Production and Process validation

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Production and Process validation

• 17 January 2006

by...Wiriya charoenkunathum
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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
  2validation WHO,1997

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GMP

• The good practices outlined are to be considered
  general guides and they may be adapted to meet
  individual needs.

4
GMP

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

5
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.

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Production 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
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Good 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.

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Good 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

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Good practices in productionGeneral

• Checks on yields and reconciliation of quantities
  to ensure that there are no discrepancies outside
  acceptable limits.

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Good 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.

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Good 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

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Good 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.

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Good 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.

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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

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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

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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

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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

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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

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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.

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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
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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.

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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 PQvalidation
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

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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

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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
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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
• 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
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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