Title: Production and Process validation
1Production and Process validation
by...Wiriya charoenkunathum
2References
- 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
2validation WHO,1997
3GMP
- The good practices outlined are to be considered
general guides and they may be adapted to meet
individual needs.
4GMP
- are aimed primarily at diminishing the risks
inherent in any pharmaceutical production - Cross contamination unexpected contaminants
- Mix-ups confusion (false labels)
5Good 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.
6Production of Vaccine
GMP
Master seed
Working seed
Inoculum
Media/Cell culture
Single harvest
Excipients Validation - process -
method Stability studies
Pool/Concentrated material
Purified/Bulk material
Final bulk
Final lot
7Good practices in productionGeneral
- 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.
8Good practices in productionGeneral
- 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
9Good practices in productionGeneral
- Checks on yields and reconciliation of quantities
to ensure that there are no discrepancies outside
acceptable limits.
10Good practices in productionGeneral
- 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.
11Good practices in productionGeneral
- At all time during processing
- all materials
- bulk containers
- major items of equipment
- rooms
- packaging lines
- being used should be labeled or identified
12Good practices in productionGeneral
- 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.
13Good practices in productionGeneral
- 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.
14Good 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 -
15Good 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
16Good 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
17Good 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
18Good 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
19Good 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
20Good 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
21Good 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
22Good 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
23Good 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
24GMP 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
25GMP 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.
26GMP 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
27- 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.
28- 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.
29Validation Definition
- Validation is the documented act of proving that
any procedure, process, equipment,
material,activity or system actually leads to the
expected result.
30Validation 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
31Validation 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.
32Type 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
33Type 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
34Facility systems and equipment Stage of
validation
- Design qualification (DQ)
- Installation Qualification (IQ)
- Operational Qualification (OQ)
- Performance Qualification (PQ)
Systems and EQ PQvalidation
Depending on the function and operation of some EQ
35Facility 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.
36Facility 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
37Facility 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
38Facility 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.
39Facility 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
40Process 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.
41Process 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
42Process 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
43Process validation
- Example
- cleaning
- sanitization
- fumigation
- depyrogenation
- sterilization
- sterile filling
- fermentation
- bulk production
- purification
- inactivation
- filling, capping, sealing
- lyophilization
44Process 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
45Process 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
46Typical content requirements for process
validations
- Cleaning, Fumigation, Sanitization Process
- collecting liquid and swab samples for testing of
residual product - residual protein
- endotoxin tests
- microbial tests (bioburden)
- chemical tests (chlorine and phosphoric acid)
- residual cleaning agents
- conductivity tests
- pH
As relevant to the cleaning process
All analytical tests must be validated before
47Typical content requirements for process
validations
- Sterilization
- sterilization filtration of solutions
- microbial challenge
- filter integrity tests
- performance tests
48Typical content requirements for process
validations
- Depyrogenation process (dry heat, column
chromatography, other) - endotoxin content reduction of 3 logs
49Typical 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
50Typical 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
51Typical 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
52Validation Type of Documentation
- Validation master plan (VMP)
- Validation protocol (VP)
- Validation reports (VR)
- Standard operating procedures (SOPs)
53Master 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)
54Master 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
55Master validation plan (MVP)
- indicate how to deal with any deviations
- state the time interval permitted between each
validation
56Validation VMP
- Enables overview of entire validation project
- List items to be validated with planning schedule
as its heart - like a map
57Validation 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
58Validation 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
59Validation Report
- Title
- objective of the study
- Refer to the protocol
- Details of material
- Equipment
- Programmes and cycles use
- Details of procedures and test methods
60Validation 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