Qualification And Validation In

Pharmaceutical Manufacturing
OBJECTIVES
• Discuss the requirements for Qualification and Validation
in Pharmaceutical Manufacturing
• Appreciate the need for Validation
OUTLINE
• Definitions
• Validation documentation
• Qualification
• Types of validation
• Approaches
• Life cycle concept of validation
• Conclusion
 INTRODUCTION

• Safety, quality and efficacy are built

into the product – cannot be
"inspected or tested into a product"
• Need for confidence that the product will consistently meet
predetermined specifications and attributes
WHAT IS VALIDATION?
•“Validation is defined as the collection &
evaluation of data, from the process
design stage through commercial
production, which establishes scientific
evidence that a process is capable of
consistently delivering quality product.”
•Documenting that a process or system
meets its pre-determined specifications
and quality attributes
WHAT IS VALIDATION?
• EU GMP - it is “Action of proving, in accordance
with the principles of Good Manufacturing
Practice (GMP), that any procedure, process,
equipment, material, activity or system actually
leads to expected results.”
• The US FDA defines “Validation as establishing
documented evidence which provides high
degree of assurance that a specific process will
constantly produce a product meeting its pre-
determined specification and quality attributes.”
WHAT IS QUALIFICATION
• Performed to establish confidence that process
equipment and ancillary systems are capable of
consistently operating within established limits
and tolerances.
• Provides documented evidence that the subject
equipment has been installed as per
specification (manufacturer’s recommendation)
and will attain and maintain critical process
parameters repeatedly and reliably.
• A subset of validation, typically done as part of a
larger validation effort.
 Comparison between Qualification and
Validation
• Validation and Qualification are essentially
components of the same concept.
• Qualification is normally used for equipment,
utilities and systems
• Validation is normally used for processes and
methods
• In this sense, qualification is often a part (the initial
stage) of validation but the individual qualification
steps alone do not constitute process validation.
• Process validation cannot take place without first
carrying out qualification
WHY VALIDATION?

•Assures Quality

•Regulatory Requirement

•Reduces Cost

•It’s the LAW !

 Consequences of NOT Validating Systems
and Processes

Poor Product Quality

Death Bad Publicity

Financial losses
 Systems

equipment
• What to Qualify/Validate
 Responsibility
✓ Responsibility for
qualification and
validation is a multi-
disciplinary one which
includes:
✓ Heads of
Production and QC
✓Heads of
Engineering and
Contractors/suppliers
✓Respective
responsibilities
clearly defined in the
VMP.

Pharm.(Mrs) Edosa Ogbeide 12

Validation Life Cycle Process
Validation should not be
viewed as a one-off event.
Validation must follow a
structured documented
process applying a lifecycle
approach having the
following key elements: Structured
Documented
✓Initial Validation Lifecycle
✓Validation Review and Approach
✓Change Management Validation Review

Validation encompasses the entire life of the system

from the initial requirements definition through to
maintenance and eventual decommissioning of the
system

Pharm.(Mrs) Edosa Ogbeide 13

Validation Documentation
• Validation Master Plan (VMP)
• Validation Protocols (VP)
• Validation Reports (VR)
• Standard Operating Procedures (SOPs)
Validation Documentation
Validation Master Plan
• Contains key elements of the validation program.
• Concise, clear, contains at least:
❑a validation policy
❑organizational structure of validation activities
❑summary of facilities, systems, equipment and
processes validated (and to be validated)
❑documentation format (e.g. protocol and report)
❑planning and scheduling
❑change control and references to existing
documents
Validation Documentation
Validation Protocol
• A validation protocol is a detailed document relating
to a specific part of the validation process.
• Outlines tests to be carried out, the acceptance
criteria and the information that must be recorded.
• Defines the approval process for the validation.
• Describes the procedure to be followed for
performing validation.
• Objectives of the validation/qualification study, the
site of the study, the responsible personnel
Validation Documentation
Validation Protocol
• Description of the equipment to be used (including
calibration before and after validation)
• SOPs to be followed (e.g. the operation and cleaning
of the equipment) and the standards and criteria for
the relevant products and processes.
• Type of validation and time/frequency should also be
stipulated.
• Processes and/or parameters to be validated (e.g.
mixing times, drying temperatures, drying times,
physical characteristics, content uniformity, etc.)
Validation Documentation
Validation Report
• Record of results obtained during the performance
of the validation.
• Reflects the final test results and other documents
such as instrument calibration certificates.
• Basis on which the decision is taken on whether a
particular process is judged to be validated.
• Includes evaluation, analysis and comparison of
results with acceptance criteria by the responsible
personnel.
• Results should meet acceptance criteria and satisfy
the stated objective.
Validation Documentation
Validation Report
• Refer to the protocol, state details of material,
equipment, programs and cycles used, together with
details of procedures and test methods.
• Include recommendations on the limits and criteria to
be applied to all future production batches.
• Protocol and the report may be combined into a
single set of documents.
• The protocol is approved as a form on which the test
results are recorded as they become available.
QUALIFICATION

Types (Stages) of Qualification

• Design qualification (DQ)

• Installation qualification (IQ)
• Operational qualification (OQ)
• Performance qualification (PQ)
QUALIFICATION

DQ IQ OQ PQ

Training
Calibration Certification

Change
control GMP Process
under control
Review
periodically
Pharm.(Mrs) Edosa Ogbeide 22
Commissioning
• Include equipment start- • Supplements validity and
up, adjustments, fine- regulatory compliance
tuning, cycle • checks to verify the
development, testing system or equipment is
and documentation built to design
flexibility. specifications
• Leaves the equipment in • No safety issues
a “State of Control”, • Takes place at the
which ensures the manufacturer’s premise
equipment is ready for (FAT) or User/Client’s
formal qualification, Premise (SAT)
testing, and approval.
Design qualification (DQ)
• Process of completing and documenting
design reviews to illustrate that all quality
aspects have been fully considered at the
design stage.
• To ensure that all the requirements for the
final systems have been clearly defined at the
start.
• In other words, has it been designed and
selected correctly?
Design qualification (DQ)
Before purchasing, a manufacturing
equipment
• Collection of data about similar equipment
available in the market
• Assessing your needs
• Resources to buy, operate, space and
maintenance they would need, etc.
• Making the decision
Installation Qualification (IQ)
• Process of checking the installation, to ensure that the
components meet the approved specification and are
installed correctly, and to see how that information is
recorded.
• To ensure that all aspects (static attributes) of the facility or
equipment are installed correctly and comply with the
original design.
Installation Qualification (IQ)
Considerations include:
• Equipment design features (i.e. materials of
construction cleanability, etc.)
• Installation conditions (functionality, utilities, wiring,
etc.)
• Calibration, preventative maintenance, cleaning
schedules; safety features
• Supplier documentation, prints, drawings and
manuals, software documentation
• Environmental conditions (such as clean room
requirements, temperature, humidity)
• Spare parts list
Installation Qualification (IQ)
E.g., a manufacturing equipment

• After purchasing (or critical repair)

• Place it on its intended place
• Connect with other equipment, electric power,
material flow devices.
• Collect its documents including Operation Manual,
etc.
• Its formally “released”: it is ready for working with
Operational Qualification
•Process of testing to ensure that the
individual and combined systems
function to meet agreed performance
criteria and to check how the result of
testing is recorded.
•To ensure that all the dynamic attributes
comply with the original design.
•Does it work correctly?
Operational Qualification
• Assuring that the critical components and systems are capable of
operating within established limits and tolerances
• “Worst case” (Proven Acceptable Range) demonstration that the
equipment will perform as expected while operating at the extremes of
the proposed range of operation.
Operational Qualification
Considerations include:
• Process control limits (e.g. time, temperature,
pressure, line speed, setup conditions)
• Software parameters; starting material specifications
• Process operating procedures; material handling
requirements
• Process change control; training; short term stability
and capability of the process, (latitude studies or
control charts)
• Risk analysis and potential failure modes, action
levels and worst-case conditions (Failure Mode and
Effects Analysis, Fault Tree Analysis
Operational Qualification
E.g., a manufacturing equipment
• ”Model manufacturing” experiments with model materials,
similar to those to be used in the real manufacture
• E.g. qualifying an autoclave, we use culture-media
• Permit the acceptable fluctuations of parameters, even set
the ”worst conditions”
Operational Qualification
Worst Conditions
• For example, if an equipment is to be
operated within the limits of:
• Temperature: 20 and 35 oC
• Pressure: 0.9 and 1.2 atm
• The worst cases are when it operates at
• 20 oC and 0.9 atm
• 35 oC and 1.2 atm
• 20 oC 0.9 and 1.2 atm
• 35 oC and 0.9 atm
Performance Qualification
• Also called process qualification
• Process of testing to ensure that the individual
and combined systems function to meet agreed
performance criteria on a consistent basis and
to check how the result of testing is recorded.
• To ensure that the criteria specified can be
achieved on a reliable basis over a period of
time.
• Does it produce the product correctly.
Performance Qualification
PQ includes:
• Actual product and process parameters and
procedures established in OQ
• Assurance of process capability as
established in OQ
• Acceptability of the product
• Process repeatability, long term process
stability
Performance Qualification
• Similar to the Operational Qualification, but the
real manufacture is running
• Permits accepted fluctuations up to their limits
(incl. worse conditions, if occur)
• Integrates procedure, personnel, systems, and
materials to verify that the pharmaceutical grade
utility, environment, equipment, or support system
produces the required output
• Production is done under conditions that simulate
those planned to be used during actual
manufacturing
Change Control
• Policy and procedure
• Risk assessment
• Authorization
• Failure to properly document changes to the system means
invalidation of the process
Change Control
Changes that require revalidation
• Software changes; Controllers
• Site changes; Operational changes
• Change of source of material
• Change in the process
• Significant equipment change
• Production area changes
• Support system changes
Validation
Types
• Process Validation
• Analytical Method Validation
• Cleaning Validation
• Water Systems Validation
• Computerized System Validation
Process Validation
• Means of ensuring, and providing documentary
evidence that processes (within their specified
design parameters) are capable of repeatedly
and reliably producing a finished product of the
required quality.
• PV should be completed prior to commercial
manufacturing
• Where this is not possible, it may be necessary to
validate processes during routine production
Approaches to Validation
Prospective Validation
• Prospective validation is carried out during the
development stage.
• Includes division of the production process into
separate steps
• Analysis of potentially critical points in the
manufacturing process e.g. mixing times, or
temperature.
• Trials are carried out in which these steps and
critical points are simulated and the effect on the
process is assessed.
 Approaches to Validation
Prospective Validation
❑Each step should be
evaluated on the basis of
experience or theoretical ❑Representatives
considerations to from Production,
determine the critical QC/QA, Engineering,
factors/parameters that and in some cases
may affect the quality of Research and
the finished product. Development (if
❑ May incorporate available) will
a challenge element normally be
to determine the involved in this
robustness of the process.
process.
❑ Such a challenge
is generally referred
to as a "worst case"
exercise.
Pharm.(Mrs) Edosa Ogbeide 42
Approaches to Validation
Concurrent Validation
• Carried out during normal production.
• Requires full understanding of the process based on
prospective work.
• Involves very close and intensified monitoring of the steps
and critical points in at least the first three production-scale
batches
 Approaches to Validation
❑ Documentation
Concurrent Validation requirements are the
❑In certain circumstances same as specified for
it may not be possible to Prospective Validation
complete a validation and the testing to be
programme before carried out in-process
routine production starts. and on the finished
In these cases it will be product will be as
known in advance that specified in approved
the finished product will protocols.
be for sale or supply.
❑ It is important however, ❑ The completed
protocols and reports
that the premises and should be reviewed
equipment to be used and approved before
product is released for
have been qualified sale or supply.
previously and that the
decision to carry out
Concurrent Validation is
made by appropriately
authorised people.
Pharm.(Mrs) Edosa Ogbeide 44
Approaches to Validation
Retrospective Validation
• The analysis of accumulated results from past
production to assess the consistency of a process.
• Includes trend analysis on test results and a close
examination of all recorded process deviations.
• It is important to analyze 10 to 25 batches
manufactured over a period of 12 months to provide
a statistically significant picture.
• It is not the preferred method of validation and
should be used in exceptional cases only and never
for sterile products
 Approaches to Validation
Retrospective Validation
❑ There are many
processes in routine
❑This type of validation
use in many
exercise is only
companies that have
not undergone a Data acceptable for well
established processes
formally documented
and will be inappropriate
validation process.
where there have been
❑ Validation of these recent changes in the
processes is possible, composition of the
using historical data ❑ The steps involved in this product, operating
to provide the type of validation still procedures or
necessary
documentary require the preparation equipment.
evidence that the of a protocol, the
process is doing reporting of the results
what it is believed to of the data review,
do. leading to a conclusion
and recommendation.
Pharm.(Mrs) Edosa Ogbeide 46
 REQUIREMENTS FOR PROCESS VALIDATION
Fully qualify all equipment, the production
1 environment and analytical testing methods
Operatives taking part in the validation work should
2 have been appropriately trained

3 Calibration and maintenance schedule developed

4 Standard Operating Procedures followed

5 Materials (APIs and Excipients) must meet Raw

Material specifications

6 Analytical methods must be fit for the purpose

7 Pre-approved validation protocol

Pharm.(Mrs) Edosa Ogbeide

47
The Lifecycle concept of Process
Validation
Stage 1: Process Design
•Define Process Knowledge Space
•Identify Critical Process Parameters
•Determine Control Strategy

Process Stage 2: Process Qualification

Validation •Equipment/Utility/Facility
Qualification
Lifecycle •Identify Critical Process Parameters
•Process Performance Qualification

Stage 3: Process Maintenance

•Monitoring of Critical Process
Parameters

48
Pharm.(Mrs) Edosa Ogbeide
The Lifecycle concept of Process
Validation
• The Lifecycle concept links product and
process design, qualification of the
commercial manufacturing process and
maintenance of the process in a state of
control during routine production
• A science- and risk-based approach to verify
and demonstrate that a process operating
within predefined specified parameters
consistently produces material that meets all
its critical quality attributes.
 Validation Maintenance
V M
A 1
A
I Change
2 Management Program
L
I N
D T
3 re-qualification
Periodic
A E
T N
I A
Periodic Validation Review
O N
N C
E

Pharm.(Mrs) Edosa Ogbeide 50

Validation Maintenance
• Change Management is • Changes should be
the primary mechanism formally documented
by which validation is and approved before
maintained implementation and
• Effective change control records maintained
system must be in place • Commitment of the
to control changes to company to control is
validated systems essential to ensure a
continued validation
status of the systems
concerned.
Validation Maintenance
Revalidation
➢change in operating
parameters
➢component
specifications have
changed
➢new accessories or
components are added
to previously qualified
equipment
➢process changes that
potentially impact
product effectiveness or
quality
Decommissioning
• Documented
demonstration that at the
time of removal from
routine operational use,
system was operating in
compliance with specific
requirements and fit for
purpose
• Should be planned
• Requirements depends
on system complexity
• Outcome should be
reported and provide
conclusion
Continuous Process Verification
• Introduced to cover an alternative approach to
process validation based on a continuous
monitoring of manufacturing performance
• Based on the knowledge from product and process
development studies and / or previous
manufacturing experience.
• Can be introduced at any time in the lifecycle of the
product. It can be used for the initial commercial
production, to re-validate commercialized products
as part of process changes or to support continual
improvement
Continuous Process Verification
• Involves extensive in-line, on-line or at-line
controls and monitoring process performance
and product quality on each batch.
• Relevant data on quality attributes of incoming
materials or components, in-process material
and finished products should be collected.
• Verification of attributes, parameters and end
points, and assessment of CQA and critical
process parameter (CPP) trends
Cleaning Validation
• Establishing documented evidence that the
equipment is consistently cleaned of product,
microbial and cleaning agent residues to
predetermined acceptable levels
• Provides a high degree of assurance that the
Cleaning procedure can effectively remove
residues of a product and a cleaning agent from
the manufacturing equipment, to a level that
does not raise patient safety concerns
Cleaning Validation
Basic Considerations
• Cleaning mechanisms: Mech. action, dissolution,
chem. reaction, detergency
• Cleaning Procedure: SOPs, tools & materials
• Cleaning method: CIP, COP, manual cleaning
• Determination of contamination limits: TD,
blanket spec.
• Worst case selection
• Clean Hold times
• Sampling: swab, rinse, location, surface area,
swab recovery, analytical method
Analytical Method Validation
ICH Q2 (R1)
• Specificity
• Linearity
• Accuracy
• Precision
• Robustness
• LOD
• LOQ
Water Systems Validation
Conducted in 3 phases:
• Phase 1: 2-4 weeks - intensive system
monitoring, develop operating ranges,
implement & refine SOPs
• Phase 2: 2-4 weeks – deploy refined SOPs,
demonstrate operation within established
ranges, demonstrate production of required
quality & quantity
• Phase 3: 1 year – verify long-term control,
demonstrate consistent production of
required quality & quantity
• Ongoing system monitoring
Computerized Systems Validation
Basic Considerations
• System specification – hardware, software,
user training
• Functional specification – testing, operating &
maintaining the system
• Security – controls against unauthorized data
manipulation, audit trail
• Back-ups – secure data storage
Conclusion
▪Validation is an essential component of GMP
▪ Helps to achieve goal of is assuring product
quality, safety and efficacy
▪ Offers huge business benefits
▪ Lifecycle approach covers entire systems
and processes and must be structured,
planned and documented
▪ Validation maintenance is essential element
of validation lifecycle
Benefits of
Validation and
Qualification

Eqmt
Facilities ****Note: Eqmt= equipment
Utilities
Processes
VALIDATION

Pharm.(Mrs) Edosa Ogbeide 62

References
• NAFDAC cGMP for Medicinal Products Regulations 2009
• WHO Supplementary Training Modules on GMP. WHO TRS No.
937, 2006. Annex 4
• ICH Tripartite Guidelines: Validation of Analytical Procedures:
Text and Methodology Q2(R1)
• WHO TRS 986 Annex 2; Good manufacturing practices for
pharmaceutical products: Main principles
• NAFDAC Good manufacturing Practice for Pharmaceutical
Products Guidelines 2016
• Chukwumerije O. (2016). Presentation on Pharmaceutical
Qualification & Validation
• Ogbeide E. (2013). Presentation on Equipment Qualification &
Process Validation