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Good Manufacturing Practices

Good Manufacturing Practices. Guilin, PRC Dr AJ van Zyl for Quality Assurance and Safety: Medicines Medicines Policy and Standards Health Technology and Pharmaceuticals Cluster World Health Organization. Program. Good Manufacturing Practices Presentation on GMP (Production focus)

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Good Manufacturing Practices

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  1. Good Manufacturing Practices Guilin, PRC Dr AJ van Zyl for Quality Assurance and Safety: Medicines Medicines Policy and Standards Health Technology and Pharmaceuticals Cluster World Health Organization

  2. Program • Good Manufacturing Practices • Presentation on GMP (Production focus) • Product specific focus • Group session • Presentation on GMP (QC focus) • Product specific focus • Group session

  3. Guidelines and references GMP: World Health Organization WHO Technical Report Series, No. 908, 2003, Annex 4. Good Manufacturing Practices for pharmaceutical products: main principles WHO Technical Report Series, No. Annex 3. Water WHO Technical Report Series, No. Annex 3. HVAC

  4. Good Manufacturing Practices (GMP) Introduction General considerations Glossary Quality management in the drug industry: philosophy and essential elements 1. Quality assurance 2. Good manufacturing practices for pharmaceutical products (GMP) 3. Sanitation and hygiene 4. Qualification and validation 5. Complaints 6. Product recalls 7. Contract production and analysis General The contract giver The contract accepter The contract

  5. Good Manufacturing Practices (GMP) 8. Self-inspection and quality audits Items for self-inspection Self-inspection team Frequency of self-inspection Self-inspection report Follow-up action Quality audit Suppliers’ audits and approval 9. Personnel General Key personnel 10. Training 11. Personal hygiene 12. Premises General Ancillary areas Storage areas Weighing areas Production areas Quality control areas

  6. Good Manufacturing Practices (GMP) 13. Equipment 14. Materials General Starting materials Packaging materials Intermediate and bulk products Finished products Rejected, recovered, reprocessed and reworked materials Recalled products Returned goods Reagents and culture media Reference standards Waste materials Miscellaneous 15. Documentation General Documents required

  7. Good Manufacturing Practices (GMP) 16. Good practices in production General Prevention of cross-contamination and bacterial contamination during production Processing operations Packaging operations 17. Good practices in quality control Control of starting materials and intermediate, bulk and finished products Test requirements Batch record review Stability studies

  8. Good Manufacturing Practices (GMP) • Production • Utilities • Equipment • Dosage form and data verification (development, validation, biobatch, stability, BMR and specification) • Quality control • API, excipients • Packaging material • Data verification (e.g. stability)

  9. Good Manufacturing Practices (GMP) • Production • Product focus • Premises • Utilities • Equipment • Dosage form and data verification (development, validation, biobatch, stability, BMR and specification) • Documentation

  10. Good Manufacturing Practices (GMP) • Where to start the inspection? • Facility layout • Flow of personnel and material, activities • Product list • Type of products, dosage forms, activities • Utilities (HVAC, water, etc) • Validation status

  11. Example of Materials and People Flow Zone: Clean Zone: Packaging Zone: Controlled

  12. Facility layoutFlow of personnel and material, activities • Sampling (starting materials and packaging materials) • Weighing • Mixing • Milling • Sieving/sifting/screening • Granulation • Drying • Sieving • Blending • Compression

  13. Facility layoutFlow of personnel and material, activities • In process bulk stores • Packaging areas (primary and secondary packaging) • Finished product

  14. Product listType of products, dosage forms, activities • Multi-product • Various tablets • Uncoated artesunate • Risk of cross-contamination and contamination • Non dedicated areas and equipment • Batch to batch consistency

  15. Facility layoutFlow of personnel and material, activities • Batch Manufacturing Document • Formula and manufacturing steps • API and excipients • Properties and requirements for temperature or RH control • Material quantities, batch size • Sub lots • Equipment and utilities • Production areas

  16. Equipment and utilities (1) Sieving/sifting – sifter (e.g. vibrosifter) Mixing – mixer Granulation - granulator Drying – fluid bed drier Blending – octagonal blender Compression – compression machine Packaging - blister machine Others include Metal detector, sieves, punches and dies In process quality control instruments and equipment may include hardness tester, disintegration tester, balance, caliper

  17. Equipment and utilities (2) • HVAC – air supply and extraction • Compressed air – machine operation, drying of equipment and parts • Water – washing, rinsing, manufacture • Steam – cleaning

  18. Utilities • The environment may be influenced by: • Light • Temperature • Humidity • Air movement • Microbial contamination • Particulate contamination • Uncontrolled environments can lead to: • Product degradation • Product contamination • Loss of Product & Profit

  19. Utilities • HVAC: GMP and GEP • Effective ventilation • Cross-contamination and contamination • Qualification/validation • Design • Installation • Operation • Performance

  20. Air supply and extraction Red: Supply Green: Exhaust

  21. Filters Fan Flow rate controller Control damper Humidifier Cooling coil Ducts Problems with components • Incorrect retention rate/leaking/badly installed • Low air flow ® loss of pressure cascade • Blocked ® poor pressure cascade ® cross-contamination • Poorly adjusted, bad pressure differential system • Bad water/steam quality/poor drainage/ • No elimination of condensed water/poor drainage/stagnating water • Inappropriate material/internal insulation • Leaking ducts

  22. Utilities: Water systems • Type of water • Intended use • Quality (specification) • Design of the system • Qualification and validation • Ongoing monitoring and quality control • Sampling, testing, trends

  23. Validation status • Validation Master Plan • Manufacturing areas • Utilities • Equipment • Manufacturing process • Cleaning validation • Computer systems • Others…

  24. On site verification • From receiving to stores • Sampling and weighing • Manufacturing areas • Utilities • Documentation review

  25. Sampling and weighing

  26. Weighing

  27. Granulation

  28. Blending

  29. Blister line

  30. AHU

  31. Examples of control measures:

  32. Re-circulation Air System HEPA filters installed? ISPE Baseline Vol. 2 #6.3.3 (d) WHO HVAC Guideline

  33. Typical de-ionizer schematic from water softener HCl NaOH 6 6 5 5 4 4 3 3 2 2 1 1 Water must be kept circulating Anionic column Cartridge filter 5 µm Cartridge filter 1 µm Cationic column UV light Eluates to neutralization plant Ozone generator Hygienic pump Return to de-ioniser Outlets or storage. Drain line Air break to sewer

  34. Documentation review • HVAC • DQ, IQ, OQ, PQ • Important aspects including air flow direction, filtration, air changes, pressure differentials • Water • DQ, IQ, OQ, PQ • Sampling and testing

  35. Documentation review • Equipment and utilities • SOPs (operation, cleaning, calibration) • Records and use logs • Calibration records/certificates • Preventative maintenance and maintenance • Qualification

  36. Documentation review • Product related • Batch Manufacturing document as per product dossier • Process Validation protocol and report • Bio-batch records • Stability batches • Batch records

  37. Documentation review • Other documents • SOPs including: • Cleaning • Complaints • Recalls • Validation protocols and reports including: • Cleaning validation • Computer validation

  38. Documentation review • Inspection of the quality control laboratory…

  39. Group session • Group 1 • Group 2

  40. Documentation review • Q

  41. Documentation review • Q

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