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Production and Process validation

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Title: Production and Process validation


1
Production and Process validation
  • 17 January 2006

by...Wiriya charoenkunathum
2
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

3
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.

6
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
7
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.

8
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

9
Good practices in productionGeneral
  • Checks on yields and reconciliation of quantities
    to ensure that there are no discrepancies outside
    acceptable limits.

10
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.

11
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

12
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.

13
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.

14
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

15
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

16
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

17
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

18
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

19
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

20
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

21
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

22
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

23
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

24
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

25
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.

26
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

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.

29
Validation Definition
  • Validation is the documented act of proving that
    any procedure, process, equipment,
    material,activity or system actually leads to the
    expected result.

30
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
31
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.

32
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

33
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
34
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
35
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.

36
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

37
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

38
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.

39
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
40
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.

41
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

42
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
43
Process validation
  • Example
  • cleaning
  • sanitization
  • fumigation
  • depyrogenation
  • sterilization
  • sterile filling
  • fermentation
  • bulk production
  • purification
  • inactivation
  • filling, capping, sealing
  • lyophilization

44
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

45
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

46
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
47
Typical content requirements for process
validations
  • Sterilization
  • sterilization filtration of solutions
  • microbial challenge
  • filter integrity tests
  • performance tests

48
Typical content requirements for process
validations
  • Depyrogenation process (dry heat, column
    chromatography, other)
  • endotoxin content reduction of 3 logs

49
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

50
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

51
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

52
Validation Type of Documentation
  • Validation master plan (VMP)
  • Validation protocol (VP)
  • Validation reports (VR)
  • Standard operating procedures (SOPs)

53
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)

54
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

55
Master validation plan (MVP)
  • indicate how to deal with any deviations
  • state the time interval permitted between each
    validation

56
Validation VMP
  • Enables overview of entire validation project
  • List items to be validated with planning schedule
    as its heart
  • like a map

57
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

58
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

59
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

60
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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