Current Good Manufacturing Practice ( cGMP )

for

Active Pharmaceutical Ingredients ( API )

Dr. Rajiv A. Desai

Dr. Reddy’s Laboratories
Hyderabad
Major International Codes of cGMP

• World Health Organisation ( WHO ) 1992

• European Union Guide to GMP - 1997

• United States - FDA CFRs

• ISO 9001 / EN 46001/0 / ISO 13485 Medical Devices

• ICH cGMP for API 2000 / 2001

• Canadian cGMP - 1999

References and Websites

• US FDA www.fda.gov

21 CFR
Part 210 cGMP in Manufacturing, Processing, Packing or Holding of Drugs
Part 211 cGMP for Finished Pharmaceuticals
Center for Drug Evaluation and Research, US FDA

• International Conference for Harmonisation ( ICH) www.ifpma.org

• Medicines Control Agency ( MCA) www.open.gov.uk/mca

• Therapeutic Goods Administration ( TGA) www.health.gov.au/tga

• PDA www.pda.org

• WHO
Facility and AHU Validation
Validation

Establishing documented evidence which provides a high degree of

assurance that a specific process will consistently produce a product
meeting its pre-determined specifications and quality attributes

FDA guideline : General Principles of Process Validation

Validation Policy

The overall process of creating a complete quality system

The term “Validation” can be used for a number of tasks

• Production processes
• Cleaning Procedures
• Analytical methods
• In-process control test procedures
• Computerised systems
• Personnel

All the above activities should be documented …

Validation Master Plan ( VMP )

A document that summarises the firm’s overall philosophy, intentions

and approach to be used for establishing performance adequacy

A document providing information on the company’s validation work

program. It should define details of timelines for the validation work
to be performed.

Responsibilities related to the plan should be stated.

• Responsibilities
• Standards
• Content / Guidance
• Schedule of work
alidation Master Plan ( VMP )
art A – Organisation and Scope

Introduction

Scope of the Validation Master Plan 7 Requalification of Critical GMP Systems

Regulatory Standards Industry guide 8 Validation Plans

Glossary of terms 9 Documentation Structure

1 General Definitions 1 Document flow

2 Validation Definitions 2 Validation Support Documents
3 Documentation Definitions 3 Qualification ( IQ and OQ ) commissioning protocol

Managerial Responsibilities
10 Structure of Support Data files
1 Quality Assurance Manager
2 Operations Manager 11 Documentation Control and Archiving
3 Validation Document Preparations and Authorisation
12 Change control
Validation Phases
Part B – General Validation Standards and
1 Design Qualification Guidelines – List of Guidelines
2 Installation Qualification
3 Operation Qualification
Part C – Schedule of Validation Actvities
4 Performance Qualification
Validation Standards and Guidelines ( Examples )

1 Design Qualifications – GMP Design Review and Qualification of Specifications

2 Installation Qualification of Clean Rooms
3 GMP of Clean Rooms
4 Critical Utilities – Heating, Ventilation and Air conditioning ( HVAC )
5 Critical Utilities – Electrical and Lighting in Manufacturing Areas
6 Qualification of Process and Purified Water Systems
7 Qualification of Water for Injection
8 Qualifications of Compressed Gases Systems ( Air, Nitrogen and CO 2 )
9 Requalification of Existing Manufacturing Equipment
10 Qualification of Sterilised Equipment and Processes
11 Process Validation – Parameters to be monitored for Critical process Steps
12 Guidelines for content of Process Validation Protocols
13 Guidelines for Equipment cleaning Program – CIP and Manual
14 Validation of Quality Control Testing procedures
15 Validation of Sterilisation filtration of Liquids
16 Validation of Steam Supply
17 Validation of Freeze Dryers
18 Validation of Aseptic Processess
Validation of a particular Equipment would include its -

• Qualification records
• Maintenance contracts
• Daily calibration
Qualifications

Use of any Equipment or System and is usually carried out by conducting the following :

Design Qualification ( DQ )
Documented evidence and verification that the proposed design of the equipment or system is suitable for the intended use

Installation Qualification ( IQ )
Documented evidence and verification that the equipment or systems, as installed or modified, comply with the approved
design and the manufacturer’s recommendations.

Operational Qualification ( OQ )
Documented evidence and verification that the equipment or systems, as installed or modified, perform as intended
throughout the anticipated operating ranges

Performance Qualification ( PQ )
Documented evidence and verification that the equipment and ancillary systems, as connected together, can perform
effectively and reproducibly based on the approved process method and Specifications

Retrospective Qualification ( RQ )
Applicable only for ancient equipment or systems which have not undergone the four steps above. It is documented
evidence and verification that the equipment or systems is suitable for the intended use, and perform as intended
Calibration

Demonstration, that a particular instrument or device produces results within specified limits
by comparison with those produced by a reference or traceable standard over a appropriate
range of measurement

Maintenance
The documented evidence that a particular Instrument is properly cleaned, repaired and
checked for any potential malfunction at regular intervals of time
Building and Facility

Design and Construction

Criteria –

• Location selection
• Design ( Flow of Man and material )
• Ease of cleaning, Maintenance,
• Ease of Operation
• Minimise potential Contaminations ( different stages , Microbial )
• Adequate space for Equipment and Material to prevent mixup
Design and Construction

Designated areas for –

• Material receipt, storage

• Quarantine
• Sampling / Dispensing
• Place for rejected materials
• Storage for Finished products
• Production operations
• Packaging and Labeling operations
• Laboratory
• Aseptic Processing
Design and Construction

• Aseptic Processing

• Floors, walls and ceilings of smooth , hard surfaces are easily cleanable

• Temperature and Humidity controls

• Air supply filtered through HEPA under +ve pressure ( laminar and Non-laminar)

• System for monitoring environmental conditions

• Procedure for cleaning and disinfecting facility to produce aseptic conditions

• System for maintaining equipment used to control aseptic conditions

Ventilation, Air filtration, Air heating and cooling

Adequate ventilation

Equipment for control over air pressure, micro-organism, dust, humidity and
temperature

Air filtration systems ( prefilters and Particulate matter filters )

• Recirculation of air to production areas

• Control on recirculation
• Exhaust systems and control on contaminations

AHU for manufacturing, processing and packing of Penicillin shall be separate

Plumbing

Potable Water supply under continuous positive pressure

Plumbing system should be free of defects to avoid contamination to drug product

Potable Water shall meet the standards

prescribed in Environmental protection Agency’s Primary drinking water regulations as per 40 CFR part 141

Drains should be of adequate size,

with air breaks or mechanical device to prevent back-siphoning
Sewage and refuge

 Sewage, trash and other refuge should be disposed of in a safe and sanitary manner

 Washing and toilet facility

• Hot and cold water

• Soap and detergent

• Air drier, single service towels

• Clean toilet facilities near work place

Sanitation

 Building used for the manufacture, processing, packing or holding of a drug shall be
maintained clean and in good sanitary condition

 Written down procedure for

 Assigning responsibility for sanitation

 Describing in detail the cleaning schedules
 Details about method, equipment and material for cleaning
 Use of rodenticides, insecticides, fungicides, fumigating agents
 Measures for avoiding contamination of equipment, products, containers,
Packing and labeling material
 Rodenticides, insecticides and fungicides shall not be used unless registered or
used in accordance with the federal Insecticides, Fungicides and Rodenticide Act
 Sanitary procedures shall be applicable to work done by contractors or temporary
employees as well as full-time employees
Equipment

 Design, Size and Location

To facilitate operations for the intended use and for its cleaning and maintenance

 Construction

Surface should be not reactive, add or absorb so as to alter the safety, identity,
strength, quality or purity of the drug product beyond official or established requirement

 Cleaning and Maintenance

Appropriate cleaning, maintaining and sanitisation at specified intervals to prevent

malfunction or contamination
Equipment

 Written procedure shall be established and followed for cleaning and maintenance

 Assigning responsibilities
 Schedule
 Details of the method, equipment and material used
 Instructions for disassembling and reassembling each article of equipment
to ensure proper cleaning
 Removal or defacing previous batch identification
 Protection of clean equipment from contamination prior to use
 Inspection of equipment for cleanliness immediately before use
 Records of the work done
Automatic, mechanical and electronic Equipment

• All equipment used shall be routinely calibrated, inspected or checked according to a

written program designed to assure proper performance

• Written records of calibration checks and inspections will be maintained

• Appropriate controls on computers or related systems avoid unauthorised changes

• Input to and output from computers or related systems of formulas or other records
should be checked for accuracy

• A suitable backup data management system should be in place

• Computer systems used in GMP environment should be validated. The level of

validation will depend on the criticality of the application

• Appropriate IQ / PQ should demonstrate the suitability of computer hardware and

software to perform assigned tasks.
Computerized Systems

Commercially available software does not necessarily require the same level
of validation as a customised software.
If an existing system was not validated at time of installation, a retrospective
validation could be conducted if appropriate documentation is available.
Computerized systems should have sufficient controls to prevent unauthorized
access or changes to data. There should be controls to prevent omissions in
data (e.g., system turned off and data not captured). There should be a record
of any data change made, the previous entry, who made the change, and
when the change was made. ( 21 CFR Part 11 )
 
Computerized Systems

Written procedures should be available for the operation and maintenance

Changes to computerized systems should be made according to a change procedure

and should be formally authorized, documented, and tested. Records should be kept of
all changes, including modifications and enhancements made to the hardware, software,
and any other critical component of the system.

These records should demonstrate that the system is maintained in a validated state.
If system breakdowns or failures would result in the permanent loss of records,
a back-up system should be provided. A means of ensuring data protection should be
established for all computerized systems.
Containment
Dedicated production areas for -
Highly sensitising materials.
Eg. Penicillins or Cephalosporins

Infectious nature or high pharmacological activity or toxicity

E.g. steroids or cytotoxic anti-cancer agents

Avoid sharing of Equipment and facility ( Production, Handling, Storage )

Measures to avoid cross contamination ( Restricted movement of Man and material)
Validated cleaning procedures are established and maintained.
PROCESS EQUIPMENT
 Equipment should only be used within its qualified operating range.
 Major equipment and permanently installed processing lines should be appropriately
identified.
 Any substances associated with the operation of equipment, such as lubricants, heating
fluids or coolants, should not contact intermediates or APIs
 Use of closed or contained equipment should be used. If open equipment is used or
equipment is opened, appropriate precautions should be taken to minimize the risk of
contamination.
 A set of current drawings should be maintained for equipment and critical installations
Equipment Maintenance and Cleaning

 Dedicated equipment should be cleaned at appropriate time intervals to prevent

built-up and carry-over of contaminants

 Non-dedicated equipment should be cleaned between production of different

materials to prevent cross-contamination.

 Acceptance criteria for residues and the choice of cleaning procedures and
cleaning agents should be defined and justified.

 Equipment should be identified as to its contents and its cleanliness status by

appropriate means.
Calibration

The current calibration status of critical equipment should be known and

verifiable. Instruments that do not meet calibration criteria should not be used.

Deviations from calibration on critical instruments should be investigated

to determine If these could have had an effect on the quality of the drug substance
manufactured using this equipment since the last successful calibration.
Air Handling Units
(AHU)
AHU :
Air handling Unit. This unit consists of a Blower, Cooling & Heating
coils and Filters for the supply of clean air.

HEPA :
High Efficiency Particulate Absolute Air Filter. This is a 0.3 µm filter
made from cellulose fiber and is the heart of a Clean room.
ACPH :
Air Changes Per Hour. It is the number of times, the air within
the Clean room is completely replaced.

Differential Air Pressure :

Every room should have a differential air pressure of at least
1.25 mm of WC between them so that the integrity of each room
is maintained and the doors are firmly shut due to this pressure
differential.
Characteristics of Air Handling systems

1. Turbulent or uni-directional air flow

2. Filter positions

3. Air re-circulation v/s Fresh air

4. Return air systems (positions)

5. Over pressure requirements

 Air Handling Systems
Air flow patterns (1)
Turbulent Uni-directional / laminar
dilution of dirty air displacement of dirty air

0,30 m/s

Annex 1, 17.3
Module 3, Part 3: Design, qualification and maintenance Slide 3 of 27 WHO - EDM
 Air flow patterns (2)

Filtered air entering a production room or covering a process can be

Turbulent
Uni-directional ( Laminar )
GMP aspect
Economical aspect

New Technologies : Barrier technology / Isolator technology

 Air Handling Systems
Air flow patterns (3) Prefilter
Annex 1, 17.3
AHU

Main filter

1 2 3

Turbulent Uni-directional Turbulent

Module 3, Part 3: Design, qualification and maintenance Slide 5 of 27 WHO - EDM

 Air Handling Systems

Air flow patterns (4)

Workbench (vertical) Cabin/ booth Ceiling

Module 3, Part 3: Design, qualification and maintenance Slide 6 of 27 WHO - EDM

 Air Handling Systems
Positioning of filters (1)

AHU mounted final filter Filter in terminal position

HEPA Filter

Production Room Production Room

HEPA Filter

Module 3, Part 3: Design, qualification and maintenance Slide 7 of 27 WHO - EDM

 Air Handling Systems
Positioning of filters (2)
Prefilter

AHU

Main filter
Ceiling
exhausts

1 2 3

Low level exhausts

Module 3, Part 3: Design, qualification and maintenance Slide 8 of 27 WHO - EDM
 Air Handling Systems
Positioning of filters (3) Final filter

AHU
Prefilter

1 2

Module 3, Part 3: Design, qualification and maintenance Slide 9 of 27 WHO - EDM

Air re-circulation

The filtered air entering a production room can be

• 100 % exhausted

Or

• a proportion re-circulated

GMP aspect
Economical reasons
 Air Handling Systems
Ventilation with 100% fresh air (no air re-circulation)
Washer (optional)
Exhaust Unit

Central Air Handling Unit

Production Rooms
Annex 1, 17.24

Module 3, Part 3: Design, qualification and maintenance Slide 11 of 27 WHO - EDM

 Air Handling Systems
Ventilation with re-circulated air + make-up air
Exhaust Unit

Central Air Handling Unit

Return air

Module 3, Part 3: Design, qualification and maintenance Slide 12 of 27 WHO - EDM

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Qualification / Validation issues

A good design is essential, but it has to be complemented by –

 Qualification of Air handling systems

 Process validation

 Maintenance and periodic re-qualification

 Adequate documentation
 Qualification ( OQ, PQ ) ( 1 )

Uni-directional Turbulent /
Test airflow/ LAF Mixed airflow
Description

Differential pressure on filters 2 2

Room differential pressure N/A 2, 3

1 As built ( Used to perform IQ )

Air flow velocity / Uniformity 2, 3 Optional 2 At rest ( Used to perform OQ )

Airflow volume / rate 2 2 3 Operational (Used to perform PQ )

Parallelism 2 N/A
Air flow pattern 2 3

IQ tests not mentioned here

 Qualification ( OQ, PQ ) ( 2 )

Uni-directional Turbulent /
Test airflow/ LAF Mixed airflow
Description

Recovery time N/A 2

1 As built ( Used to perform IQ )
Room classification
2 2, 3 2 At rest ( Used to perform OQ )
( Airborne particle)
3 Operational (Used to perform PQ )
Temperature, Humidity N/A 2, 3

IQ tests not mentioned here

Clean room monitoring program ( 1 )

Clean rooms should be monitored for micro-organisms and particles

air

Sampling point
 Microbiological validation

 Definition of alert / action limits as a function of cleanliness zone

 Identification and marking of sampling points
 Definition of transport, storage and incubation conditions

Action Limit Alert Limit Alert Limit Action Limit

Design condition

Normal Operating range

Operating range – Validated acceptance criteria

Ask the question :

What are the alert and action Limits and what procedures are followed if these points are exceeded ?
Clean room monitoring program (2)

Routine monitoring program as part of quality assurance

Additional monitoring and triggers

 Shutdown

 Replacement of filter elements

 Maintenance of air handling systems

 Exceeded established limits

How is clean room cleanliness measured?
Clean room cleanliness is measured by how many micron sized particles pass
through one Cubic foot of air per minute (CFM).

What do the classifications mean?

A Class 10 clean room has no more than ten micron sized particles passing
through each cubic foot of air per minute. That's really clean. A Class 100,000
may have up to one hundred thousand particles per cubic foot. For
comparison, your home has around 300,000 and a hospital operating room
has about 1,000.

How big is a micron?

A micron is equal to one-thousandth of a millimeter. Compared to a
human hair which is about 100 microns. The smallest particle the human eye
can see is 50 microns.
 Air Changes
Decided based on the level of dust within the room, number of
people working in the room, heat generated from motors and other
drives and also the Clean room Class.

What is Federal Standard 209E/ ISO 14644?

Its an official document that outlines the classes of air cleanliness.

Federal Standard 209 E Class ISO 14644 – 1 Class Air Changes Per Hour

Class 100000 ISO Class 8 20 – 30

Class 10000 ISO Class 7 30 - 70

Class 1000 ISO Class 6 70 - 160

Class 100 ISO Class 5 400 - 540

Class 10 ISO Class 4 400 - 540

Class 1 ISO Class 3 540 - 600

Total room Air flow = Air velocity X Effective Grill Size

Air changes = Total room Airflow X 60

Volume of the room

Eg:

Air flow = 1784 CFM

Volume of the room = 3364

No of Air changes = [1784 X 60]/3364 = 32 ACPH.

CFM = Cubic Feet per minute

ACPH = Air changes per hour.
 What does HEPA stand for?

High Efficiency Particulate Air. These replaceable filters will capture

almost 100% of particles as small as 0.3 microns. You might find them
in your own home or office as part of an air conditioner filtering system
or a vacuum filter.

How long will the HEPA filter last?

A HEPA filter can last three to five years or more in a standard

clean room environment. Life of the HEPA also depends on ambient
conditions and maintenance of the pre-filters.
 CLASS LIMITS (particles/m3)
ISO Maximum concentration limits (particles/m3 of air) for particles equal to and larger
classification than the considered sizes shown below
number (N)
0.1 um 0.2 um 0.3 um 0.5 um 1 um 5 um

ISO Class 1 10 2

ISO Class 2 100 24 10 4

ISO Class 3 1000 237 102 35 8

ISO Class 4 10000 2370 1020 352 83

ISO Class 5 100000 23700 10200 3520 832 29

ISO Class 6 1000000 237000 102000 35200 8320 293

ISO Class 7 352000 83200 2930

ISO Class 8 3520000 832000 29300

ISO Class 9 35200000 8320000 293000

Note: Uncertainties related to the measurement process require that concentration data with no more than three significant figures be used in determining the
classification level.
 Cleanroom maintenance program (1)

Schedule of Tests to Demonstrate Continuing Compliance

Maximum
Test Parameter Class Test Procedure
Time interval

ISO 5 6 months ISO 14644 – 1 Annex A

Particle Count Test
ISO 14644 – 1 Annex A
ISO 5 12 months

ISO 14644 – 1 Annex B 5

Air Pressure Difference All Classes 12 months

Air Flow All Classes 12 months ISO 14644 – 1 Annex B 4

 Cleanroom maintenance program (2)

Schedule of Additional Optional Tests

Maximum
Test Parameter Class Test Procedure
Time interval

Installed Filter Leakage All Classes 24 months ISO 14644 – 1 Annex B 6

ISO 14644 – 1 Annex B 4

Containment Leakage All Classes 24 months

ISO 14644 – 1 Annex B 13

Recovery All Classes 24 months

Air Flow Visualisation All Classes 24 months ISO 14644 – 1 Annex B 7

Air Pressure gradients

Maintain a positive air pressure between connecting rooms to the tune of

1.25 mm WC (+).

The dust generating areas shall be maintained at a negative pressure. Clean

corridors shall be maintained at positive pressure. The air lock shall be maintained
at a positive pressure. Change rooms at a positive pressure with respect to
washroom.

The air pressure gradients are maintained as follows:

Corridors > Air lock > Change room > Wash room
(++++) (+++) (++) (+)
Process areas Ante room
(++) (+)

Comfortable work environment of 25 + 2°C and 50 + 5% RH.

Documentation Requirements

 Description of Installation and functions

 Specification of the requirements

 Operating procedures

 Instructions for Performance control

 Maintenance instructions and records

 Maintenance records

 Training of personnel ( Program and records )

Inspecting the Air Handling Plant

• Verification of design documentation, including

Description of installation and function
Specification of the requirements
• Operating procedures
• Maintenance instructions
• Maintenance records
• Training Logs
• Environmental records
• Discussion on actions if OOS values
• Walking around the plant
Conclusion

Air Handling systems –

 Play a major role in the quality of Pharmaceuticals

 Must be designed properly by professionals

 Must be treated as a critical systems

 Air Handling Systems
S a m p lin g
Rooom S e rv ic e C o rrid o r

A ir S h o w e r
Group
Typical Session
Clean room layout
( c o n t a in s V a c u u m & R O w a t e r s u p p ly )

W a re h o u se
W e ig h in g T a b le t 1 T a b le t 2 L iq u id s M ix S o ftg e l C a p su le
A ir L o c k 2

P a c kin g
A / Lock 1

C le a n C o rri d o r
E m erge nc y
E x it

M a le F e m a le
2 S ta g e Change 2 Change 2
S te rile e y e d ro p s p e rso n n e l P rim a ry & S e c o n d a ry
d isp e n sin g e n try fo r P a c ke d
P a c kin g
& a c e p tic fillin g e y e d ro p s G oods
A ir L o c k 3
Q u a ra n tin e

M a le F e m a le
Change 1 Change 1
E q u ip m e n t W a sh A ir L o c k 4
S e rv ic e R o o m

Module 3, Part 3: Design, qualification and maintenance Slide 26 of 27 WHO - EDM

 20P a S a m p lin g
Air Handling Systems
Rooom 0P a S e rv ic e C o rrid o r

Modified
Group Clean
Session room layout
– modified layout
30P a ( c o n t a in s V a c u u m & R O w a t e r s u p p ly )
A ir S h o w e r
20P a 30P a
10P a
W e ig h P o st
B o o th S ta g in g S o ftg e l C a p su le
W a re h o u se
M AL 2 20P a 30P a T a b le t 1 T a b le t 2 L iq u id s M ix P a c kin g
15P a 15P a 30P a
0P a
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M A L1

15P a

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C le a n C o rri d o r
E m erge nc y
E x it

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P AL
40P a M a le F e m a le 10P a
M A L 3 Change 2 Change 2 S e c o n d a ry P rim a ry
S te rile e y e d ro p s P a c kin g P a c kin g
40P a d isp e n sin g P a c ke d
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Q u a ra n tin e 20P a 30P a
10P a 10P a
60P a
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E q u ip m e n t W a sh 50P a A ir L o c k 4
S e rv ic e R o o m 0P a
0P a

0P a

Module 3, Part 3: Design, qualification and maintenance Slide 27 of 27 WHO - EDM

Thank you