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Training on basic aspect of Good Manufacturing Practices GMP

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Title: Training on basic aspect of Good Manufacturing Practices GMP


1
Training on basic aspect of Good Manufacturing
Practices (GMP)
Section 4. QUALIFICATION and VALIDATION
  • János Pogány, Ph.D., consultant to WHO
  • Bangkok, 20 October 2004
  • E-mail pogany_at_axelero.hu

2
SUPPORTING GUIDELINES
  • WHO good manufacturing practices main principles
    for pharmaceutical products -Validation of
    manufacturing processes
  • Supplementary guidelines on good manufacturing
    practices (GMP) Validation (2003) - Draft

3
TECHNICAL PHARMACY
  • PHARMACEUTICAL PRODUCTION SYSTEM (PURCHASING gt
    PACKAGING)
  • UTILITY SUPPORT SYSTEM
  • PROCESS (TABLET MAKING)
  • (UNIT) OPERATION (GRANULATION)
  • STEP (SIFTING, SIZING)
  • PROCEDURE, METHOD (SOP)

4
QUALIFICATION
  • QUALIFICATION is the Action of proving that any
    premises, (pharmaceutical utility) systems and
    items of equipment work correctly and actually
    lead to the expected results. The meaning of the
    word validation is sometimes extended to
    incorporate the concept of qualification.
  • REQUALIFICATION is the main part of the
    preventive maintenance programme of proving that
    any premises, system and equipment ... keeps on
    leading to the expected results.

5
VALIDATION
  • VALIDATION is the Action of proving, in
    accordance with the principles of GMP, that any
    procedure, process, equipment, material, activity
    or (pharmaceutical utility) system actually leads
    to the expected results (see also
    qualification).
  • REVALIDATION is a part of the change control
    system of proving ... keeps on leading to...
    (normal wear and tear)

6
QUALIFICATION - VALIDATION
  • Premises, equipment and supporting utilities must
    be qualified to operate in a validated process.
    (E.g. you qualify an autoclave (analytical
    instrument), whereas you validate a sterilization
    (assay, impurity test) process (method,
    operation).

7
4.1-4.2 VALIDATION MASTER PLAN
  • In accordance with GMP, each pharmaceutical
    company should identify what qualification and
    validation work is required to prove that the
    critical aspects of their particular operation
    are controlled.
  • The key elements of a qualification and
    validation programme of a company should be
    clearly defined and documented in a validation
    master plan (VMP).

8
VALIDATION MASTER PLAN
  • Cover manufacturers validation policy and needs
  • Provides information on validation organization
  • It should describe
  • why?
  • what?
  • where?
  • by whom?
  • how?
  • when?

9
VALIDATION MASTER PLAN (1)
  • PRODUCTION AND QC PREMISES, IN-CLUDING CONTROLLED
    ENVIRONMENTS
  • PROCESS AND QC EQUIPMENT
  • PHARMACEUTICAL AIR (HVAC) AND WATER SYSTEMS
  • ALL CRITICAL UTILITIES, e.g., COMPRESSED AIR,
    STEAM, COOLING LIQUIDS
  • COMPUTER CONTROL SYSTEMS

10
VALIDATION MASTER PLAN (2)
  • QC AND IPC METHODS
  • MANUFACTURING PROCESS
  • EQUIPMENT CLEANING
  • PRODUCT QUALITY
  • REVALIDATION PROGRAM
  • WORKER AND ENVIRONMENT SAFETY
  • COMPUTER CONTROL SYSTEMS

11
4.3 DOCUMENTARY EVIDENCE
  • (a) the premises, supporting utilities, equipment
    and processes have been designed in accordance
    with the requirements for GMP (design
    qualification or DQ) VMP
  • (b) the premises, supporting utilities and
    equipment have been built and installed in
    compliance with their design specifications
    (installation qualification or IQ) manual law
  • (c) the premises, supporting utilities and
    equipment operate in accordance with their design
    specifications (operational qualification or OQ)
    manual
  • (d) a specific process will consistently produce
    a product meeting its predetermined
    specifications and quality attributes (process
    validation or PV, also called performance
    qualification or PQ).

12
VALIDATION DOCUMENTS/1
  • QUALIFICATION PROTOCOLS
  • ENGINEERING DESIGN AND CONSTRUCTION DOCUMENTS
  • MACHINE MANUALS
  • INSTALLATION QUALIFICATION (IQ)
  • OPERATION QUALIFICATION (OQ)

13
VALIDATION DOCUMENTS/2
  • VALIDATION PROTOCOLS
  • OPERATION QUALIFICATION REPORT FOR PERFORMANCE
    QUALIFICATION (PQ)
  • DEVELOPMENT PHARMACEUTICS DOCUMENTS
  • PRODUCT FILES AS WELL AS BATCH MANUFACTURING, QC
    AND IPC RECORDS

14
VALIDATION DOCUMENTS/3
  • MAIN OUTPUTS INCLUDE
  • QUALIFICATION REPORTS
  • VALIDATION REPORTS
  • SOPs INCLUDING EQUIPMENT CLEANING
  • REQUALIFICATION AND REVALIDATION PROGRAM
  • PREVENTATIVE MAINTENANCE PROGRAM

15
GMP, QUALIFICATION and
  • VALIDATION STARTS WITH
  • DESIGN CONSTRUCTION
  • OF FACILITIES AND
  • PURCHASING EQUIPMENT

16
(No Transcript)
17
4.4 WHAT SHOULD BE VALIDATED?
  • Any aspect of operation, including significant
    changes to the premises, facilities, equipment or
    processes, which may affect the quality of the
    product, directly or indirectly, should be
    qualified and validated.

18
TYPES OF VALIDATION
  • EXPERIMENTAL APPROACH
  • PROSPECTIVE VALIDATION (RD)
  • CONCURRENT VALIDATION (FIRST 3 BATCHES)
  • ANALYSIS OF HISTORICAL DATA
  • RETROSPECTIVE VALIDATION
  • (DIFFERS CONCEPTUALLY FROM THE EXPERIMENTAL
    APPROACH)

19
CONCURRENT VALIDATION
  • FIRST THREE PRODUCTION SCALE BATCHES ARE
    MONITORED EXTENSIVELY
  • PROVISIONAL IPC ACCEPTANCE CRITERIA ARE
    ESTABLISHED
  • MACHINERY AND EQUIPMENT PARAMETERS ARE DESCRIBED
    IN SOPs
  • CRITICAL ASPECTS ARE MONITORED, NON-CRITICAL ONES
    ARE TESTED OCCASIONALLY
  • CONCURRENT VALIDATION NEVER ENDS

20
IN-PROCESS CONTROL
  • PROCESS PARAMETERS AND THE CORRESPONDING
    IN-PROCESS CONTROLS MUST BE DEDUCED FROM THE
    KNOWLEDGE ACTUALLY AVAILABLE AT THE TIME, BASED
    ON EXPERIENCE FROM DEVELOPMENT PHARMACEUTICS AND
    HISTORICAL EXPERIENCE WITH DOSAGE FORM

21
CONTINUOUS IMPROVEMENT
  • ALL POTENTIALLY CRITICAL PARAMETERS SHOULD BE
    MONITORED.
  • FEEDBACK LOOP WOULD CORRELATE THE QC AND IPC DATA
    WITH THE QUALITY OF THE FINISHED PRODUCT.
  • AFTER CORRELATION ANALYSIS HAS BEEN FINALIZED,
    IPC ACCEPTANCE CRITERIA ESTABLISHED, ONLY
    CRITICAL PARAMETERS ARE TO BE MONITORED

22
EXAMPLES OF CRITICAL QUALITY PARAMETERS
  • Critical API parameters purchasing
    specifications
  • Critical operation parameters chopper and
    impeller speeds, drying temperature, LOD,
    porosity, etc. of the granules may affect the
    quality and stability of tablets. Internal
    customer.
  • Critical equipment parameters homogenization of
    granules, RPM of the tableting machine.
  • Critical product parameters hardness, friability
    and thickness of tablets may affect the packing
    operation.

23
TABLET MANUFACTURING VARIABLES (1)
  • OUTPUT VARIABLES (validated quality, yields)
    MANIPULATE (independent) VARIABLES
  • Binder
  • Solvent
  • dryer inlet temperature
  • blending parameters
  • RPM of the tabletting machine

24
TABLET MANUFACTURING VARIABLES (2)
  • STATE (dependent) VARIABLES (IPC)
  • granulation yield
  • LOD of the compression blend
  • flowing properties of the compression blend
  • tablet hardness, friability, weight
  • tablet compression yield
  • coated tablet yield, and so on

25
4.5-4.7 VALIDATION POLICY
  • Qualification and validation should not be
    considered as one-off exercises. An on-going
    programme should follow their first
    implementation and should be based on an annual
    review.
  • The commitment to maintain continued validation
    status should be stated in the relevant company
    documentation, such as the quality manual or
    validation master plan.
  • The responsibility of performing validation
    should be clearly defined.

26
PROCESS APPROACH
  • CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT
    SYSTEM

CUSTOMER
CUSTOMER
SATISFACTION
Management responsibility
REQUIREMENTS
Resource management
Monitoring, improvement
Manufacture
Inputs
Product
27
ANNUAL FPP QUALITY REVIEW (1)
  • Starting materials used in the product,
    especially those from new sources.
  • Critical in-process controls and finished product
    results.
  • All batches that failed to meet established
    specification(s).
  • All critical deviations or non-conformances and
    related investigations.
  • All changes carried out to the processes or
    analytical methods.
  • Marketing Authorisation variations submitted, or
    granted, or refused, including those for third
    country dossiers.

28
ANNUAL FPP QUALITY REVIEW (2)
  • Results of the stability monitoring programme.
  • All quality-related returns, complaints and
    recalls, including export only medicinal
    products.
  • Adequacy of previous corrective actions.
  • For new marketing authorisations, a review of
    post-marketing commitments.
  • A list of validated procedures and their
    revalidation dates.
  • A list of qualified equipment, support utility
    systems and their requalification dates,
    including calibration programmes.

29
CASE SUMMARY of 20 BATCHES (1)
30
CASE SUMMARY of 20 BATCHES (2)
  • ACCEPTANCE CRITERIA FOR ASSAY AND DISSOLUTION
    RATE ARE LOOSE
  • POTENTIALLY CRITICAL IMPURITIES ARE NOT TESTED
  • IPC DATA ARE NOT INCLUDED IN THE RETROSPECTIVE
    ANALYSIS OF BATCH RECORDS

31
4.8-4.9 PROTOCOLS AND REPORTS
  • Validation studies are an essential part of GMP
    and should be conducted in accordance with
    predefined and approved protocols.
  • A written report summarizing the results recorded
    and the conclusions reached should be prepared
    and stored.

32
4.10 SCIENTIFIC APPROACH
  • Processes and procedures should be established on
    the basis of the results of the validation
    performed.

33
4.11 QC, COMPUTERS and CLEANING
  • It is of critical importance that particular
    attention is paid to the validation of analytical
    test methods, automated systems and cleaning
    procedures.

34
ANALYTICAL METHODS
  • Qualified and calibrated instruments
  • Documented methods
  • Reliable reference standards
  • Qualified analysts
  • Sample integrity

35
CRITERIA FOR DIFFERENT METHODS
  • selectivity
  • precision
  • repeatability
  • intermediate precision
  • reproducibility
  • accuracy
  • linearity
  • range
  • limit of detection
  • limit of quantitation
  • robustness, ruggedness

36
ACCURACY AND PRECISION
Inaccurate and imprecise
Accurate
Accurate and precise
Precise
37
CLASSES OF ANALYTICAL TESTS
  • Class A To establish identity
  • Class B To detect and quantitate impurities
  • Class C To determine quantitatively the
    concentration
  • Class D To assess the characteristics

38
CRITERIA FOR ANALYTICAL CLASSES
39
CLEANING VALIDATION
  • Potential contaminants
  • Product residues
  • Cleaning agent residues
  • Airborne matter
  • Lubricants, ancillary material
  • Decomposition residues
  • Bacteria, mould and pyrogens

40
AUTOMATED SYSTEMS
  • Protection of records, backups
  • Access controls (use, read, write, execute,
    delete, or create)
  • Authentication (user ID and static passwords
    user ID and dynamic passwords and biometric
    devices)
  • Audit-trail controls

41
VISUALLY CLEAN
  • Always first criterion
  • Can be very sensitive but needs verification
  • Use between same product batches of same
    formulation
  • Illuminate surface
  • Spiking studies

42
NOT MORE THAN 0.1
  • APIs are often considered to be non-active at 0.1
    of their normally prescribed dosages.
  • Need to identify worst case (least water-soluble,
    most toxic API)
  • One should identify the equivalent of 0.1 of the
    lowest therapeutic dose of the most toxic product
    to be cleaned away. No more than this 0.001 of a
    dose should be detectable in the largest daily
    dose of the product being manufactured
    subsequently in the same equipment.

43
10ppm
  • This criterion requires that there be no more
    than 10 ppm of the cleaned compound in the next
    product to be manufactured.
  • Assumes residue to be harmful as heavy metal
  • Useful for materials for which no available
    toxicological data
  • Not for pharmacologically potent material

44
LITERATURE METHODOLOGY (1)
45
LITERATURE METHODOLOGY (2)
46
HYPOTHETICAL EXAMPLE
0.1 dosis criterion (mg in 4-in.2 swab area)
10 ppm criterion (mg in 4-in.2 swab area)
Visibility criterion 0.100mg in 4-in.2 swab area
47
LITERATURE SOURCE
  • Cleaning Validation and Residue Limits A
    Contribution to Current Discussions1
  • Andreas O. Zeller, Dr phil. nat., is manager of
    the quality assurance department for the quality
    planning and testing of initial materials at
    Sandoz AG, Deutschhermstrasse 15, Postfach,
    W-8500 Nürnberg 1, FRG, tel. 49 911 273 0, fax
    49 911 27 38 02.1 Published in Pharmaceutical
    Technology Europe, October 1993

48
BEST PROCESS
  • MINIMUM REQUIRED INPUT
  • MAXIMUM OUTPUT
  • AT NO COST TO SOCIETY (industrial safety, labour
    safety, internal and external environment
    protection)

49
COSTS OF QUALITY
  • Visible costs, e.g., waste and returned goods
  • Hidden costs, e.g., wrong decisions,
    non-competitive manufacturing process,
  • low yield, maintenance, idle machine time,
    workers attitude, etc.
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