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. [phone] 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.