Basic Principles of GMP

1. Basic Principles of GMP Active Pharmaceutical Ingredients Part Three, 18

2. Active Pharmaceutical Ingredients Objectives • To discuss the GMP guidelines for the manufacture of Active Pharmaceutical Ingredients (APIs) • To examine key problems experienced during inspections of the manufacturers of APIs and to seek possible solutions Part Three, 18.1–18.59

3. Active Pharmaceutical Ingredients Areas to be Covered • General considerations • Personnel • Premises • Equipment • Sanitation • Documentation • Retention of records and samples • Production Part Three, 18.1–18.59

4. Active Pharmaceutical Ingredients General Considerations • Overall control • Consistent uniform batches • Compliance with GMP • production • quality control • General guidelines • Cooperation in production • Human and veterinary preparations Part Three, 18.1–18.6

5. Active Pharmaceutical Ingredients Personnel • Qualified and competent • production and quality control • sufficient number • education, knowledge, experience • Organizational chart with responsibilities • Written job description or instructions • Trained • Health • diseases • open lesions Part Three, 18.7–18.10

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

7. Active Pharmaceutical Ingredients Premises (continued) • Hygiene • clothes, washing, toilets • eating, drinking, smoking Part Three, 18.11–18.13

8. Active Pharmaceutical Ingredients Equipment • Design, construction, location and maintenance • intended use, cleaning, contamination • validated operation • Cleaning • sterilized, used, maintained: SOPs, records and checks Part Three, 18.14–18.18

9. Active Pharmaceutical Ingredients Equipment (continued) • Process monitoring and control • calibrated, checked • records • Defective equipment • removed or labelled • repaired, documented Part Three, 18.14–18.18

10. Active Pharmaceutical Ingredients Sanitation • Written programmes • validated for premises and equipment • quality standard for water • hygiene, health and clothing practices • waste disposal • Implementation and training • Practices not permitted: • eating, smoking • unhygienic practices Part Three, 18.19–18.22

11. Active Pharmaceutical Ingredients Documentation • Master formulae • written instructions • master formula contents • authorization • outdated documents • amendments • Batch documentation • batch manufacturing record contents • contract production • data recording Part Three, 18.23–18.30

12. Active Pharmaceutical Ingredients Record and reference sample retention • Activities are traceable • production and quality control • Retention of records and samples • retention period Part Three, 18.31–18.32

13. Active Pharmaceutical Ingredients Production • Processing procedures • master formula • critical steps defined and validated • supervision • labelling • vessels, containers, equipment • daily activities - information Part Three, 18.33–18.37

14. Active Pharmaceutical Ingredients Production (continued) • Starting materials • receiving, quarantine, sampling • testing • release, reject, storage, labelling • dispensing SOP • exceptions for hazardous materials • Intermediates • testing • labelling • storage Part Three, 18.38–18.40

15. Active Pharmaceutical Ingredients Production (continued) • Active pharmaceutical ingredients • meet specifications • limits for residue and reactants • sterile APIs Part Three, 18.41–18.42

16. Active Pharmaceutical Ingredients Production (continued) • Packaging • packaging material selection • procedures to prevent error • 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. Active Pharmaceutical Ingredients Quality Control • Independent unit • Duties: approve, reject or release • specifications and methods • sampling, sanitation and hygiene • reprocessing • stability • complaints • Laboratory access and requirements • Contract laboratories Part Three, 18.46–18.51

18. Active Pharmaceutical Ingredients Stability Studies • Written programme • stability indicating methods • Samples • containers • storage conditions • Expiry or retest date Part Three, 18.46–18.51

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

20. Active Pharmaceutical Ingredients Complaints and Defects • Written instructions • Prompt action and investigation • record facts • Product review system Reject materials • Written procedures • starting materials, intermediates, packaging materials • identified • storage pending fate Part Three, 18.56–18.59

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

22. Active Pharmaceutical Ingredients Possible Issues • Manufacturers supplying various types of industries • Imports through brokers • Hazardous processes • Commercial secrecy • Unsatisfactory final facilities

23. Active Pharmaceutical Ingredients Possible Issues (continued) • The interpretation of the meanings of expiry dates and retest dates • The use of APIs close to their expiry date • Blending of rejected APIs • Reprocessing, recovery and/or reworking of APIs • Recycling and treatment of solvents • Addition of impurities to batches of APIs • Traceability, repacking and relabelling