Workshop on Quality Assurance and GMP of Multisource HIV /AIDS medicines

1. János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March 2005 E-mail: pogany@axelero.hu Workshop on Quality Assurance and GMP of Multisource HIV/AIDSmedicines QUALIFICATION and VALIDATION I. Dr. Pogány - WHO, Shanghai

2. Subjects for Discussion • Regulatory background, definitions • Characteristics of processes • Validation master plan (VMP) • Pharmaceutical manufacturing process validation (tablet-making) • Concluding remarks Dr. Pogány - WHO, Shanghai

3. WHO GMP and Guidelines • Guideline on Submission of Documentation for Prequalification of Multi-source (Generic)Finished Pharmaceutical Products (FPPs)Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis. • WHO good manufacturing practices (GMP): main principles for pharmaceutical products – Section 4. Validation of manufacturing processes. • Supplementary guidelines ongood manufacturing practices(GMP):Validation (2003) – Draft. Dr. Pogány - WHO, Shanghai

4. Qualification • QUALIFICATIONis the „Action of proving that any premises, (pharmaceutical utility) systems and items of equipmentwork correctly and actually lead to the expected results. The meaning of the word “validation” is sometimes extended to incorporate the concept of „qualification”. • REQUALIFICATIONis the main part of the preventive maintenance programme of proving that any premises,(pharmaceutical utility) systems and items of equipmentwork correctly and keep on leading to the expected results.(normal wear and tear) Dr. Pogány - WHO, Shanghai

5. Validation • VALIDATIONis the „Action of proving, in accordance with the principles of GMP, that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually leads to the expected results (see also qualification)”. • REVALIDATION is a part of the change control system of proving that any procedure, process, equipment, material, activity or (pharmaceutical utility) system actually keeps on leading to the expected results. Dr. Pogány - WHO, Shanghai

6. Qualification - Validation Regulatory requirements DQ,IQ,OQ inputs DQ,IQ,OQ process DQ,IQ,OQ outputs Process Qualification Verification Validation Premises, equipment and supporting utilities must be qualified to operate in a validated process. Dr. Pogány - WHO, Shanghai

7. Technical pharmacy • Pharmaceutical production system (from purchasing API to packaging FP) • Utility support system (HVAC, water, HPLC, etc. equipment containing many items) • Process (tablet making) • (Unit) operation(granulation, compression) • Step(sifting, sizing) • Procedure, method, technique(SOP) Dr. Pogány - WHO, Shanghai

8. 4.10 Scientific approach • „Processes and procedures should be established on the basis of the results of the validation performed.” Objectives • To prove that the tests, measurements, results and interpretation of formal studies on (manufacturing) processes and procedures/methods are appropriate and accurate. • To stabilize new processes (to reduce variability, to increase batch to batch consistency of quality attributes of products). • To reduce defect levels (standardize yields). • To reduce production costs. Dr. Pogány - WHO, Shanghai

9. Measure of variation (spread of data) 68.26% 95.46% Dr. Pogány - WHO, Shanghai

10. Mean (average) chart Abnormal variation of process – special causes UCL Upper control limit Normal variation due to common causes average = mean LCL Lower control limit Abnormal variation of process – special causes Dr. Pogány - WHO, Shanghai

11. Causes of variation • Man (different operators - lack of proper training) • Machine / equipment (variation of tablet weight) • Measurement (lack of calibration) • Method (accuracy of validated analytical methods) • Material (batch-to-batch variation of the same crystal form – different crystal forms (ASA)] • Environment (OoS T and RH in capsule filling) Dr. Pogány - WHO, Shanghai

12. Process under control • Mostpoints fall near the central line (68% within one σ) • A few points fall near the control limits (5% in the third σ) • Points shold balance on both sides of the mean • Points should cross the mean line often. • Points should show a random pattern (no trends, cycles, clustering) Dr. Pogány - WHO, Shanghai

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15. UNDER CONTROL OUT OF CONTROL Dr. Pogány - WHO, Shanghai

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18. Innovator FPPs Well-established, multisource, generic FPPs Dr. Pogány - WHO, Shanghai

19. VALIDATIONSTARTS WITH DESIGN + CONSTRUCTION OF FACILITIESAND PURCHASING EQUIPMENT GMP, QUALIFICATION and Dr. Pogány - WHO, Shanghai

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21. VALIDATION MASTER PLAN (VMP) ILLUSTRATIVE ISSUES

22. 4.1-4.2 Validation master plan • „In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled. • The key elements of a qualification and validation programme of a company should be clearly defined and documented in avalidation master plan (VMP).” Dr. Pogány - WHO, Shanghai

23. Project oriented VMP • Construction of new premises • Major renovation or additions to existing premises • First time validationof previously unvalidated processes (ARV FPPs) • Automation or computerized implementations that span a number of applications Dr. Pogány - WHO, Shanghai

24. Validation master plan • The VMP is a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as • Policy Documents (Quality Manual), • SOP's and • Validation Protocols/Reports. Dr. Pogány - WHO, Shanghai

25. Content of VMP • Approval (top management and all participating departmental heads) • Scope [separate VMPs for manufacturing processes, pharmaceutical utility systems (e.g. HVAC, water)]. • Responsibilities • Production and QCpremises (including controlled environments) • Process and QCequipment • Pharmaceutical air (HVAC) and water systems Dr. Pogány - WHO, Shanghai

26. Content of VMP • All critical utilities(such ascompressed air, steam and cooling liquids) • Computer control systems • Manufacturing processes • Product specifications including prospective IPC acceptance criteria • QC and IPC methods Dr. Pogány - WHO, Shanghai

27. Content of VMP • Equipmentcleaning • Validationrequirements • Workerandenvironment safety • Change Control/Revalidation • Training requirements • Documentationrequirements • Security plans Dr. Pogány - WHO, Shanghai

28. DESIGN,INSTALLATION and OPERATION QUALIFICATION

29. 4.3 Documentary evidence (a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (designqualification or DQ); (b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installationqualification or IQ); Dr. Pogány - WHO, Shanghai

30. DQ and IQ • DQ protocols and reports • GMP • VMP • National law • Engineering design and construction documents Do not start IQ before DQ has been completed! • IQ/OQ protocols and reports • Above inputs + machine manuals • Separate VMPsfor HVAC and water systems Do not start OQ before IQ has been completed! Dr. Pogány - WHO, Shanghai

31. 4.3 Documentary evidence (c) the premises, supporting utilities and equipment operate in accordance with their design specifications (operational qualification or OQ); (d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance qualification or PQ). Dr. Pogány - WHO, Shanghai

32. Tablets Workshop on Quality Assurance and GMP of Multisource HIV/AIDSmedicines MANUFACTURING PROCESS VALIDATION Dr. Pogány - WHO, Shanghai

33. Risks in manufacturing processes • Small quantity of waste creates serious danger to health(1/3 of 5% dextrose infusion was not sterile, Evans Medical, 1972) • Low chance that patient or doctor recognizes non-conformance to specification in time (DEG in glycerol,1996 -Haiti) • Limitations of sampling • Percent of nonconformance: 0,1 1,0 5,0 10,0 • Percent probability of release: 98 82 36 12 Dr. Pogány - WHO, Shanghai

34. SAMPLING PROBLEM The whole batch is released to the patient But only the sample is tested BATCH Sample Dr. Pogány - WHO, Shanghai

35. Types of process validation EXPERIMENTAL APPROACH PROSPECTIVE VALIDATION (R&D) CONCURRENT VALIDATION (FIRST ≥3 BATCHES) ANALYSIS OF HISTORICAL DATA RETROSPECTIVE VALIDATION (DIFFERS CONCEPTUALLY FROM THE EXPERIMENTAL APPROACH) Dr. Pogány - WHO, Shanghai

36. 4.4 What should be validated? „Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.” Dr. Pogány - WHO, Shanghai

37. 4.8-4.9 Protocols and reports • Validation studies are an essential part of GMP and should be conducted in accordance with predefined and approved protocols. • A written report summarizing the results recorded and the conclusions reached should be prepared and stored. Dr. Pogány - WHO, Shanghai

38. Essential parts of the process validation protocol • Short description of the process with a summary of the critical processing steps or critical parameters to be monitored during validation. • Additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical validation as appropriate). • Sampling plan — where, when, how and how many samples are taken. • Details of methods for recording and evaluation of results. Dr. Pogány - WHO, Shanghai

39. Illustrative variables of wet granulation Dr. Pogány - WHO, Shanghai

40. Illustrative variables of wet granulation Dr. Pogány - WHO, Shanghai

41. Illustrative variables of compression and film-coating Dr. Pogány - WHO, Shanghai

42. Illustrative variables of tablet packaging Dr. Pogány - WHO, Shanghai

43. Validation batches • Process validation reports should be submitted in the application forprequalification. • Formal studies of production scale batches (not less than three) are required to identify the critical variables. • Provisional equipment control parameters and the corresponding in-process acceptance criteria must be deduced from the results of experiments with the validation batches. • Critical parameters are to be monitored, non-critical ones should be tested occasionally. Dr. Pogány - WHO, Shanghai

44. 4.5-4.7 Validation policy • Qualification and validation should not be considered as one-off exercises. An on-going programme should follow their first implementation and should be based on an annual review. • The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan. • The responsibility of performing validation should be clearly defined. Dr. Pogány - WHO, Shanghai

45. Process approach CONTINUOUS IMPROVEMENT OF THE QUALITY MANAGEMENT SYSTEM CUSTOMER SATISFACTION CUSTOMER Management responsibility REQUIREMENTS Resource management Monitoring, improvement Manufacture Product Inputs Dr. Pogány - WHO, Shanghai

46. Annual FPP quality review (1) • Starting materials used in the product, especially those from new sources. • Critical in-process controls and finished product results. • All batches that failed to meet established specification(s). • All critical deviations or non-conformances and related investigations. • All changes carried out to the processes or analytical methods. • Marketing Authorisation variations submitted, or granted, or refused, including those for third country dossiers. Dr. Pogány - WHO, Shanghai

47. Annual FPP quality review (2) • Results of the stability monitoring programme. • All quality-related returns, complaints and recalls, including export only medicinal products. • Adequacy of previous corrective actions. • For new marketing authorisations, a review of post-marketing commitments. • A list of validated procedures and their revalidation dates. • A list of qualified equipment, support utility systems and their requalification dates, including calibrationprograms. Dr. Pogány - WHO, Shanghai

48. Case summary of 20 batches (1) Dr. Pogány - WHO, Shanghai

49. Case summaryof 20 batches (2) • Acceptance criteria for assay and dissolution rate are loose and should be tightened. • Potential degradation products were not tested. • IPC data were not included in the retrospective analysis of batch records. • Failures were not reported, etc. Dr. Pogány - WHO, Shanghai

50. 4.11 Analytical methods, computers and cleaning procedures • It is of critical importance that particular attention is paid to the validation of analytical test methods, automated systems and cleaning procedures. Dr. Pogány - WHO, Shanghai