1. Module 14Slide 1 of 23 WHO - EDM Basic Principles of GMP Active Pharmaceutical Ingredients Part Three, 18

2. Module 14Slide 2 of 23 WHO - EDM Active Pharmaceutical Ingredients Objectives l To discuss the GMP guidelines for the manufacture of Active Pharmaceutical Ingredients (APIs) l To examine key problems experienced during inspections of the manufacturers of APIs and to seek possible solutions Part Three, 18.1–18.59

3. Module 14Slide 3 of 23 WHO - EDM Active Pharmaceutical Ingredients Areas to be Covered l General considerations l Personnel l Premises l Equipment l Sanitation l Documentation l Retention of records and samples l Production Part Three, 18.1–18.59

4. Module 14Slide 4 of 23 WHO - EDM Active Pharmaceutical Ingredients General Considerations l Overall control l Consistent uniform batches l Compliance with GMP ä production ä quality control l General guidelines l Co-operation in production l Human and veterinary preparations Part Three, 18.1–18.6

5. Module 14Slide 5 of 23 WHO - EDM Active Pharmaceutical Ingredients Personnel l Qualified and competent ä production and quality control ä sufficient number ä education, knowledge, experience l Organizational chart with responsibilities l Written job description or instructions l Trained l Health ä diseases ä open lesions Part Three, 18.7–18.10

6. Module 14Slide 6 of 23 WHO - EDM Active Pharmaceutical Ingredients Premises l General ä suitable construction and environment ä adequately adapted and sufficient size ä mix-ups or contamination ä logical work flow l Special purposes ä antibiotics, hormones, cytostatic substances ä separate specifically designed enclosed areas ä separate air handling systems Part Three, 18.11–18.13

7. Module 14Slide 7 of 23 WHO - EDM Active Pharmaceutical Ingredients Premises l Hygiene ä clothes, washing, toilets ä eating, drinking, smoking Part Three, 18.11–18.13

8. Module 14Slide 8 of 23 WHO - EDM Active Pharmaceutical Ingredients Equipment l Design, construction, location and maintenance ä intended use, cleaning, contamination ä validated operation l Cleaning ä sterilised, used, maintained: SOPs, records and checks Part Three, 18.14–18.18

9. Module 14Slide 9 of 23 WHO - EDM Active Pharmaceutical Ingredients Equipment l Process monitoring and control ä calibrated, checked ä records l Defective equipment ä removed or labelled ä repaired, documented Part Three, 18.14–18.18

10. Module 14Slide 10 of 23 WHO - EDM Active Pharmaceutical Ingredients Sanitation l Written programmes ä validated for premises and equipment ä quality standard for water ä hygiene, health and clothing practices ä waste disposal l Implementation and training l Practices not permitted: ä eating, smoking ä unhygienic practices Part Three, 18.19–18.22

11. Module 14Slide 11 of 23 WHO - EDM Active Pharmaceutical Ingredients Documentation l Master formulae ä written instructions ä master formula contents ä authorisation ä outdated documents ä amendments l Batch documentation ä batch manufacturing record contents ä contract production ä data recording Part Three, 18.23–18.30

12. Module 14Slide 12 of 23 WHO - EDM Active Pharmaceutical Ingredients Record and reference sample retention l Activities are traceable ä production and quality control l Retention of records and samples ä retention period Part Three, 18.31–18.32

13. Module 14Slide 13 of 23 WHO - EDM Active Pharmaceutical Ingredients Production l Processing procedures ä master formula ä critical steps defined and validated ä supervision ä labelling – vessels, containers, equipment ä daily activities - information Part Three, 18.33–18.37

14. Module 14Slide 14 of 23 WHO - EDM Active Pharmaceutical Ingredients Production (continued) l Starting materials ä receiving, quarantine, sampling ä testing ä release, reject, storage, labelling ä dispensing SOP ä exceptions for hazardous materials l Intermediates ä testing ä labelling ä storage Part Three, 18.38–18.40

15. Module 14Slide 15 of 23 WHO - EDM Active Pharmaceutical Ingredients Production (continued) l Active pharmaceutical ingredients ä meet specifications ä limits for residue and reactants ä sterile APIs Part Three, 18.41–18.42

16. Module 14Slide 16 of 23 WHO - EDM Active Pharmaceutical Ingredients Production (continued) l Packaging ä packaging material selection ä procedures to prevent error ä labelling, including: – Product name – Quality – Batch number – Expiry or retest date – Warnings, if required – Storage conditions – Names of manufacturers and suppliers Part Three, 18.43–18.45

17. Module 14Slide 17 of 23 WHO - EDM Active Pharmaceutical Ingredients Quality Control l Independent unit l Duties: Approve, reject or release ä specifications and methods ä sampling, sanitation and hygiene ä reprocessing ä stability ä complaints l Laboratory access and requirements l Contract laboratories Part Three, 18.46–18.51

18. Module 14Slide 18 of 23 WHO - EDM Active Pharmaceutical Ingredients Stability Studies l Written programme ä stability indicating methods l Samples ä containers ä storage conditions l Expiry or retest date Part Three, 18.46–18.51

19. Module 14Slide 19 of 23 WHO - EDM Active Pharmaceutical Ingredients Self-Inspection and Quality Audits l Regular independent inspection ä expert or team of experts ä production and quality control l Records Storage l Suitable conditions based on stability studies l Distribution records for each batch ä written SOP ä facilitate recalls Part Three, 18.52–18.55

20. Module 14Slide 20 of 23 WHO - EDM Active Pharmaceutical Ingredients Complaints and Defects l Written instructions l Prompt action and investigation ä record facts l Product review system Reject materials l Written procedures ä starting materials, intermediates, packaging materials ä identified ä storage pending fate Part Three, 18.56–18.59

21. Module 14Slide 21 of 23 WHO - EDM Active Pharmaceutical Ingredients Group Session l Identify major deficiencies experienced in GMP in active pharmaceutical ingredients manufacture. l Are there any deficiencies that should prevent material being released? l Within what timescale should these deficiencies be corrected? l What are the implications for bulk active supply to your country?

22. Module 14Slide 22 of 23 WHO - EDM Active Pharmaceutical Ingredients Possible Issues l Manufacturers supplying various types of industries l Imports through brokers l Hazardous processes l Commercial secrecy l Unsatisfactory final facilities

23. Module 14Slide 23 of 23 WHO - EDM Active Pharmaceutical Ingredients Possible Issues l The interpretation of the meanings of expiry dates and re- test dates l The use of APIs close to their expiry date l Blending of rejected APIs l Reprocessing, recovery and/or reworking of APIs l Recycling and treatment of solvents l Addition of impurities to batches of APIs l Trace-ability, repacking and re-labelling