1. 1 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines

2. Good Manufacturing Practices – Part I Purpose and Principles of GMP Anton Norder, MSc Technical Officer WHO EMRO 1 st Workshop on the WHO Prequalification Programme: Priority Essential Medicines, Cairo, Egypt, 6 and 7 June, 2007 2 20 Avenue Appia CH-1211 Geneva 27 Switzerland E-mail: nordera@who.int

3. 3 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Guidelines and references GMP applies to both Active Pharmaceutical Ingredients (APIs) and Finished Pharmaceutical Products (FPPs)  FPP: WHO Good Manufacturing Practices for pharmaceutical products: main principles. WHO Technical Report Series, No. 908, 2003, Annex 4.  API: WHO Good Manufacturing Practices: starting materials. WHO Technical Report Series, No. 823, 1992. ä (ICH Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, International Conference on Harmonization http://www.ich.org/cache/compo/276-254-1.html) http://www.ich.org/cache/compo/276-254-1.html

4. 4 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (FPP):  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 ä General ä The contract giver ä The contract accepter ä The contract

5. 5 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd)  8. Self-inspection and quality audits ä Items for self-inspection ä Self-inspection team ä Frequency of self-inspection ä Self-inspection report ä Follow-up action ä Quality audit ä Suppliers’ audits and approval  9. Personnel ä General ä Key personnel  10. Training

6. 6 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd)  11. Personal hygiene  12. Premises ä General ä Ancillary areas ä Storage areas ä Weighing areas ä Production areas ä Quality control areas  13. Equipment

7. 7 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd)  14. Materials ä General ä Starting materials ä Packaging materials ä Intermediate and bulk products ä Finished products ä Rejected, recovered, reprocessed and reworked materials ä Recalled products ä Returned goods ä Reagents and culture media ä Reference standards ä Waste materials ä Miscellaneous

8. 8 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd)  15. Documentation ä General ä Documents required: l Labels l Testing procedures l Specifications for starting and packaging materials, for intermediate and bulk products and for finished products l Master formulae and Batch Processing Records l Packaging instructions and Batch Packaging Records l Standard Operating procedures (SOP's) and records l Logbooks

9. 9 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices (cont'd)  16. Good practices in production ä General ä Prevention of cross-contamination and bacterial contamination during production ä Processing operations ä Packaging operations  17. Good practices in quality control ä Control of starting materials and intermediate, bulk and finished products ä Test requirements ä Batch record review ä Stability studies

10. 10 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines GMP is actually Good Common Sense Quality Management Quality Assurance GMP Production and Quality Control Section 1 and 2

11. 11 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Management: Philosophy and essential elements What is Quality Management? ä The aspect of management function that determines and implements the “quality policy” ä The overall intention and direction regarding quality, as formally expressed and authorized by top management

12. 12 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Management  The basic elements are: ä An appropriate infrastructure or “quality system” encompassing the organization structure, procedures, processes and resources ä 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 referred to as “Quality Assurance”

13. 13 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Intermezzo: the five P's  Premises  Primary materials  People  Procedures  Processes defined and recorded

14. 14 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance  Quality assurance is a management tool  In contractual situations, it also serves to generate confidence in a supplier  QA, GMP and Quality Control are interrelated aspects of Quality Management ä They are described on the following slides in order to emphasize their relationship and their fundamental importance to the production and control of pharmaceutical products 1.1

15. 15 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance  Wide-ranging concept ä covers all matters that individually or collectively influence the quality of a product  Totality of the arrangements ä to ensure that the drug is continuously of the right quality for the intended use  Quality Assurance incorporates GMP ä and also includes product design and development, with special focus on process design 1.1

16. 16 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines The position of QA Director ProductionQC labOther Depts QA

17. 17 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance means to assure:  Products are designed and developed correctly ä Complying with, e.g. GMP, GCP, GLP  Production and control operations are defined  Managerial responsibilities are defined ä In job descriptions  The manufacture, supply and use of correct starting and packaging materials 1.1 a- d

18. 18 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance means to assure: (cont'd)  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 ä Complying with marketing authorization, production and QC requirements  Proper storage, distribution and handling 1.1 e - h

19. 19 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance means to assure: (cont'd)  Procedures for self-inspection and quality audits are applied  Deviations are reported, investigated and recorded  System for change control is applied  Regular evaluation of product quality to verify consistency and continued improvement 1.1 i - l

20. 20 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Quality Assurance includes:  Responsibility of the Manufacturer for the quality of the product ä Fit for intended use ä Comply with marketing authorization ä Safety, efficacy and quality  Commitment of senior management and involvement of all staff  Comprehensively designed and well implemented quality system  Full documentation and monitoring of effectiveness  Competent personnel, sufficient premises, equipment and facilities 1.3

21. 21 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Good Manufacturing Practices  That part of QA that ensures that products are consistently produced and controlled ä Quality standards ä Marketing authorization  Aim: Diminishing risks that cannot be controlled by testing of product ä Contamination and cross-contamination ä Mix-ups (confusion) 2.1

22. 22 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 1 10 100 Preliminary Design Code & Debug Validate Detailed Design IntegrateOperation 1.2 1.6 1.4 3 5 2 4 18 8 80 Relative Cost of Correcting Error Maximum Minimum The cost of change

23. 23 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Basic requirements for GMP:  Clearly defined and systematically reviewed processes  Qualification and validation is performed  Appropriate resources are provided: ä Qualified and trained personnel ä Premises, space, equipment and services ä Materials, containers, labels ä Procedures, storage, transport ä Laboratories and in-process control 2.1 a - c

24. 24 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Basic requirements for GMP: (cont'd)  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

25. 25 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines GMP = continuous urge for improvement  Involvement of the management  Annual Product Quality Review  Complaints handling  Self-inspection

26. 26 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Involvement of the management  The senior management is responsible to attain the company's quality objectives  All different departments and all levels within departments should be involved; and it's the senior management who should facilitate this  Also suppliers and distributors should be involved  The senior management should make available the required resources  The basis of the quality system is the quality statement and quality policy, by the senior management

27. 27 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Annual Product Quality Review Objectives to do an Annual Product Quality Review:  To review and verify the consistency and appropriateness of the existing process  To identify and highlight any trends in the process, e.g. in analytical results, yields etc.  To identify any possible product or process improvements Not yet mandatory in WHO GMP, but it is likely to become mandatory like it is in other GMP's

28. 28 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Annual Product Quality Review (cont'd)  Review of starting materials/ packaging materials, esp from new sources  Review of in-process control results and finished product analytical control results  Amount of batches and packaging units produced and their yields  Reviews of: ä Out-of-spec situations ä Rejections ä Deviations ä Changes ä Plus their investigations as well as a trend analysis of causes

29. 29 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Annual Product Quality Review (cont'd)  Review of Marketing Authorization variations submitted, granted or refused (incl. third countries)  Review of stability monitoring programme and its trends  Review of adequacy of previous decisions on changes or improvements or corrective actions  For new Marketing Authorizations (plus new variations) a review of post marketing commitment  The qualification status of all relevant equipment and utilities (like water, HVAC, gases, etc.)  Review of Technical Agreements (if applicable), to verify they are up- to-date.

30. 30 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.1 Complaints handling Complaints: Principle “ All complaints and other information concerning potentially defective products must be carefully reviewed according to written procedures and corrective action should be taken. ”

31. 31 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.2 – 5.3 Complaints handling (cont'd) Complaints Procedure:  Designated responsible person: ä To handle complaint ä Decide on measure to be taken ä May be authorized person - if not, must advise authorized person of results ä Sufficient support staff ä Access to records  Written procedure (SOP): ä Describes action to be taken ä Includes need to consider a recall (e.g. possible product defect)

32. 32 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.4 – 5.6 Complaints handling (cont'd) Complaints Procedure – cont'd  Thorough investigation: ä QC involved ä With special attention to establish whether "counterfeiting" may have been the cause ä Fully recorded investigation – reflect all the details  Due to product defect (discovered or suspected): ä Consider checking other batches ä Batches containing reprocessed product

33. 33 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.7 – 5.9 Complaints handling (cont'd) Complaints Procedure – (cont'd)  Investigation and evaluation should result in appropriate follow- up actions ä May include a "recall"  All decisions and measures taken should be recorded  Referenced in batch records  Records reviewed - trends and recurring problems

34. 34 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 5.10 Complaints handling (cont'd) Other actions  Inform competent authorities in case of serious quality problems such as: ä Faulty manufacture ä Product deterioration ä Counterfeiting ä Have a thorough recall procedure that is fitting completely to the complaints handling procedure ä Keep track on trends in complaints, their investigations and results

35. 35 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Self-Inspection Purpose is to evaluate whether a company’s operations remain compliant with GMP  The programme should ä cover all aspects of production and quality control ä be designed to detect shortcomings in the implementation of GMP ä recommend corrective actions ä set a timetable for corrective action to be completed  Be performed routinely  Also on special occasions such as ä Recalls ä Repeated rejections ä When a GMP inspection is announced by the national drug regulatory authority 8.1

36. 36 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 8.3, 8.4 Self-Inspection (cont'd) The Self-Inspection Team  Team appointed by management, with: ä authority ä sufficient experience, expertise in their own field. knowledge of GMP ä may be from inside or outside the company  Frequency should normally be at least once a year ä May depend on company requirements ä Size of the company and activities

37. 37 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines 8.5, 8.6 Self-Inspection (cont'd) Carrying out a Self-Inspection  Report prepared at completion of inspection, including: ä results ä evaluation ä conclusions ä recommended corrective measures  Follow-up action ä Effective follow-up programme ä Company management to evaluate both the report and corrective actions

38. 38 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines Summary and conclusions:  GMP is mandatory in countries with a regulated pharmaceutical market, and in the WHO Prequalification Programme too.  GMP's are very similar, they are nothing but Good Common Sense  Good Practices cover all aspects of company's activities prior to sales  GMP is not a reward, nor an external assignment, it should be built into the company  Just like quality, which should be built into the product  The role and involvement of senior management is crucial  GMP means an urge for continuous improvement, 3 of the tools to do so are: ä Annual Product Quality Reviews ä Complaint handling and trending ä Self-inspection

39. 39 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification Programme: Priority Essential Medicines http://www.who.int/prequal