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) Product specific focus Group session Presentation on GMP (QC focus)

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

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

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 Ancillary areas Storage areas Weighing areas Production areas Quality control areas

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 Documents required

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

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)

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

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

Example of Materials and People Flow This sheet shows the flow of material and personnel. The green arrows indicate the material flow, and show materials that are brought in each room through the corridor zone. The cubicle between the corridor and the work zone may be an airlock, but in some countries this is required to be an air shower. The red arrows indicate the people flow and show how people enter each room through the corridor divided by the zones. Zone: Clean Zone: Packaging Zone: Controlled

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

Facility layout Flow of personnel and material, activities In process bulk stores Packaging areas (primary and secondary packaging) Finished product

Product list Type 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

Facility layout Flow 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

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

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

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

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

Air supply and extraction Red: Supply Green: Exhaust

Problems with components Filters Fan Flow rate controller Control damper Humidifier Cooling coil Ducts 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

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

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

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

Sampling and weighing

Weighing

Granulation

Blending

Blister line

AHU

Examples of control measures: Temperature Cooling coil Relative humidity Dehumidifier Particulate matter Filters Air movement and pressure differentials Fan

Re-circulation Air System HEPA filters installed? HEPA filters must be installed! Note final filtration is in the AHU ISPE Baseline Vol. 2 #6.3.3 (d) WHO HVAC Guideline

Typical de-ionizer schematic Cationic column Anionic column Hygienic pump Outlets or storage. Ozone generator UV light HCl NaOH Eluates to neutralization plant Air break to sewer Drain line from water softener Water must be kept circulating Typical de-ionizer schematic 1 2 3 4 5 6 Return to de-ioniser Cartridge filter 5 µm filter 1 µm This schematic drawing of a typical de-ionizer is given in handout 2-2-8. Use it to explain the pathway of water through a twin bed de-ionizer. Softened water enters at the top right into the twin bed de-ionizer. Cation and anion exchange agents are resins with large surface areas. Cations are exchanged for H+, anions for OH-, the combination is H-OH, or water! After Cation and anion exchange, the water is filtered (to remove resin particles and sometimes bacteria) before being re-circulated through the distribution system and returned to the de-ionizer, usually via a buffer tank. The Cation and anion resins are regenerated using hydrochloric acid and sodium hydroxide respectively. There should be specifications available for these two materials for the inspector to check. Mixed bed de-ionizers are also common. They may be more prone to bacterial contamination and so the inspector should check them carefully. They should be disinfected at regular intervals. Heat is not a option, because of the resin material. Furthermore, many of the de-ionizers are made of plastic materials. However, the regenerating chemicals are very effective biocides and so the system should be regenerated frequently, at least once a week, regardless of the conductivity readings. Inspectors should ask for the sanitation records so that these can be checked. Disinfection of the circulating water is necessary; this can be achieved by inline UV irradiation and or ozonization.

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

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

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

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

Documentation review Inspection of the quality control laboratory…

Group session Group 1 Group 2

Documentation review Q

Documentation review Q