Production and Process

validation

17 January 2006

by...Wiriya charoenkunathum
References:

• GMP for pharmaceutical products: main principles;

WHO TRS No. 908,2003
• GMP for biological products; WHO TRS
No.822,1992
• A WHO guide to GMP requirements, part
2:validation; WHO,1997

2
 GMP

• The good practices outlined are to be

considered general guides and they may
be adapted to meet individual needs.

3
 GMP
are aimed primarily at diminishing the
risks inherent in any pharmaceutical
production
• Cross –contamination; unexpected
contaminants
• Mix-ups; confusion (false labels)

4
 Good practices in production
• Principle: production operations must
follow clearly defined procedures in
accordance with manufacturing and
marketing authorizations, with the
objective of obtaining products of the
requisite quality.

5
 Production of Vaccine GMP

Master seed Working seed

Inoculum
Media/Cell culture
Single harvest
Excipients
Validation Pool/Concentrated material
- process
- method Purified/Bulk material
Stability studies

Final lot Final bulk 6

 Good practices in
production:General
• All handling of materials and products;
– receipt
– cleaning
– quarantine
– sampling
– storage
– labelling
– dispensing
– processing
– packaging
– distribution
• should be done in accordance with written procedures and
recorded.

7
 Good practices in
production:General
• Any deviation from instructions or
procedures should be avoid as far as
possible.
– If deviations occur: should be done in
accordance with an approved procedure
– approved in writing by a designated
person

8
 Good practices in
production:General
• Checks on yields and reconciliation of
quantities to ensure that there are no
discrepancies outside acceptable limits.

9
 Good practices in
production:General
• Operation on different products should
not be carried out simultaneously or
consecutively in the same room or area
unless there is no risk of mix-up or
cross-contamination.

10
 Good practices in
production:General
• At all time during processing
– all materials
– bulk containers
– major items of equipment
– rooms
– packaging lines
• being used should be labeled or identified

11
 Good practices in
production:General
• Access to production premises should be
restricted to authorized personnel.
• Non-medicinal products should not be
produced in areas or with equipment
destined for the production of
pharmaceutical products.

12
 Good practices in
production:General
• In-process controls are usually
performed within the production area.
– The performance should not have any
negative effect on the quality of the product
or another product.

13
Good practices in production: Prevention of cross-
contamination during production

 When dry materials and products are used in

production, special precaution should be taken to
prevent the generation and dissemination of dust.
– proper air control e.g. supply and extraction of air of
suitable quality

14
Good practices in production: Prevention of
cross-contamination during production

 Contamination of a starting material or of a product by

another material or product must be avoid.
– accidental cross-contamination arises from
 uncontrolled release of dust, gases, particles, vapours. sprays or
organisms from materials and products in process
 residues on equipment
 intruding insects
 operators’ clothing, skin, etc.
– most hazardous, highly sensitizing materials
 living organisms, hormones, cytotoxic substances, and others

15
Good practices in production: Prevention of
cross-contamination during production

 Avoided by taking appropriate technical e.g.

– carrying out production in dedicated and self-contained
areas
– conducting campaign production followed by
appropriate cleaning in accordance with a validated
cleaning procedure
– providing appropriately designed airlocks, pressure
differentials and air supply and extraction systems

16
Good practices in production: Prevention of
cross-contamination during production

 minimizing the risk of contamination caused by

recirculation or re-entry of untreated or insufficiently
treated air
 wearing protective clothing
 using cleaning and decontamination procedures of known
effectiveness
 using a closed system in production
 testing for residues
 using cleanliness status labels on equipment

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Good practices in production: Prevention of
cross-contamination during production

 Measures to prevent cross-contamination and

their effectiveness should be checked
periodically according to SOP

 Production areas periodic

environmental monitoring

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Good practices in production:
Processing operations

 Before any processing operation

 work area and equipment
• clean and free from any starting materials,
products, product residues, labels or
documents not required for the current
operation

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 Good practices in production:
Processing operations
 Any necessary in-process controls and environmental
controls should be carried out and recorded
 Indicate the failures of equipment or services (e.g. water,
gas) to equipment
 defective EQ withdrawn
 after use, production EQ
• cleaned without delay,
• stored under clean and dry conditions in separate area

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Good practices in production:
Processing operations
 Time limits for storage of EQ after
cleaning and before use
 Containers for filling should be cleaned
before filling
 Any significant deviation from the
expected yield
 recorded and investigated

21
Good practices in production:
Processing operations
 Checks
 pipelines and other pieces of EQ used for
transportation of products
 Pipe used for conveying distilled or
deionized water
 sanitized and stored according to written
procedures (action limits for
microbiological contamination and
measures

22
Good practices in production:
Processing operations
 EQ and instruments
 serviced and calibrated at prespecified interval
 records maintained
 checked daily or prior to use
 clearly indicated the date of calibration and
servicing, recalibration (label attached to
instrument)
 Repair and maintenance operations
 not present any hazard to the quality of the
products

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 GMP for biological products
:Production
• SOP for manufacturing operations:
available, up date
• Starting material: source, origin,
method of manufacture, QC
• Media and culture shall be added to
fermenter and other vessels under
carefully controlled conditions, avoid
contamination
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 GMP for biological products
:Production
• Media should be sterilized in situ. In line
sterilizing filters for routine addition of gases,
media, acids, alkalis, deforming agents, etc.
to fermenter should be used where possible.
• Validation of sterilization.
• Inactivation process: measures should be
taken to avoid risk of cross-contamination
between treated and untreated products.

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 GMP for biological products
:Production
• A wide equipment used for
chromatography
– should be dedicated to purification of one
product
– should be sterilized or sanitized between
batches
– define the life span of columns and the
sterilization method

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• In-process controls play a specially
important role in ensuring the consistent
quality of biological products because
certain deficiencies may not be revealed
by testing the finished product.
– Tests that are crucial for quality control but
that cannot be carried out on the finished
product shall be performed at an
appropriate stage of production.

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• Samples of intermediate and final products
shall be retained in sufficient amount and
under appropriate storage conditions to allow
the repetition or confirmation of a batch
control.
• Certain operations require the continuous
monitoring of data during a production
process e.g.monitoring and recording of
physical parameters during fermentation.

28
Validation: Definition
 Validation is the documented act of proving
that any procedure, process, equipment,
material,activity or system actually leads to
the expected result.

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Validation studies
 analytical test
 equipment
 facility systems (air, water, steam, process;
manufacturing processes, cleaning,
sterilization, sterile filling, lyophilization)

Separate validation for

lyophilizer/ lyophilization process cleaning of
glassware/ cleaning of facility sterilization
process/ sterility test 30
Validation studies
 verify the system under test under the
extremes expected during the process to
prove that the system remains in control.
 Critical equipment and processes are
routinely revalidated at appropriate intervals
to demonstrate that the process remains in
control.

31
Type of validation
 Prospective
• pre-planned protocol
 Concurrent
• base on data collected during actual performance of a process
already implemented in a manufacturing facility
• suit manufacturers of long standing, have well-controlled
manufacturing process
 Retrospective
• for production for a long time, but has not been validated
according to a prospective protocol and concurrent validation is
not realistic option
• is not generally accepted

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 Type of validation
 Laboratory-and pilot-scale validations
• some production processes cannot be carried out
in production facility

removal of impurities by individual purification steps in process

- not acceptable to bring unacceptable impurities (endotoxin,
unwanted protein, contaminating bacteria and virus) spike into
process

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 Facility systems and equipment:
Stage of validation
 Design qualification (DQ)
 Installation Qualification (IQ)
 Operational Qualification (OQ)
 Performance Qualification (PQ)

Systems and EQ; PQ=validation

Depending on the function and operation of some EQ

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Facility systems and equipment
 Design qualification (DQ)
• necessary when planning and choosing EQ or
systems to ensure that components selected will
have adequate capacity to function for the
intended purpose, and will adequately serve the
operations or functions of another piece of EQ or
operation.

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Facility systems and equipment
 Installation Qualification (IQ)
• written for critical processing EQ and systems
• list all the identification information, location, utility
requirements, and any safety features of EQ
• verify that the item matches the purchase
specifications

36
Facility systems and equipment
 Operational Qualification (OQ)
• outlines the information required to provide evidence that all
component of a system or of a piece of EQ operate as
specified.
• should provide a listing of SOPs for operation, maintenance
and calibration
• define the specification and acceptance criteria
• include information on EQ or system calibration, pre-
operational activities, routine operations and their
acceptance criteria

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Facility systems and equipment
 Performance Qualification (PQ)
• performed after both IQ and OQ have been completed,
reviewed and approved
• describes the procedures for demonstrating that a system
or piece of EQ can consistently perform and meet required
specification under routine operation and, where
appropriate, under worst case situations
• include description of preliminary procedures required,
detailed performance tests to be done, acceptance criteria
• other supporting EQ used during qualification have been
validated.

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Facility systems and equipment
pH meter, incubator, centrifuge, freezer; IQ,OQ

system: air (HVAC), compressed air, pure steam,

raw steam, purified water, WFI, central vacuum; IQ,
OQ, PQ

EQ: autoclave, oven, lyophilizer, continuous flow

centrifuge; IQ, OQ, PQ

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Process validation
 A process is a series of interrelated functions and
activities using a variety of specified actions and
EQ which is designed to produce a defined result.

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Process validation studies
 examine a process under normal operating
conditions to prove that the process is in control
 re-validation
 modification to the process
 problems occur
 EQ or systems are changed

41
Process validation
 To validate the reproducibility and consistency of a
process
 full defined process is carried out using validated EQ
 at least 3 times, under established procedure
 process must successfully and consistently meet all acceptance
criteria at all steps throughout the procedure at least 3 times
consecutively

Validated process

Worst case: to ensure that process is

acceptable in the extreme case 42
Process validation
 Example
 cleaning
 sanitization
 fumigation
 depyrogenation
 sterilization
 sterile filling
 fermentation
 bulk production
 purification
 inactivation
 filling, capping, sealing
 lyophilization

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Process validation
 specific process clearly described in Master
formula or in SOP
 all EQ; identity, code number, construction, operation
capacity, actual operating range
 processing parameter; sufficiently detailed to permit
complete reproducibility (time period, pH, volume,
temp.etc.)
 specification at each step

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Process validation
 Very important
 specifications for a process undergoing validation be
pre-determined
 all critical processing parameters for which
specifications have been set, there must be equipment
to measure all of those parameters during the
validation study

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Typical content requirements for
process validations
 Cleaning, Fumigation,
Sanitization Process As relevant to the
 collecting liquid and swab cleaning process
samples for testing of residual
product
 residual protein
All analytical tests must
 endotoxin tests
be validated before
 microbial tests (bioburden)
 chemical tests (chlorine and
phosphoric acid)
 residual cleaning agents
 conductivity tests
 pH
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Typical content requirements for
process validations
 Sterilization
 sterilization filtration of solutions
 microbial challenge
 filter integrity tests
 performance tests

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Typical content requirements for
process validations
 Depyrogenation process (dry heat, column
chromatography, other)
 endotoxin content reduction of 3 logs

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Typical content requirements for
process validations
 Sterile filling
 test filling process
 perform filling process with nutrient media
 run at full scale for at least one fill size
 worst case; large volume and number of vials
 filled vials incubated, observed and test for contamination by
validated sterility test
 must be sterile for 3 consecutive runs
 media fill performed twice a year
 size of run must be large enough to detect low levels of
contamination e.g. contamination rate of 1/1000, 3000 units are
needed to provide 95% confidence
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Typical content requirements for
process validations
 Mock fermentation
 full scale fermentation of a representative fermentation
process
 to validate the parts of process involving connections,
sampling, and additions of nutrients etc.
 fermentor prepared and operated in simulated process with
uninoculated nutrient media
 process follow the full fermentation process
 3 consecutive runs at each stage

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Typical content requirements for
process validations
 Production processes(fermentation, bulk
production, purification, filling, lyophilization)
 run according to approved Master formula including all
raw material, personnel, equipment, and facility
preparations, in-process tests, processing, through to
final testing of the batch lot.
 all facility systems must be monitored
 3 consecutive lots must be produced and all facility,
EQ, support systems, product spec, and process
being validated must pass at all steps

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Validation: Type of Documentation
 Validation master plan (VMP)
 Validation protocol (VP)
 Validation reports (VR)
 Standard operating procedures (SOPs)

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Master validation plan (MVP)
 is a document pertaining to the whole facility
that describes which EQ, systems, methods
and processes will be validated and when
they will be validated.
 provide the format required for each
particular validation document (IQ, OQ, PQ
for EQ and systems; process validation,
analytical assay validation)

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Master validation plan (MVP)
 indicate what information is to be contained
within each document
 indicate why and when revalidations will be
performed
 who will decide what validations will be
performed
 order in which each part of the facility is
validated

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Master validation plan (MVP)
 indicate how to deal with any deviations
 state the time interval permitted between
each validation

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Validation: VMP
 Enables overview of entire validation project
 List items to be validated with planning
schedule as its heart
 like a map

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Validation: In summary, VMP
should contain at least
 Validation policy
 Organizational structure
 Summary of facilities, systems, equipment,
processes to be validated
 Documentation format for protocols and reports
 Planning and scheduling
 Change control
 Training requirements

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Validation: Protocol
Objectives of the validation and qualification
study
Site of the study
Responsible personnel
Description of the equipment
SOPs
Standards
Criteria for the relevant products and
processes
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Validation: Report

 Title
 objective of the study
 Refer to the protocol
 Details of material
 Equipment
 Programmes and cycles use
 Details of procedures and test methods
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Validation: changes that require
revalidation
 Software changes; controllers
 Site changes; operational changes
 Change of source of material
 Change in the process
 Significant equipment changes
 Production area changes
 Support system changes

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