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) 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.

4. Good Manufacturing Practices (GMP) Introduction General considerations Glossary 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

5. Good Manufacturing Practices (GMP) 8. Self-inspection and quality audits 9. Personnel 10. Training 11. Personal hygiene 12. Premises Quality control areas 13. Equipment 14. Materials Reagents and culture media Reference standards 15. Documentation

6. Good Manufacturing Practices (GMP) 16. Good practices in production 17. Good practices in quality control Control of starting materials and intermediate, bulk and finished products Test requirements Batch record review Stability studies

7. Good Practices for Quality Control Laboratories (GPQCL) Part One. Management and infrastructure 1. Organization and management 2. Quality system 3. Control of documentation 4. Records 5. Data processing equipment 6. Personnel 7. Premises 8. Equipment, instruments and other devices

8. Good Practices for Quality Control Laboratories (GPQCL) Part Two. Materials and set-up of equipment, instruments and other devices 9. Specifications archive 10. Reagents 11. Reference materials 12. Calibration, validation and verification of equipment, instruments and other devices 13. Traceability

9. GPQCL Part Three. Working procedures 14. Incoming sample 15. Analytical worksheet 16. Testing 17. Evaluation of test results 18. Retained samples Part Four. Safety in pharmaceutical control laboratories 19. General rules

10. Good Manufacturing Practices (GMP) Where to start the inspection? Laboratory layout – overview of the QC laboratory, activities, personnel Chemical analysis, instrumentation, micro Product to be inspected API, excipients, bulk, FP Specification, test methods, parameters and acceptance criteria Utilities (HVAC, water, etc)

11. Good Manufacturing Practices (GMP) Where to start the inspection? (2) Packaging material control Data verification (e.g. stability) Other documents: SOPs Reports and records Validation and qualification OOS Trend analysis

12. (GMP) - QC "On site" inspection Sample inward register Artesunate and selected excipients Date of entry Date received and cross references Purchase order and delivery note Approved supplier and manufacturer Number of containers and batch number(s) Damaged containers Samples taken Control number (AR) allocated

13. (GMP) - QC Documents requested: Select specific batches for verification Artesunate specification and excipients specifications Standard Test Methods Analytical reports for the batches selected Pharmacopoeia SOPs (e.g. sampling, pooling of samples and sampling plan), reagents and volumetric solution preparation, reference standard control...

14. (GMP) - QC General information: How are the samples taken? Size of the sample? Pooling for composite samples? Sample containers? Sampling tools? Sample storage Work allocation Current specifications

15. (GMP) - QC Data verification: Analytical reports against the specifications COAs (suppliers, own) and raw data 1. Number of samples verified (cross check) 2. Tests as per specification with acceptance criteria 3. Individual tests/parameters 4. Source or raw data in analyst work books or data sheets 5. Issuing of the sheets/books

16. (GMP) - QC Artesunate: Parameter Acceptance criteria Result Description Identification

17. (GMP) - QC Artesunate: Identification (and assay?) Each sample, from each container Method used – "in-house" or pharmacopoeia Validated method Reference standard (RS) used Official RS or Working standard Preparation Control Records Storage, container etc Chromatograms or spectra Date, traceability (batch numbers, time, analyst, equipment)

18. (GMP) - QC Artesunate (cont): Chromatograms or spectra (cont) Manual integration, Peak symmetry, system suitability Equipment logbook date used, analyst, calibrated (records), maintenance (record), qualification reports, computer system validated, access control, changes, column used, column performance, column log, column washing and storage, analyst information, qualification, training, signature

19. (GMP) - QC Artesunate: Follow the same procedure for each test or selected tests Excipients: Follow the same procedure for the excipients Also micro tests as applicable Finished product: Follow the same procedure Release and rejection procedure

20. (GMP) - QC Other checks may include: Environment of the laboratory Glassware calibration and use Equipment and instruments Other products and materials tested Impact Glass ware Cleaning, condition, storage SOPs Specifications archive Analytical method validation Analyst performance

21. (GMP) - QC Documentation review may include: OOS SOP, reports, investigations CAPA Water system Water system qualification Water sampling and testing Cleaning validation Environmental control Particulate matter Micro Air samples, settle plates, contact plates, personnel

22. (GMP) - QC Primary packaging material, e.g. Aluminium foil and PVC, PVDC HDPE containers Cotton wool Dessicant Procedure for receiving, sampling, testing Where? Who? How? How many? Supplier? Batch control? AR numbers? Traceability? Specifications, test methods, release reports

23. (GMP) - QC Printed packaging material e.g. Labels and cartons Leaflets Procedure for receiving, sampling, testing Where? Who? How? How many? Supplier? Batch control? AR numbers? Traceability? Specifications, test methods, release reports

24. (GMP) - QC Retention samples APIs Excipients Packaging materials Finished Products Area Environmental conditions Period kept Packaging Quantity

25. (GMP) - QC Stability testing Conditions e.g. Zone II, Zone IV (now a and b) Periods Accelerated Real time Procedure and plan with intervals Compliance with program Verify source data Incubators or chambers Qualification (DQ, IQ, OQ, PQ) Packaging

26. (GMP) - QC Stability P

27. (GMP) - QC Micro lab Personnel Organization structure, job descriptions and responsibilities Qualifications and experience Activities Excipients Environmental monitoring Water monitoring Instruments and equipment Status (qualification, calibration, SOPs and records)

28. (GMP) - QC Micro lab Media Storage Preparation procedure and records Positive and negative control Microbiologist training Waste materials Cleaning

29. (GMP) - QC Micro lab P