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János Pogány, Ph.D., consultant to WHO Bangkok, 20 October 2004 E-mail: pogany@axelero.hu. Training on basic aspect of Good Manufacturing Practices (GMP). Section 4. QUALIFICATION and VALIDATION. SUPPORTING GUIDELINES.

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j nos pog ny ph d consultant to who bangkok 20 october 2004 e mail pogany@axelero hu
János Pogány, Ph.D., consultant to WHO

Bangkok, 20 October 2004

E-mail: pogany@axelero.hu

Training on basic aspect of Good Manufacturing Practices (GMP)

Section 4.

QUALIFICATION and VALIDATION

Dr. Pogány - WHO, Bangkok

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

Dr. Pogány - WHO, Bangkok

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

Dr. Pogány - WHO, Bangkok

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

Dr. Pogány - WHO, Bangkok

validation
VALIDATION
  • VALIDATIONis 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)

Dr. Pogány - WHO, Bangkok

qualification validation
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 validatea sterilization (assay, impurity test) process (method, operation).

Dr. Pogány - WHO, Bangkok

4 1 4 2 validation master plan
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 avalidation master plan (VMP).

Dr. Pogány - WHO, Bangkok

validation master plan
VALIDATION MASTER PLAN
  • Cover manufacturer’s validation policy and needs
  • Provides information on validation organization
  • It should describe:
    • why?
    • what?
    • where?
  • by whom?
  • how?
  • when?

Dr. Pogány - WHO, Bangkok

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

Dr. Pogány - WHO, Bangkok

validation master plan 2
VALIDATION MASTER PLAN (2)
  • QC AND IPC METHODS
  • MANUFACTURINGPROCESS
  • EQUIPMENTCLEANING
  • PRODUCT QUALITY
  • REVALIDATION PROGRAM
  • WORKERANDENVIRONMENT SAFETY
  • COMPUTER CONTROL SYSTEMS

Dr. Pogány - WHO, Bangkok

4 3 documentary evidence
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).

Dr. Pogány - WHO, Bangkok

validation documents 1
VALIDATION DOCUMENTS/1

QUALIFICATION PROTOCOLS:

  • ENGINEERING DESIGN AND CONSTRUCTION DOCUMENTS
  • MACHINE MANUALS
    • INSTALLATION QUALIFICATION (IQ)
    • OPERATION QUALIFICATION (OQ)

Dr. Pogány - WHO, Bangkok

validation documents 2
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

Dr. Pogány - WHO, Bangkok

validation documents 3
VALIDATION DOCUMENTS/3

MAIN OUTPUTS INCLUDE:

  • QUALIFICATION REPORTS
  • VALIDATION REPORTS
  • SOPs INCLUDING EQUIPMENT CLEANING
  • REQUALIFICATION AND REVALIDATION PROGRAM
  • PREVENTATIVE MAINTENANCE PROGRAM

Dr. Pogány - WHO, Bangkok

gmp qualification and
VALIDATION STARTS WITH

DESIGN + CONSTRUCTION

OF FACILITIES AND

PURCHASING EQUIPMENT

GMP, QUALIFICATION and

Dr. Pogány - WHO, Bangkok

4 4 what should be validated
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.

Dr. Pogány - WHO, Bangkok

types of validation
TYPES OF VALIDATION

EXPERIMENTAL APPROACH

PROSPECTIVE VALIDATION (R&D)

CONCURRENT VALIDATION (FIRST ≥3 BATCHES)

ANALYSIS OF HISTORICAL DATA

RETROSPECTIVE VALIDATION

(DIFFERS CONCEPTUALLY FROM THE EXPERIMENTAL APPROACH)

Dr. Pogány - WHO, Bangkok

concurrent validation
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

Dr. Pogány - WHO, Bangkok

in process control
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

Dr. Pogány - WHO, Bangkok

continuous improvement
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

Dr. Pogány - WHO, Bangkok

examples of critical quality parameters
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.

Dr. Pogány - WHO, Bangkok

tablet manufacturing variables 1
TABLET MANUFACTURING VARIABLES (1)

OUTPUTVARIABLES (validated quality, yields)MANIPULATE (independent) VARIABLES

  • Binder
  • Solvent
  • dryer inlet temperature
  • blending parameters
  • RPM of the tabletting machine

Dr. Pogány - WHO, Bangkok

tablet manufacturing variables 2
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

Dr. Pogány - WHO, Bangkok

4 5 4 7 validation policy
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.

Dr. Pogány - WHO, Bangkok

process approach
PROCESS APPROACH

CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM

CUSTOMER

SATISFACTION

CUSTOMER

Management

responsibility

REQUIREMENTS

Resource

management

Monitoring,

improvement

Manufacture

Inputs

Product

Dr. Pogány - WHO, Bangkok

annual fpp quality review 1
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.

Dr. Pogány - WHO, Bangkok

annual fpp quality review 2
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.

Dr. Pogány - WHO, Bangkok

case summary of 20 batches 1
CASE SUMMARY of 20 BATCHES (1)

Dr. Pogány - WHO, Bangkok

case summary of 20 batches 2
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

Dr. Pogány - WHO, Bangkok

4 8 4 9 protocols and reports
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.

Dr. Pogány - WHO, Bangkok

4 10 scientific approach
4.10 SCIENTIFIC APPROACH
  • Processes and procedures should be established on the basis of the results of the validation performed.

Dr. Pogány - WHO, Bangkok

4 11 qc computers and cleaning
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.

Dr. Pogány - WHO, Bangkok

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

Dr. Pogány - WHO, Bangkok

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

Dr. Pogány - WHO, Bangkok

accuracy and precision
ACCURACY AND PRECISION

Inaccurate and imprecise

Accurate

Precise

Accurate and precise

Dr. Pogány - WHO, Bangkok

classes of analytical tests
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

Dr. Pogány - WHO, Bangkok

criteria for analytical classes
CRITERIA FOR ANALYTICAL CLASSES

Dr. Pogány - WHO, Bangkok

cleaning validation
CLEANING VALIDATION

Potential contaminants

  • Product residues
  • Cleaning agent residues
  • Airborne matter
  • Lubricants, ancillary material
  • Decomposition residues
  • Bacteria, mould and pyrogens

Dr. Pogány - WHO, Bangkok

automated systems
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

Dr. Pogány - WHO, Bangkok

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

Dr. Pogány - WHO, Bangkok

not more than 0 1
NOT MORE THAN 0.1%
  • APIsare 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.

Dr. Pogány - WHO, Bangkok

10ppm
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

Dr. Pogány - WHO, Bangkok

literature methodology 1
LITERATURE METHODOLOGY (1)

Dr. Pogány - WHO, Bangkok

literature methodology 2
LITERATURE METHODOLOGY (2)

Dr. Pogány - WHO, Bangkok

hypothetical example
HYPOTHETICAL EXAMPLE

0.1% dosis criterion (mg in 4-in.2swab area)

10 ppm criterion (mg in 4-in.2swab area)

Visibility criterion: 0.100mg in 4-in.2swab area

Dr. Pogány - WHO, Bangkok

literature source
LITERATURE SOURCE

Cleaning Validation and Residue Limits:A Contribution to Current Discussions[1]

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

Dr. Pogány - WHO, Bangkok

best process
BEST PROCESS

MINIMUM REQUIRED INPUT

MAXIMUM OUTPUT

AT NO COST TO SOCIETY (industrial safety, labour safety, internal and external environment protection)

Dr. Pogány - WHO, Bangkok

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.

COSTS OF QUALITY

Dr. Pogány - WHO, Bangkok