. It provides for more gentle and controlled product feeding (quantity dosing) and
serves as a lock from a depressurized container emptying system to a pressurized container in which a chemical
reaction takes place. The prerequisite is that the pneumatic conveyor system can be used as a lock.
Pneumatic conveyors are distinguished from pressurized conveyors and vacuum conveyors. Vacuum conveyors
are usually used to transport products up to a distance of around 50 m from the feeding station to the separator.
If the delivery distance is greater than 50 m, pressurized conveyors are usually used. These conveyor sections
are less likely to be found in API production or in drug product manufacturing and are not to be advocated due to
hygienic reasons.
There are two different kinds of vacuum conveyor systems that can be used. First, a vacuum conveyor with a
separator, and second, a powder transport system (PTS, see chapter 4.J.11 Containment on equipment).
4.L.6.1 Vacuum conveyor with separator
Dilute-phase conveyor system

Vacuum conveyors working with the dilute phase (little product with a high volume of air) usually have large
separators which contain the filter medium for separating the product before the vacuum generator (Figure 4.L-
40).
Figure 4.L-40 Vacuum conveyor

system with separator
Due to their size and filter surfaces, these systems are only suitable for use in sanitation if they are mono-
production systems or if the filters are easy to change and the system easy to clean. Another weakness of this
system is the separation of the product during delivery. Due to the low product load during transport and the high
delivery speed, the small, light particles are delivered more quickly than the larger, heavy particles. The abrasion
and mechanical stress of the product during delivery are high. For products with a low ignition energy, this can
even mean that they have to be transported with nitrogen.
Cleaning of these systems is usually very time-consuming and requires high manual effort. Preliminary cleaning
by means of WIP (Washing in Place) is possible.
4.L.6.2 Powder transport system (PTS)
Dense-phase conveyor system

The powder transport system (PTS, see chapter 4.J.11 Containment on equipment) is also a system that works
with a vacuum. The difference between this and a conventional system is that the PTS system works with a very
high vacuum. This high vacuum means the product to be conveyed is delivered in a pipe or preferably a tube
system with very high loads. Due to the high load and the lower air volume, the separator has a small filter
surface.
The filter used is a membrane in the diameter of the separator. At around 6-8 m/sec, the delivery speed of the
PTS systems is about a quarter the speed of a normal conveyor system. This also makes it easier to deliver very
sensitive products with a minimum ignition energy of <1 mJ without having to add nitrogen during delivery.
Separation of the product is prevented by the dense loads during delivery.
The product is added to the containers or reactor in a nitrogen atmosphere. To this end, the product delivered in
air is placed under a very high vacuum in the separator and evacuated from the oxygen. Then the separator is
filled with nitrogen and the outlet flap to the reactor is opened. The advantage is that the addition of nitrogen
significantly reduces the oxygen concentration in the reactor.
The system can also be cleaned with validation by integrating a CIP system (Cleaning in Place) and a liquid
separator. With a comparable delivery rate, the PTS system is about half the size of a conventional delivery
system.
4.L.7 Dosing systems

Dosing systems are used to empty or fill a predefined quantity. This can be a blend of different raw materials or a
single dose of the same product. A dosing system is also used to create portions in smaller containers or even to
empty the product into a reaction vessel.
The dosing system is fitted between the pack, container or process equipment to be emptied and the pack,
container or process equipment to be filled.
There are many kinds of dosing systems. This is due to the flow behavior of the products, which varies from free
flowing to sticky and splurging. Room heights, facility offset and metering accuracy also play a role in the
selection of a dosing system.
4.L.7.1 Vibration dosing device

A vibration dosing device is usually suitable for easy flowing products and granulates. Advantage of a vibration
dosing channel: There are no attachments in the dosing system. A vibration dosing device consists of a dosing
pipe or dosing feeder, usually with a round inlet and outlet. The drive is located beneath the dosing system and
can be a magnetic drive or a pneumatic drive, which transfers vibrations to the dosing system and thus causes
the product to flow.
The product flow is reduced or increased by setting different frequencies on a magnetic drive or different
pressures on a pneumatic drive, which enables dosing to a predefined value.
4.L.7.2 Dosing screw

A dosing screw can convey and dose a wider range of products than a vibration dosing device. These can range
from very free flowing to sticky, heavy flowing products. The reason for this is that a dosing screw is a forced
delivery system. Once the product has been added to the screw workings, it is usually then also conveyed. The
dosing system consists of an external pipe, a screw, sealing flange at the ends with bearing and shaft
feedthrough as well as a drive.
By actuating the drive via frequency regulation, the speed of the screw can be increased or reduced. The dosing
screw is always cleaned manually by dismantling the dosing screw. The dosing screw can be pre-cleaned when
fully installed, but dismantling is unavoidable for complete cleaning. Easier dismantling can be achieved through
the use of quick connections.
4.L.7.3 Slide dosing gate (knife-gate)

The slide dosing gate is used as a so-called in-line dosing system. In-line means that there is no offset between
the area to be emptied and the area to be filled, as with the dosing screw, for example. The products are added
to the dosing gate by means of gravity. The dosing gate consists of a housing and a sliding plate, which is
actuated via a drive. For example, it might be a pneumatic cylinder which opens and closes the gate. To make
the system into a dosing system, the pneumatic cylinder is fitted with a position sensor. This enables the dosing
control to open or close the gate in different positions.
The cross-section through which the product can flow is regulated in this way and the product is dosed. When
selecting a slide dosing gate, it is important to note that it does not have any dead space and is quickly
dismantled for cleaning purposes.
In the case of thick, heavy flowing products, a product supply system must be added upstream of the dosing gate.
The product supply system keeps the product moving and supplies it continuously to the gate. This means a high
metering accuracy can be achieved even when dosing heavy flowing products.
4.L.7.4 Flexidos dosing system

The Flexidos dosing system, like the slide dosing gate, is an in-line dosing system but with a dosing slit in the
product-contact area. This dosing slit is opened externally by two synchronously controlled dosing pushers. A
closing spring in the dosing system pulls the dosing slit together again after the dosing pushers have released the
dosing system. The dosing pushers are moved by the dosing control and open the dosing slit according to the
dosing output and accuracy. With the Flexidos dosing system, the slowest flowing products can be dosed with
maximum accuracy <1g. The dosing system is easy to change and clean. As with the dosing gate, the Flexidos
also needs a product supply system for heavy flowing products.
4.L.7.5 Transbatch feeder

The transbatch feeder is a combination of a pneumatic conveyor system and a vibration dosing device. The
pneumatic conveyor sucks the product into the separator which is attached to the vibration dosing device. The
vibration dosing device conveys the product, which has been loosened by the pneumatic conveyor, into the pack
or container to be dosed.
4.L.8 Platforms and stands

Stands or platforms are required for the implementation, operation and maintenance of a solids system. The
stands hold adapters or components. The platforms make it easier for the operator or service staff to access the
facilities. Here too, hygienic design is important.
4.L.8.1 Platforms
The following points should be taken into account when designing a platform:
The steps of the stairs should be added in two side walls (Figure 4.L-41).
Figure 4.L-41 Stairs, platform
The walls should be made of thick-walled smooth sheets.

The steps should be made of polished stud plate surfaces, which are edged at both ends in the
opposite direction.
The step surfaces should be slightly sloped so that the cleaning fluid can flow off more easily
during cleaning.
The hand rail on the stairs should be made of round piping, which is closed at the ends.
The mounting closure on the rails should be implemented with cover nuts.
The substructure of an operating platform should be made of a closed square pipe or round pipe
construction.
The platform surface, like the steps, should be made of polished stud plate.
The foot edge should be edged on all sides and the joints at the corners should then be welded.
The bearing surfaces on the platform should, like the steps, be slightly sloped, so that the
cleaning fluid can flow off more easily during cleaning and no puddles form or liquid residues remain.
There should be spacer bolts between the square pipe or round pipe construction and the stud plate surface
(Figure 4.L-42) so that the space between can be more easily cleaned.
Figure 4.L-42 Design of bottom plates on stands
If the stud plate surface is welded directly onto the substructure, (Figure 4.L-43), the stud plate must be welded
right through. If this is not possible, due to excess warping of the platforms because of the long welds, the spaces
between the individual welding seams must be filled with a flexible stainless steel jointing medium. The thread
ends on screw connections on the substructure should also be sealed with a cover nut.
Figure 4.L-43
Stand with welded surface
4.L.8.2 Stands
The question of which profile to choose for stands and the substructure of platforms cannot be answered in
general. Round pipes certainly have an advantage in terms of cleaning. However, they are more costly to
manufacture. When using square pipes, there is more available horizontal bearing surface on which the product
or dust can be deposited, but this surface is too small to justify the higher costs of a round pipe construction. A
cleanly processed stand or the substructure of a frame produced from square piping is in any case suitable for
installation in a controlled area (Figure 4.L-44).
What must be avoided is open profiles such as U-tubes or similar.
Sloping covers (Figure 4.L-45) should be used. This makes the surfaces easier to inspect for impurities, if they
are in an elevated position, and the cleaning fluid can flow off more easily.
Figure 4.L-44 Connection of profiles Figure 4.L-45 Covers
4.L.9 Clean room installations

For clean room installations, attention should be paid not only to the product-contact surfaces, but also to the
overall design of the external parts. The surfaces in the clean room must be easy to clean not only on the product
side, but also on the external surfaces. The surfaces, cable ducts and attachments should be designed
specifically to facilitate exterior cleaning.
4.L.9.1 Rail design

Example 1 (Figure 4.L-46 and Figure 4.L-47): Rails attached to a Pharma Terrazzo.
Figure 4.L-46 Rail guide - unfavourable due to contamination and

tripping points

Figure 4.L-47 Structure of the unfavourable rail guide
Example 2 (Figure 4.L-48 and Figure 4.L-49): Rails integrated in the hexagon tiled floor
Figure 4.L-48 Rail system integrated in the floor
Figure 4.L-49 Schematic of the integrated rail system

Both systems initially appear to be hygienic implementations. The difference between the two systems is the
implementation and attachment of the rails. In example 1, the rails are attached to the floor and screwed down.
This is initially a very attractive, cost-effective and quick solution. In practice, however, the connection at the
transition from the rail to the flooring will rupture and contamination will build up in the crevices, thus increasing
the gaps. After a period of time, there will be a GMP deficiency, which can only be corrected with great difficulty.
A further disadvantage is the increased risk of tripping.
The best solution is example 2. Here, a special rail design is integrated in the floor, before the hexagonal tiles are
laid. The profile is integrated flush with the surface, making a semicircular sphere with the neighboring flooring.
This shape is optimal as a track for the carriage and is also easy to clean due to its geometric shape.
The disadvantage is that the installation costs are higher than with the first example. But the follow-up costs for
maintenance and repair are much lower.
The choice of hexagonal tiles was also a good decision, as the tiles are more robust and durable and still look
like new after ten years.
4.L.9.2 Control panels

If possible, installation flush with the surface of the clean room wall is always recommended (Figure 4.L-50).
to enlarge, click here! to enlarge, click here!
Figure 4.L-50 Panel installation flush with Figure 4.L-51 Unfavourable installation of
the wall surface operating panels
Installation of the control panel with the front flush with the wall means there are no surfaces as shown
in Figure 4.L-51 which require cleaning. In addition, the operating keypad has no surfaces on which anything can
be deposited. The cables to the operating panel should be routed and laid within the clean room wall (sandwich
construction) so that no additional pipes for cable ducts are required in the clean room.
4.L.9.3 Cable ducts

Cables are required in a clean room to control valves, motors, sensors, etc. Flexible lines are also required for
compressed air-operated facility components. Most errors are made when laying the connections or if, for cost
reasons, clean room compliant installation is not used.
As shown in Figure 4.L-52, cables or pneumatic tubes are bundled together via cable ties and openly laid in the
grating channels or half open in pipes.
Figure 4.L-52 Unfavourable cable routing
This has the disadvantage of not permitting the external parts to be cleaned. Product dust which collects between
the tubes is difficult to remove through manual separation of the tubes or cables. The half open routing of cables
and tubes (necessary to hold tubes or cables over a long distance) in open pipes increases the cleaning problem
for facility components. If unavoidable, such cable ducts should be laid vertically and the ends should be sealed
after the cables have been laid. As shown in Figure 4.L-52 , the pipes are laid horizontally, which leads to a GMP
deficiency. Product dust, which can rarely be avoided when handling solids, collects in the pipes. The external
surfaces of the pipes can be cleaned, but the impurities remain in the pipe.
A closed cable system should always be used in clean room installations or in controlled rooms. This type of
system contains the cable duct within closed square pipes used as mounting stands or in round pipes that are
only used for holding cables. The design of the overall facility must be thought out in detail, as the openings at
the cable inlets and outlets must be taken into account and provided for in the detailed design (Figure 4.L-
53 to Figure 4.L-55).
The cables from the cable outlet to the consumer should take the shortest route (around 300-400 mm). The
cables should also exit the pipe via individual connections, so that each cable can be cleaned independently. The
cable outlet is also the entrance from the black area to the white area in the clean room and, accordingly, must
be leak-tight. Therefore, the cable feed into the pipe should be implemented with a closed system such as a PG
screw fitting for cables or a quick screw fitting for hoses.
In any case, pneumatic boxes with the valves should be set up outside the clean room and the hoses then
routed into the clean room bundled together and enclosed.
Compressed air should never be blown out in the clean rooms through quick ventilation valves on installed
pneumatic cylinders. The air should be routed out of the clean room to the services area.
Figure 4.L-53 GMP-conform solids facilities installation

All cables and hoses routed in the lifting columns
and brought into the services area via closed systems
through the clean room ceiling.
Quick release connections in all components for easy
cleaning and inspection
Floor balance with fold-up cover for easy cleaning
Floor clearance beneath the facility. This means the
area weighing platform the balance is also easy to clean.
Advantage of the lifting column for the dosing
system: The dosing screw can be brought to operating
height for cleaning and maintenance work.
Cable ducts to the dosing screw are laid in the
square pipes and lifting column.
The outside of the lifting column has no attachments
and is therefore easy to clean
Figure 4.L-54 Example of a clean room installation - dispensing advantage: closed cladding,
no installations on the floor
Figure 4.L-55 Example of a clean room installation -

container filling

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PHARMACEUTICAL QUALITY SYSTEM GMP MANUAL

Author: Lothar Hartmann Ph. D. / Update 09

The GMP Manual contains three chapters related to quality:

 Pharmaceutical Quality System (chapter 1)

1.B The road to a Pharmaceutical Quality System

Author: Lothar Hartmann Ph. D. / Update 09

Here you will find answers to the following questions:

1.C Introduction to the PQS

Here you will find answers to the following questions:

1.C.1 General requirements

Implementing a PQS has a significant impact on the "classical" organization of a company. It

 Determining responsibilities within the organization (global, regional, local)

A documentation system remains a fundamental component of a PQS. The objective of such

 senior management's commitment to quality,

GMP documentation, especially regarding Master Production Instructions and laboratory

1.C.2.2 Quality manual

The main elements to be incorporated include:

1.C.2.4 Control of records

The control of records includes hard copies as well as electronically-stored data.

Details about GMP-conformity of documentation are given in chapter 15 Documentation.

1.D Main elements of a PQS

Author: Lothar Hartmann Ph. D. / Update 09

Here you will find answers to the following questions:

1.D.1 Management responsibility

1.D.1.1 Management commitment

 communicating the importance of meeting patient needs as well as regulatory (GMP)

1.D.1.2 Quality policy

1.D.1.3 Quality planning

Senior management is responsible for the quality planning of the organization.

The "SMART" criteria

should be applied to establish quality objectives.

This representative should report to senior management.

1.D.1.5 Resource management

1.D.1.6 Internal communication

1.D.1.7 Management review

A consolidation of available data is to be provided as input to senior management review to support

These data include, but are not limited to:

 audit observations/results (internal and external audits as well as inspections by

 continual improvement of the effectiveness of the PQS and its processes,

1.D.1.8 Outsourced operations

 Assessment, prior to outsourcing, of the suitability and competency of the contract

1.D.2 Resource management

1.D.2.1 Provision of resources

Senior management needs to determine and provide the resources:

1.D.2.2 Human resources

Competence, awareness and training are ensured by senior management through:

 implementing an adequate and effective organization,

Buildings have to:

 be located, designed, and constructed to facilitate cleaning, maintenance, and

Equipment should be:

Computerized systems should be:

 of appropriate design and adequate capacity,

 identify information needs

1.D.3 Manufacturing operations

The majority of GMP requirements relate to this major process of a PQS.

Materials used in manufacturing operations should be defined by appropriate specifications and

Particular attention should be paid to:

 Sampling is to be performed at defined locations and by procedures designed to prevent

 Materials should be handled and stored in a manner to prevent degradation,

1.D.3.4 Production and service provision

 document control, pre-approved manufacturing procedures, batch record review and

1.D.4 Evaluation activities

1.D.4.1 Deviation investigation

Further information on this issue is given in chapter 11.K Deviations.

Pharmaceutical Quality System (chapter 1)

Determining responsibilities within the organization (global, regional, local)

senior management's commitment to quality,

communicating the importance of meeting patient needs as well as regulatory (GMP)

audit observations/results (internal and external audits as well as inspections by

continual improvement of the effectiveness of the PQS and its processes,

Assessment, prior to outsourcing, of the suitability and competency of the contract

implementing an adequate and effective organization,

be located, designed, and constructed to facilitate cleaning, maintenance, and

of appropriate design and adequate capacity,

identify information needs

Sampling is to be performed at defined locations and by procedures designed to prevent

Materials should be handled and stored in a manner to prevent degradation,

document control, pre-approved manufacturing procedures, batch record review and

in-process control and test results for trending

significance of the proposed change

Internal quality audits should be planned, performed, recorded and followed up by

Improvement initiatives ongoing and/or completed

Preventive action is intended to avoid the initial occurrence of a non-conformity.

chapter 11.K Deviations

Integration and alignment of processes to enable achievement of planned results.

Manufacturing processes (realization of the product) and

Definition of the needs of the receiver (customer requirements)

Definition of the activities within the process

Identification of process-related indicators

Orient new employees

understand the work flows through functional boundaries

Decision/agreement of senior management to establish a relationship map

connections and interfaces on a "high-level"