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
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)
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.
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
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
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
ENGINEERING DESIGN AND CONSTRUCTION DOCUMENTS
INSTALLATION QUALIFICATION (IQ)
OPERATION QUALIFICATION (OQ)
13 VALIDATION DOCUMENTS/2
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
SOPs INCLUDING EQUIPMENT CLEANING
REQUALIFICATION AND REVALIDATION PROGRAM
PREVENTATIVE MAINTENANCE PROGRAM
15 GMP QUALIFICATION and
VALIDATION STARTS WITH
OF FACILITIES AND
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
PROSPECTIVE VALIDATION (RD)
CONCURRENT VALIDATION (FIRST 3 BATCHES)
ANALYSIS OF HISTORICAL DATA
(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.
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
Reliable reference standards
35 CRITERIA FOR DIFFERENT METHODS
limit of detection
limit of quantitation
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
Cleaning agent residues
Lubricants ancillary material
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)
41 VISUALLY CLEAN
Always first criterion
Can be very sensitive but needs verification
Use between same product batches of same formulation
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.
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
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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