Quality and Good Manufacturing Practices

1. Quality and Good Manufacturing Practices Quality and Good Manufacturing Practices 5 November 2007 Jiaxing, People's Republic of China

2. Quality and Good Manufacturing Practices GMP: Quality Assurance; Documentation; and Personnel Presented by: Dr A J van Zyl 安德李 Technical Officer: WHO HTP/PSM/QSM vanzyla@who.int

3. Quality and Good Manufacturing Practices Outline and Objectives of presentation • Introduce WHO GMP texts • Main principles • Supplements • Others • In the context of Prequalification • Current and future approaches • Chinese GMP

4. Quality and Good Manufacturing Practices WHO GMP text: Main principles • WHO Technical Report Series, No. 908, 2003 • Annex 4 • Regularly reviewed and updated • Divided into "chapters" or "quality systems" • Quality Assurance of Pharmaceuticals (Vol. 2, New edition 2007) • New recommendations for change in June 2007 meeting

5. Quality and Good Manufacturing Practices • 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 • 8. Self-inspection and quality audits

6. Quality and Good Manufacturing Practices • 9. Personnel • 10. Training • 11. Personal hygiene • 12. Premises • 13. Equipment • 14. Materials • 15. Documentation • 16. Good practices in production • 17. Good practices in quality control

7. Quality and Good Manufacturing Practices Others: • Sterile products • Herbal medicines • Radiopharmaceuticals • HVAC • Water systems • Sampling etc • New: Transfer of Technology; Microbiological laboratories

8. Quality and Good Manufacturing Practices Contents of presentation: • Introduction • Quality Assurance • Documentation • Personnel • Questions…

9. Quality and Good Manufacturing Practices Introduction • Competition – India, China, Brazil • Fastest growing economies • Fastest growing pharmaceutical industry • Two main emerging players • Medicines off patent: (Opportunity) • Early 2000 – tens of billions of US $ • 2004 – 15bn US $ • 2005 – 10bn US $ • 2006 onwards - huge growth potential for India and China

10. Quality and Good Manufacturing Practices Introduction • Competition – India, China, Brazil • Fastest growing economies • Fastest growing pharmaceutical industry • Two main emerging players Medicines off patent: (Opportunity) • Early 2000 – tens of billions of US $ • 2004 – 15bn US $ • 2005 – 10bn US $ • 2006 onwards - huge growth potential for India and China

11. RDE100 identifies serious challengers in the marketplaceLists "top 100" companies RDE100

12. Quality and Good Manufacturing Practices • China has become the world leader in supply of ARV APIs. • What about FPPs? • What is the status of the GMP? • Participation in WHO prequalification?

13. Quality and Good Manufacturing Practices Law and order Capability China Resources Competition Quality Infrastructure

15. Quality and Good Manufacturing Practices WHO China

16. Quality and Good Manufacturing Practices Contents of presentation: • Introduction Quality Assurance • Whole section is missing in Chinese GMP

17. Quality Management Quality Assurance: • This section in WHO GMP is missing in Chinese GMP Quality relationships Quality Management Quality Assurance GMP Production and Quality Control Section 1 and 2

18. Quality Management Quality Management • What is Quality Management? • The aspect of management function that determines and implements the “quality policy” • The overall intention and direction regarding quality, as formally expressed and authorized by top management • The basic elements are: • An appropriate infrastructure or “quality system” encompassing the organization structure, procedures, processes and resources • The systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for “Quality” The totality of these actions is termed “Quality Assurance”

19. Quality Management Principles of Quality Assurance (QA) • Wide-ranging concept • covers all matters that individually or collectively influence the quality of a product • Totality of the arrangements • to ensure that the drug is of the right quality for the intended use • Quality Assurance incorporates GMP • and also product design and development which is outside the scope of this module 1.1

20. Quality Management QA System should ensure: • Products are designed and developed correctly • Complying with, e.g. GMP, GCP, GLP • Production and control operations are defined • Managerial responsibilities are defined • In job descriptions • The manufacture, supply and use of correct starting and packaging materials 1.1 a- d

21. Quality Management QA System should ensure (2): • Controls are performed, including intermediates, bulk, calibration and validation • Correct processing and checking of the finished product • Products are sold/supplied only after review by the authorized person • Complying with marketing authorization, production and QC requirements • Proper storage, distribution and handling 1.1 e - h

22. Quality Management QA System should ensure (3): • Procedures for self-inspection and/or quality audits • Reporting, investigation and recording of deviations • System for change control/approval • Regular evaluation of product quality to verify consistency and continued improvement 1.1 i - l

23. Quality Management Quality Assurance • Requires a comprehensively designed and well implemented QA system • Fully documented, and effectiveness monitored • Competent personnel, sufficient premises, equipment and facilities 1.3

24. Quality Management Good Manufacturing Practices (GMP) • That part of QA that ensures that products are consistently produced and controlled • Quality standards • Marketing authorization • Aim: Diminishing risks that cannot be controlled by testing of product • Contamination and cross-contamination • Mix-ups (confusion) 2.1

25. Quality Management Basic Requirements for GMP – I • Clearly defined and systematically reviewed processes • Qualification and validation is performed • Appropriate resources are provided: • Qualified and trained personnel • Premises, space, equipment and services • Materials, containers, labels • Procedures, storage, transport • Laboratories and in-process control 2.1 a - c

26. Quality Management Basic Requirements for GMP – I • Clear, written instructions and procedures • Trained operators • Records of actions, deviations and investigations • Records for manufacture and distribution • Proper storage and distribution • Systems for complaints and recalls 2.1 d - j

27. Quality and Good Manufacturing Practices Contents of presentation: • Introduction • Quality Assurance Documentation

28. Documentation General Principles – I • Good documentation is an essential part of the QA system • Should exist for all aspects of GMP • Purpose of documentation • Defines specifications and procedures for all materials and methods of manufacture and control • Ensures all personnel know what to do and when to do it • Ensure that authorized persons have all information necessary for release of product 15.1

29. Documentation General Principles – I • Purpose of documentation (cont.) • Ensures documented evidence, traceability, provide records and audit trail for investigation, communication, • Ensures availability of data for validation, review and statistical analysis • Design and use • Depends upon manufacturer • Some documents combined into one, sometimes separate 15.1

30. Documentation

31. Documentation General Principles – I • Documents should be • designed • prepared • reviewed • distributed with care • Comply with marketing authorization • Approval of documentation • Approved, signed and dated by appropriate responsible persons • No document should be changed without authorization and approval 15.2 and 3

32. Documentation General Principles – II • Contents of documents should be clear (easy to understand) and include, e.g. • Title, nature, objective or purpose • Layout in orderly fashion • Easy to be filled in and checked • Clear and readable – including copies made • No errors if master documents are copied for working documents 15.4

33. Documentation General Principles – III Documentation control • Regular review of documents • Kept up to date (current) - amended • Superseded documents removed and not used • Distribution and retrieval of documentation • Retention time for superseded documents 15.5

34. Documentation General Principles – IV Data entry • Clear, readable and indelible • Design to allow for sufficient space for entries • Changes to entries: • signed, dated and reason given • original entry still readable • Entries at the time of action • All significant actions recorded – traceable 15.6 – 15.8

35. Documentation General Principles – V Data entry (cont.) • Electronic data processing systems, photographic systems or other reliable means • Systems require SOPs and records • Accuracy of records checked • Authorized persons - access and changes • Password controlled • Entries checked 15.9

36. Documentation General Principles – VI Data entry (cont.) • Batch records stored electronically: • Protected • Back-up transfer, e.g. magnetic tape, microfilm, paper print-outs • Records kept 1 year after expiry date of product • Data readily available during retention period 15.9

37. Documentation Types of Documentation • Labels • Specifications and testing procedures • Master formulae and instructions • Batch processing and batch packaging records • Standard Operating Procedures (SOPs) • Records • Stock control and distribution records • Other documents …

38. Documentation • Photographs can be documents and part of a herbal identification, provided they are properly authorized and controlled

39. Documentation • Flow charts provide substantial information at a glance

40. Documentation Labels What must be labelled? Containers, equipment, premises Label information? Clear, unambiguous, company format Intermediates and bulk products Colours can be used, e.g. green (accepted), red (rejected) 15.10

41. Basic Principles of GMP • Different types of labels, e.g. cleaning status, production stage, status of materials • Other types of labels?

42. Basic Principles of GMP

43. Documentation Specifications and test methods • Authorized, approved, signed and dated • Starting, packaging materials and finished products: include tests on identity, content, purity, quality • Intermediates and bulk • Water, solvents and reagents • QC, QA or documentation centre • Periodic review • Compliance with current pharmacopoeia • Pharmacopoeia, reference standards and spectra available Test Procedures: • Validated (facility and equipment) before routinely used 15.14, 15.15 15.13, 15.16 -15.17

44. Basic Principles of GMP • What types of documents are associated with sampling of starting materials?

45. Documentation Other documents • Master Formulation • Batch Processing record • Batch Packaging record • ? 15.25 – 15.26

46. Documentation

47. Documentation

48. Documentation Standard Operating Procedures (SOP) - I • What is an SOP? • Who is responsible for preparing SOPs? • What is the format for an SOP? • Which activities require SOPs? • Where should SOPs be stored? • Are SOPs associated with records? 15.31

49. Documentation

50. Documentation Standard Operating Procedures - II Which activities require SOPs? • Equipment and analytical apparatus: • Assembly, validation • Calibration • Internal labelling, quarantine and storage of materials • Operation • Maintenance and cleaning • Personnel matters: • Qualification • Training • Clothing • Hygiene 15.31