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F gmp imp kl dr tajuddin

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Hemendra Dave
Hemendra Dave

This document discusses Good Manufacturing Practices (GMP) for manufacturing investigational medicinal products. It covers the key elements of GMP including quality management, personnel, facilities and equipment, documentation, production, quality control, contracts, complaints and recalls, and self-inspection. GMP aims to ensure products are consistently manufactured and controlled according to quality standards for their intended use. Compliance with GMP is crucial for ensuring quality and safety, especially for medicines that have not been fully tested. Regulators conduct audits to monitor manufacturer compliance.

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1 1 GOOD MANUFACTURING PRACTICE [GMP] Manufacture of Investigational Medicinal Products (IMPs) Tajuddin Akasah B.Pharm.Hons.(USM)., M.Phil., Ph.D. (UK) Head of Centre for GMP National Pharmaceutical Control Bureau WHO Collaborating Centre For Regulatory Control of Pharmaceuticals Member of Pharmaceutical Inspection Cooperation Scheme MS ISO 9001:2000 Certified National Pharmaceutical Control Bureau Ministry of Health Malaysia 2 SCOPE TO COVERSCOPE TO COVER Quality Background GMP and QA Elements of GMP 3 QUALITY? 4 How and Why? some assumptions I like the brand! I trust the brand! I like the box! My mother uses it! My friend uses it! My doctor says so! The pharmacist sells it! 5 THALIDOMIDE AND HEAVY METAL POISONING 6 Regulator’s concern …. Quality, Safety and EfficacyQuality, Safety and Efficacy [pharmaceuticals] Quality and SafetyQuality and Safety [health supplements and traditionals]
2 7 How do we ensure ? Quality (meet specs, intended use) and Safety (Heavy metals and microbial limits, no prohibited ingredients, ADR monitored) Efficacy (proven clinically) 8 DO YOU KNOW THAT THE MEDICINE USED IS NOT ‘TESTED’? 9 ? 10 Quality QC test is destructive Unable to do on every tablet Require sampling Compliance to GMP is crucial Quality being ‘built-in’ from the start to finish 11 WHAT IS GMP? Good Manufacturing Practice GMP is that part of QA which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation or product specifications 12 WHAT IS QA? Quality Assurance It is the sum total of the organised arrangements made with the objective of ensuring that medicinal product are of quality required for their intended use. QA therefore incorporates GMP plus Quality Control (QC).
3 13 GMP IMPLEMENTATION IN MALAYSIA GMP for pharmaceuticals in Malaysia since 1984 WHO and ASEAN Guidelines MALAYSIAN Guidelines PIC/S since 1st Jan 2002, Malaysia became the 26th member state 14 Background A short history of GMP First introduced by the Canadian Authorities – mid 1960s Since then GMP acceptance – as a ‘way of life’ in the pharmaceutical industry 15 Background It might be assumed that 40 years of experience of GMP 84 countries Would have eliminated many dangers to the patients due to quality failure in manufacturing but…. 16 MistakesMistakes 109 infants have died in Nigeria due to failure to follow GMP Supplier mislabelled ethylene glycol (anti freeze) as propylene glycol and the manufacturer failed to perform adequate QC – identification and potency test 17 OTHER EXAMPLES Slimming pills in Singapore 2002 Slimming pills in Malaysia 2004 Tablet with hairs in Brunei 2004 Adulterated Trad Med in Yemen 2004 Nepal 2004 Wrong labelling in Malaysia 2005 18 GMP COMPLIANCE IS CRUCIAL WHAT ARE THE ELEMENTS OF GMP?
4 19 Ch. 1. Quality Management System Ch. 2. Personnel Ch. 3. Premises and Equipment Ch. 4. Documentation Ch. 5. Production Ch. 6. Quality Control Ch. 7. Contract Manufacture and Analysis Ch. 8. Complaint and Product Recall Ch. 9. Self Inspection Annexes 1-18 (specific) 20 QUALITY MANAGEMENT SYSTEM Developed, established, implemented Policies and objectives Organisational structure, functions Responsibilities, procedures QC and specifications 21 PERSONNEL ~ separate people responsible for production and quality control (independent of each other) ~ appropriately trained in quality system, GMP and regulatory requirements 22 PREMISES* & EQUIPMENT* Suitably located, designed, constructed and maintained The need to avoid any risks of contamination from environment cross-contamination product mix-up 23 Premises & Equipment… Campaign working is acceptable but… Separate or dedicated facilities for Penicillin, steroids, hormones etc. 24 Hormone Production
5 25 DOCUMENTATION Complete history of each batch from starting material to finished products,traceability BMR, SOPs, Formulas 26 WHEN ATTEMPTING A TASK WE NEED SOME SORT OF DOCUMENTATION 27 If the documentation is wrong! 28 PRODUCTION – Starting materials Consistency of production is influenced by quality of starting materials Specifications 29 Manufacturing Operations Standard Operating Procedures (SOPs) Cleaning Procedures and Validations 30 Principles applicable to Comparator Product If significant changes were made to the quality of the comparator product (dosage form, packaging materials, Storage, etc.) Stability, comparative dissolution, bioavailability data should be made available to prove the original quality characteristics
6 31 Expiry Date The expiry date on the original package may NOT be applicable when repacked The sponsor is responsible to determine a suitable use-by date (product nature, characteristics of container, storage conditions) 32 Randomisation Code Procedures should describe the generation, distribution, handling & retention of randomisation code used for packaging investigational products 33 Blinding Operations A system should be implemented to allow for a proper identification of the blinded product System + randomisation code - must allow proper identification & traceability Sample of blinded IMPs should be retained 34 Milo + Nescafe Ikan kering + Telor Goreng 1/1000th 35 ValidationValidation The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results. 36 Qualify a system and/or equipment ValidateValidate a process Qualify an autoclave, whereas you validate a sterilisation processvalidate a sterilisation process Qualification or ValidationValidation ?
7 37 Production actual & theoretical yield abnormal discrepancy should be investigated 38 Packaging & Labelling Line clearance Label reconciliation Independent checking by QC staff 39 Thai labels 40 QUALITY CONTROL Concerned with sampling, specifications, testing, documentation, release procedures. 41 Quality Control… Accuracy of therapeutic dose (content uniformity) Release of active substance (solubility, dissolution) Estimation of stability (accelerated & stress conditions, shelf life, storage conditions) 42 CONTRACT MANUFACTURE & CONTRACT ANALYSIS Must be correctly defined agreed and controlled in order to avoid misunderstandings Must clearly defines the duties of the giver and receiver
8 43 COMPLAINTS AND PRODUCT RECALL Complaints must be reviewed according to SOPs For all contigencies there should be aproduct recall procedures 44 SELF INSPECTION Conducted in order to monitor the implementation and compliance with GMP principles To propose necessary corrective measures 45 GMP FLOW CONCEPTGMP FLOW CONCEPT Black Grey White 46 Contaminations Microbiological Pyrogen Particulate Sources Personnel Environment/surface Equipment 47 48 And finally… GMP
9 49 GMP – GOOD MANUFACTURING PRACTICE and not Good Massage Practice 50 IS IT TOUGH? 51 Some useful websites http://www.bpfk.gov.my http://www.picscheme.org http://www.tga.health.gov.au http://www.who.org http://www.fda.gov 52 QUESTIONS & ANSWERS 53 HOW DO WE MONITOR MANUFACTURERS? WE AUDIT [ROUTINE, VERIFICATION, INVESTIGATIVE & ETC.]! 54 Grading of GMP Compliance and Frequency of Audits 12 MTHS6 MTHS6 MTHSPOOR 18 MTHS12 MTHS12 MTHSS’FACTORY 24 MTHS24 MTHS18 MTHS STATUS GOOD LOWMEDIUMHIGHRISK
10 55 AUDIT FINDINGS EXAMPLESWHY?WHAT? BAJU KOYAK, TEMPERATURE RECORD NOT SIGNED COMMENTS FOR IMPROVEMENT MINOR PROCEDURE NOT COMPLETE, NO TRAINING, BAJU KOYAK QUALITY DEFECTS NOT EFFECTING HUMAN LIFE MAJOR WATER SYSTEM, HVACS, X- CONT’N, BAJU KOYAK EFFECT HUMAN LIFE CRITICAL

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F gmp imp kl dr tajuddin

  • 1. 1 1 GOOD MANUFACTURING PRACTICE [GMP] Manufacture of Investigational Medicinal Products (IMPs) Tajuddin Akasah B.Pharm.Hons.(USM)., M.Phil., Ph.D. (UK) Head of Centre for GMP National Pharmaceutical Control Bureau WHO Collaborating Centre For Regulatory Control of Pharmaceuticals Member of Pharmaceutical Inspection Cooperation Scheme MS ISO 9001:2000 Certified National Pharmaceutical Control Bureau Ministry of Health Malaysia 2 SCOPE TO COVERSCOPE TO COVER Quality Background GMP and QA Elements of GMP 3 QUALITY? 4 How and Why? some assumptions I like the brand! I trust the brand! I like the box! My mother uses it! My friend uses it! My doctor says so! The pharmacist sells it! 5 THALIDOMIDE AND HEAVY METAL POISONING 6 Regulator’s concern …. Quality, Safety and EfficacyQuality, Safety and Efficacy [pharmaceuticals] Quality and SafetyQuality and Safety [health supplements and traditionals]
  • 2. 2 7 How do we ensure ? Quality (meet specs, intended use) and Safety (Heavy metals and microbial limits, no prohibited ingredients, ADR monitored) Efficacy (proven clinically) 8 DO YOU KNOW THAT THE MEDICINE USED IS NOT ‘TESTED’? 9 ? 10 Quality QC test is destructive Unable to do on every tablet Require sampling Compliance to GMP is crucial Quality being ‘built-in’ from the start to finish 11 WHAT IS GMP? Good Manufacturing Practice GMP is that part of QA which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation or product specifications 12 WHAT IS QA? Quality Assurance It is the sum total of the organised arrangements made with the objective of ensuring that medicinal product are of quality required for their intended use. QA therefore incorporates GMP plus Quality Control (QC).
  • 3. 3 13 GMP IMPLEMENTATION IN MALAYSIA GMP for pharmaceuticals in Malaysia since 1984 WHO and ASEAN Guidelines MALAYSIAN Guidelines PIC/S since 1st Jan 2002, Malaysia became the 26th member state 14 Background A short history of GMP First introduced by the Canadian Authorities – mid 1960s Since then GMP acceptance – as a ‘way of life’ in the pharmaceutical industry 15 Background It might be assumed that 40 years of experience of GMP 84 countries Would have eliminated many dangers to the patients due to quality failure in manufacturing but…. 16 MistakesMistakes 109 infants have died in Nigeria due to failure to follow GMP Supplier mislabelled ethylene glycol (anti freeze) as propylene glycol and the manufacturer failed to perform adequate QC – identification and potency test 17 OTHER EXAMPLES Slimming pills in Singapore 2002 Slimming pills in Malaysia 2004 Tablet with hairs in Brunei 2004 Adulterated Trad Med in Yemen 2004 Nepal 2004 Wrong labelling in Malaysia 2005 18 GMP COMPLIANCE IS CRUCIAL WHAT ARE THE ELEMENTS OF GMP?
  • 4. 4 19 Ch. 1. Quality Management System Ch. 2. Personnel Ch. 3. Premises and Equipment Ch. 4. Documentation Ch. 5. Production Ch. 6. Quality Control Ch. 7. Contract Manufacture and Analysis Ch. 8. Complaint and Product Recall Ch. 9. Self Inspection Annexes 1-18 (specific) 20 QUALITY MANAGEMENT SYSTEM Developed, established, implemented Policies and objectives Organisational structure, functions Responsibilities, procedures QC and specifications 21 PERSONNEL ~ separate people responsible for production and quality control (independent of each other) ~ appropriately trained in quality system, GMP and regulatory requirements 22 PREMISES* & EQUIPMENT* Suitably located, designed, constructed and maintained The need to avoid any risks of contamination from environment cross-contamination product mix-up 23 Premises & Equipment… Campaign working is acceptable but… Separate or dedicated facilities for Penicillin, steroids, hormones etc. 24 Hormone Production
  • 5. 5 25 DOCUMENTATION Complete history of each batch from starting material to finished products,traceability BMR, SOPs, Formulas 26 WHEN ATTEMPTING A TASK WE NEED SOME SORT OF DOCUMENTATION 27 If the documentation is wrong! 28 PRODUCTION – Starting materials Consistency of production is influenced by quality of starting materials Specifications 29 Manufacturing Operations Standard Operating Procedures (SOPs) Cleaning Procedures and Validations 30 Principles applicable to Comparator Product If significant changes were made to the quality of the comparator product (dosage form, packaging materials, Storage, etc.) Stability, comparative dissolution, bioavailability data should be made available to prove the original quality characteristics
  • 6. 6 31 Expiry Date The expiry date on the original package may NOT be applicable when repacked The sponsor is responsible to determine a suitable use-by date (product nature, characteristics of container, storage conditions) 32 Randomisation Code Procedures should describe the generation, distribution, handling & retention of randomisation code used for packaging investigational products 33 Blinding Operations A system should be implemented to allow for a proper identification of the blinded product System + randomisation code - must allow proper identification & traceability Sample of blinded IMPs should be retained 34 Milo + Nescafe Ikan kering + Telor Goreng 1/1000th 35 ValidationValidation The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results. 36 Qualify a system and/or equipment ValidateValidate a process Qualify an autoclave, whereas you validate a sterilisation processvalidate a sterilisation process Qualification or ValidationValidation ?
  • 7. 7 37 Production actual & theoretical yield abnormal discrepancy should be investigated 38 Packaging & Labelling Line clearance Label reconciliation Independent checking by QC staff 39 Thai labels 40 QUALITY CONTROL Concerned with sampling, specifications, testing, documentation, release procedures. 41 Quality Control… Accuracy of therapeutic dose (content uniformity) Release of active substance (solubility, dissolution) Estimation of stability (accelerated & stress conditions, shelf life, storage conditions) 42 CONTRACT MANUFACTURE & CONTRACT ANALYSIS Must be correctly defined agreed and controlled in order to avoid misunderstandings Must clearly defines the duties of the giver and receiver
  • 8. 8 43 COMPLAINTS AND PRODUCT RECALL Complaints must be reviewed according to SOPs For all contigencies there should be aproduct recall procedures 44 SELF INSPECTION Conducted in order to monitor the implementation and compliance with GMP principles To propose necessary corrective measures 45 GMP FLOW CONCEPTGMP FLOW CONCEPT Black Grey White 46 Contaminations Microbiological Pyrogen Particulate Sources Personnel Environment/surface Equipment 47 48 And finally… GMP
  • 9. 9 49 GMP – GOOD MANUFACTURING PRACTICE and not Good Massage Practice 50 IS IT TOUGH? 51 Some useful websites http://www.bpfk.gov.my http://www.picscheme.org http://www.tga.health.gov.au http://www.who.org http://www.fda.gov 52 QUESTIONS & ANSWERS 53 HOW DO WE MONITOR MANUFACTURERS? WE AUDIT [ROUTINE, VERIFICATION, INVESTIGATIVE & ETC.]! 54 Grading of GMP Compliance and Frequency of Audits 12 MTHS6 MTHS6 MTHSPOOR 18 MTHS12 MTHS12 MTHSS’FACTORY 24 MTHS24 MTHS18 MTHS STATUS GOOD LOWMEDIUMHIGHRISK
  • 10. 10 55 AUDIT FINDINGS EXAMPLESWHY?WHAT? BAJU KOYAK, TEMPERATURE RECORD NOT SIGNED COMMENTS FOR IMPROVEMENT MINOR PROCEDURE NOT COMPLETE, NO TRAINING, BAJU KOYAK QUALITY DEFECTS NOT EFFECTING HUMAN LIFE MAJOR WATER SYSTEM, HVACS, X- CONT’N, BAJU KOYAK EFFECT HUMAN LIFE CRITICAL