Facility and Equipment:

Design Review and Determination

Criteria
Presented By:
Supakit Saiprasert
Global tech co., ltd.
E-mail: supakit@globaltech.co.th
Thailand-PIC/S Accession Whats the Learning Curve? 20/09/2016

Intent
To assure the drug meets the requirements as purported
Drug is Safe
Has the Identity and Strength
Meets quality and purity characteristics
Regulations cover manufacturing, processing, packaging and holding of the drug

and define:
Methods
Facility
Controls
Failure to comply with regulations will render the drug to be adulterated

Organization and Personnel

Quality Control Unit

Responsibly and authority to:

Approve or reject all components, drug product containers, in process materials, packaging

materials, labeling and drug products

Review production records to assure no errors have occurred

Investigate any errors which may have occurred
Approve or reject drug products manufactured, processed, packaged or held under contract by

another company

Provide adequate testing facilities for the testing and approval or rejection of components, packaging
materials, in process materials and drug product

Responsibility for approving or rejecting all procedures and specifications impacting on

the identity, strength, quality and purity of the drug product
All quality control procedures must be in writing and followed

Organization and Personnel

Personnel Qualifications

Each person must have education, training and experience or combination thereof to

enable that person to perform the assigned function

Training shall be in the in the particular functions the person is to perform

Training is to be conducted by qualified individuals on a continual basis and with

sufficient frequency to assure the employees remain familiar with GMPs

Supervisors of manufacturing processing, packaging or holding functions must have
the combination of education, training and experience to assure that the drug
product has the safety, identity, strength, purity and quality as purported
Adequate number of qualified personnel to perform and supervise the function

Organization and Personnel

Personnel Responsibilities

Personnel engaged in the manufacturing, processing, packaging, or holding of drug

products must

Wear clean clothing appropriate for their duties

Wear protective apparel such as head, face, hand, and arm coverings as necessary to protect

the drug product from contamination

Practice good sanitation and health habits

Buildings and facilities designated as limited access areas can only be accessed by
personnel authorized by supervision
Any employee shown to have an illness or open lesion which may adversely effect the
safety and quality of the drug product shall be excluded from any drug contact
Employees must report any health conditions that may effect the drug product

Building
and
Facilities
Design and Construction Features

Must be of suitable size, construction, and location to facilitate cleaning, maintenance

and operation
Suitably sized for the orderly placement of materials and equipment to prevent mix up of
components
Flow of drug products, components, etc through the building shall be designed to
prevent contamination
Operations performed in separate and defined areas or controls in place to prevent mix
ups or contamination during:

Holding rejected material

Storage of released components
Storage of in-process materials
Manufacturing and processing areas
Packaging and labeling operation
Quarantine storage prior to release

Building and Facilities

Design and Construction Features (Contd)

Operations performed in separate and defined areas or controls in place to
prevent mix ups or contamination during:

Storage of released drug products

Control and laboratory operations
Aseptic processing which includes:
Hard cleanable surfaces
Temperature and humidity controls
Air supply with HEPA filtration under positive pressure
Environmental monitoring systems
System for cleaning room and equipment

Penicillin production in a separate facility

Building and Facilities

Lighting: Adequate lighting must be provided

HVAC
Adequate ventilation must be provided
Control over air pressurize, micro organisms, dust, humidity and temperature
Air filtration systems for production areas

Pre filters and particulate matter filters

Control of contaminates when air is recirculated
Exhaust systems or other systems to control contaminates

Plumbing:
Potable water under continuous positive pressure
Drains must be of adequate size and provided with an air break or
mechanical device to prevent back siphoning

Building and Facilities

Sewage, trash and refuse must be disposed of in a safe and sanitary manner
Washing and Toilet Facilities must be provided
Clean toilet facilities
Hot and cold water
Soap or detergent
Air dryers or single service towels
Easily accessible from work areas
Maintenance
Must be maintained in a good state of repair

Building and Facilities

Sanitation

Maintained in an clean and sanitary condition

Trash and organic matter should be held and disposed of in a timely and
sanitary manner
Facility should be free from infestation of rodents, birds, insects or other
vermin
Written procedures and assigning responsibilities for sanitation
Description of cleaning schedules, methods, equipment and materials
Procedures for using rodenticides, insecticides, fungicides, cleaning and
sanitizing agents to prevent contamination of equipment, components, drug
product containers, etc.

Equipment
Description
Equipment used in the manufacturing, processing, packaging, holding of a
drug product shall be of appropriate design, size, and suitably located to
facilitate operations for its intended use and for cleaning and maintenance
Equipment Construction
Surfaces that contact components, in process materials or drug products
shall not be reactive, additive or absorptive to alter the safety, identity,
strength, quality or purity
Substances required for operation shall not come in contact with the contact
components, in process materials or drug products (Lubricants, coolants,
etc.)

Equipment

Cleaning and Maintenance

Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate

intervals to prevent contamination

Written cleaning procedures are required

Assignment of responsibility
Maintenance and cleaning schedules
Description of cleaning including methods, equipment and materials and methods

or disassembling and reassembling equipment

Removal or obliteration of previous batch identification

Protection of clean equipment prior to use
Inspection of equipment for cleanliness immediately before use
Maintenance of cleaning records

Equipment

Calibration

Automatic, mechanical or electrical equipment must be calibrated, inspected

or checked according to a written program.

Documentation

Records must be maintained

Filtration

Filters used for liquid product filtration must not release fibers (Sterile Mfg)

Control of Components, Drug Product Containers and Closures

Procedures

Written procedures for receipt, identification, storage, handling, sampling, testing,

approval and rejection are required

Materials must be handled and stored in a manner to prevent Stored off the floor

and suitable spaced for cleaning and inspection

Each container must be identified with a distinctive code for each lot in each

shipment received
Material Receipt

Examined for labeling as to contents, container damage, broken seals and

contamination

Held in quarantine until tested or examined as appropriate and released

Control of Components, Drug Product Containers and Closures

Testing and Approval or Rejection

Material must be withheld from use until tested and released

Samples must be taken from each lot for testing
Sampling Procedures

Selected containers must be cleaned

Opened, sampled, and sealed in a manner to prevent contamination
Identify sample containers with material sampled, lot number, date and name of

person taking sample

Mark containers that samples were taken from

Sample Testing

Tested for conformity to written specifications

Alternative is certificate of analysis by supplier if identity test is done and validation

of suppliers test results

Control of Components, Drug Product Containers and Closures

Testing and Approval or Rejection

Sample Testing (Contd)

Containers and closures are tested for conformance to written procedures

Certificate of testing from the supplier is acceptable if supplier testing is validated

and a visual inspection is performed

Any material liable to microbiological contamination shall be microbiologically tested

Any material that does not meet specifications must be rejected

Inventory

Inventory must be rotated so the oldest stock is used first (FIFO)

Material must be retested after a long period of time before use
Rejected material must be controlled under a quarantine system to prevent use

Production and Process Controls

Documentation

Written procedures for production and designed to assure the drug

product has the identity, strength, quality and purity they purport or
are represented in the process

Procedures shall be drafted, reviewed and approved by the QC unit

Procedures shall be followed and documented at the time of

performance. Deviations from procedure must be recorded and

justified

Production and Process Controls

Charge In of Components

Batch formulated to provide not less than 100% of the labeled or

established amount of active ingredient

Components are weighed, measured or subdivided as appropriate. If a

secondary container is used, the container must be identified with

the following:

Component name or item code

Receiving or control number
Weight or measure
Batch identification: Product name, strength, lot number

Production and Process Controls

Charge In of Components (Contd)

Weighing must be adequately supervised. Each component must be examined by
a second person to assure that:

Material was released

Weight or measure is correct
Container is properly identified

Each component shall be added to the batch by one person and verified by a
second person
Yields
Actual yields and percentages of theoretical yields shall be determined at the end
of each appropriate phase of manufacture. Calculations are performed by one
person and verified by a second

Production and Process Controls

Equipment Identification

All process equipment, storage containers, processing lines used during production shall be
properly identified at all times to indicate their contents and phase of manufacture
Major equipment shall be identified by a distinctive number or code that shall be recorded in
the batch record to show the specific equipment used in the manufacture

Sampling and Testing of In Process Materials and Drug

Products: Minimum Requirements

Written procedures for in process controls, tests and examination on appropriate samples and
conformance to specifications

Tablet and capsule weight variation

Disintegration time
Content uniformity and homogeneity
Dissolution time and rates
Clarity or pH of solutions

Production and Process Controls

Control of Microbiological Contamination

Written procedures to prevent objectionable microorganisms in drug products not

required to be sterile

Written procedures to prevent microbiological contamination of sterile drug products.

Procedures shall include validation of the sterilization process

Reprocessing of Materials

Written procedures for reprocessing batches that do not conform to standards and

specifications and the steps to insure reprocessed material will comply

Reprocessing must not be performed without the review and approval of the QC unit

Packing and Labeling Controls

Written procedure for receipt, identification, storage, handling, sampling, examination

and testing
Labeling and packaging materials must be examined or tested upon receipt and before
use
Must meet specifications for approval and release. Use of rejected material must be
prevented
Records must be maintained for each shipment received indicating receipt, examination
and testing, and whether accepted or rejected
Labels and labeling materials for each product, strength, dose form and quantity must
be stored separately. Access to the storage area limited to authorized personnel

Obsolete and outdated labels and other packaging materials must be destroyed

Packing and Labeling Controls

Cut Labels: Additional Controls

Dedication of different packaging lines to each different strength of each different

product

Use of electronic or electromechanical to conduct a 100% inspection of labels

100% visual inspection performed by one person and verified by a second person

Printing devices on lines used to imprint labels shall be monitored to assure that

imprinting conforms to the print specified

Label Issuance:

Written control procedures are required for label issuance

Labels must be inspected for identity and conformity to the label specified in the batch

production records

Packing and Labeling Controls

Label Issuance (Contd)
Reconciliation of labels issued, used and returned is required

Evaluation of discrepancies between quantity issued and drug product finished when

discrepancies outside narrow preset limits

Reconciliation is waived if 100% inspection of labels on the packaging or labeling line

Excess labels bearing lot and control numbers must be destroyed

Returned labels must be stored in a manner to prevent mix ups

Packing and Labeling Controls

Packaging and Labeling Operations

Written procedures for use of correct labels on drug products are required

Prevention of mix ups by physical or spatial separation of labeling operations from one

another

Identification and handling of unlabeled filled containers to prevent mislabeling

Identification of a drug product with a lot or control number that permits determination of

the history of manufacture and control of the batch

Examination of packaging and labeling materials before packaging and documentation

of the examination on the batch record

Inspection of the packaging line before start up to insure all drug product, labels and

packaging materials have been remover prior to the next batch. Inspection
documented on batch record

Packing and Labeling Controls

Tamper Evidence:

OTC Products Only

Exceptions are dermatological. Dentifrice, Insulin or lozenges
Requirements
Indications or barriers to entry that when breeched provides visible evidence
that tampering has occurred
Two piece capsules must be sealed
Labels must identify tamper evidence features
Tamper evidence methodology used must be approved by the FDA

Packing and Labeling Controls

Drug Product Inspections

Packaged and labeled products shall be inspected during the finishing

operations too insure the correct labels are being used

Representative samples shall be collected at the completion of finishing

operations and be examined for correct labeling

Results of the examinations shall be recorded in the batch records

Expiration Dating

Labels must bear expiration dating as determined by stability studies and

related to storage conditions stated on the label

If drug is reconstituted, the label must contain expiry dating for both the

reconstituted and unreconstituted drug product

Packing and Labeling Controls

Expiration Dating (Contd)

Exceptions

Homeopathic drugs
Allergenic extracts that have no potency standards
Investigational drug products except for reconstituted drug products

Holding and Distribution

Warehousing

Written procedures required for:

Quarantine of drug products prior to release by the QC unit
Storage of drug products under appropriate conditions of temperature,

humidity and light so that the product is not effected

Distribution

Written procedures for distribution of the drug product

FIFO system of distribution
System to identify distribution of reach lot to facilitate a drug product recall if

necessary

System Validation
Direct Impact System

Indirect Impact System

No Impact System

Direct Impact System

A system that is expected to have a direct impact on product
quality. These systems are designed and commissioned in line with
Good Engineering Practice and in addition, are subject to Qualification
Practices that incorporate the enhanced review, control and testing
against specifications or other requirements necessary for cGMP
compliance.

Indirect Impact System

This is a system that is not expected to have a direct impact
on product quality, but typically will support a Direct Impact system.
These systems are designed and commissioned following Good
Engineering Practice only.

No Impact System
This is a system that will not have any impact, either
directly or indirectly, on product quality. These systems are
designed and commissioned following Good Engineering Practice
only

Good Engineering Practice (GEP)

Established engineering methods and standards that are
applied throughout the project life-cycle to deliver appropriate,
cost-effective solutions.

Good Engineering Practice

&
Good Manufacturing Practice
Not all GEP will be GMP
Not all GMP will be GEP

COMMISSIONING
QUALIFICATION
VALIDATION

Commissioning
Commissioning is a well planned, documented and managed
engineering approach to the start-up and turnover of facilities,

systems, and equipment to the End-User that results in a safe and

functional environment that meets established design requirements
and stakeholder expectations

Qualification
Qualification is the planning, carrying out and recording of
tests on equipment and a system, which forms part of the validated
process, to demonstrate that it will perform as intended.

Validation
Establishing documented evidence that a system does what it

purports to do
The documented act of proving that any procedure, process,

equipment, material, activity or system actually leads to expected

results.

V-Model for Direct Impact systems

User Requirement

PQ Test Plan

(i.e. What)

Performance
Qualification

Function Design
(i.e. How as Schematic)

Design
Development
Detail Design
(i.e. How to make)

OQ Test Plan
Inc. FAT

IQ Test Plan
Inc. PDI

Impact Assessment
Implementation
(Buy and Build)

Operational
Qualification

Installation
Qualification

User Requirement Specification (URS)

A description of the requirements of the facility in
terms of product to be manufactured, required throughput and
conditions in which the product should be made.

Conceptual Design
Design stage, to generate various alternatives for
evaluation. The project team then selects the concepts to be
taken forward into the functional design stage.

Functional design
The functional design stage generates the key design
documents to be used as a framework for detailed design process.

Detailed design
Design stage when the documents required for
construction bidding and contracting, as well as system and
equipment purchase, fabrication, installation and testing are
produced.

DQ, IQ, OQ, PQ

Design Qualification (DQ) is the document verification that the proposed design of

the facilities, systems and equipment is suitable for the intended purpose
Installation Qualification (IQ) is the documented verification that all aspects of a
facility, utility or equipment that can affect product quality adheres to approved
specifications (e.g., construction, materials) and are correctly installed
Operational Qualification (OQ) is the documented verification that all aspects of a
facility, utility or equipment that can affect product quality operates as intended
throughout all anticipated ranges
Performance Qualification (PQ) is the documented verification that all aspects of
a facility, utility, or equipment that can affect product quality perform as intended
meeting pre-determine acceptance criteria

Process Validation
Process validation is establishing documented evidence
which provides a high degree of assurance that a specific process
will consistently produce a product meeting pre-determined
specifications and quality characteristics.

When is Process Validation Carried Out

Start Process Validation only after the plant, facilities,
equipment, support systems, people and the specific
manufacturing process have been properly qualified that we are
ready to proceed.

The Ten Commandment of cGMP

1. Thou shall write procedures!
2. Thou shall follow thy written procedures!
3. Thou shall document (record) thy efforts!
4. Thou shall validate thy efforts!

5. Thou shall design and build proper facilities!

The Ten Commandment of cGMP

6. Thou shall maintain thy facilities!
7. Thou shall be competent as a result of education, training, and
experience!
8. Thou shall be clean in thy own person and in thy surroundings!
9. Thou shall define and control quality in all thy efforts!
10. Thou shall audit thy efforts for compliance!