1. 2005.02.28. Dr. Pogány - WHO, Shanghai 1/62 Workshop on Quality Assurance and GMP of multisource HIV/AIDS medicines János Pogány, pharmacist, PhD, consultant to WHO Shanghai, 01 March 2005 E-mail: pogany@axelero.hupogany@axelero.hu WHO Prequalification Project Dossier Assessment

2. 2005.02.28. Dr. Pogány - WHO, Shanghai 2/62 Abbreviations and notes API(s)Active pharmaceutical ingredient(s) ARVAntiretroviral EOIExpression of interest FPP(s)Finished pharmaceutical product(s) ICHInternational Conference on Harmonization MLEMModel List of Essential Medicines Ph.Eur.European Pharmacopoeia Ph.Int.International Pharmacopoeia USPUnited States Pharmacopeia Text in green refers to WHO guidelines or requirements Text in yellow indicates an assessment issue

3. 2005.02.28. Dr. Pogány - WHO, Shanghai 3/62 Subjects for discussion 1.Which ARV FPPs are prequalified? 2.Prequalification data and information requirements for quality  WHO manuals, guides, EOI requirements  Prequalification guides Assessment of product dossiers Change control  ICH guides 3.Closing remarks

4. Which ARV FPPs are prequalified? 13th MODEL LIST OF ESSENTIAL MEDICINES and EXPRESSION OF INTEREST (January 2004)

5. 2005.02.28. Dr. Pogány - WHO, Shanghai 5/62 Nucleoside Reverse Transcriptase Inhibitors (NRTI) ABACAVIR DIDANOSINE (ddl)  buffered chewable, dispersible tablets 25 mg, 50 mg, 100 mg, 150 mg, 200 mg  buffered powder for oral solution 100 mg, 167 mg, 250 mg packets  unbuffered enteric coated capsule 125 mg, 200 mg, 250 mg, 400 mg LAMIVUDINE (3TC)  tablet, 150mg,  oral solution 50 mg/5ml

6. 2005.02.28. Dr. Pogány - WHO, Shanghai 6/62 Nucleoside Reverse Transcriptase Inhibitors (NRTI) STAVUDINE (d4T)  capsule 15mg, 20mg, 30mg, 40mg  powder for oral solution, 5mg/5ml TENOFOVIR ZIDOVUDINE (ZDV or AZT)  tablet, 300mg  capsule 100 mg, 250 mg  oral solution or syrup, 50mg/5ml  solution for IV infusion, injection 10 mg/ml in 20-ml vial

7. 2005.02.28. Dr. Pogány - WHO, Shanghai 7/62 Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) EFAVIRENZ (EFV or EFZ)  capsule, 50 mg, 100 mg, 200 mg  oral solution, 150 mg/5ml NEVIRAPINE (NVP)  tablet 200 mg  oral suspension 50 mg/5-ml

8. 2005.02.28. Dr. Pogány - WHO, Shanghai 8/62 Protease inhibitors (PI) INDINAVIR (IDV)  capsule, 200 mg, 333 mg, 400 mg (as sulfate) LOPINAVIR + RITONAVIR (LPV/r)  capsule, 133.3 mg + 33.3 mg  oral solution, 400 mg + 100 mg/5ml NELFINAVIR (NFV)  tablet, 250mg (as mesilate)  oral powder 50mg/g cont.

9. 2005.02.28. Dr. Pogány - WHO, Shanghai 9/62 Protease inhibitors (PI) RITONAVIR (r)  capsule, 100 mg  oral solution 400 mg/5ml SAQUINAVIR (SQV)  capsule, 200mg + Antibacterial and antimycobacterial agents, antiprotozoal agents, antiviral agents, antifungal agents and anti-cancer drugs listed in EOI5.

10. 2005.02.28. Dr. Pogány - WHO, Shanghai 10/62 Fixed-dose combinations (EOI)  LAMIVUDINE + STAVUDINE  LAMIVUDINE + ZIDOVUDINE  LAMIVUDINE + STAVUDINE + EFAVIRENZ  LAMIVUDINE + STAVUDINE + NEVIRAPINE  LAMIVUDINE + ZIDOVUDINE + EFAVIRENZ  LAMIVUDINE + ZIDOVUDINE + NEVIRAPINE

11. 2005.02.28. Dr. Pogány - WHO, Shanghai 11/62 Pillars of regulatory QA MANUFACTURING AUTHORIZATION DESIGN CONSTRUCTION AUTHORIZED PERSON OTHERS GMP & INSPECTION QUALITY ASSURANCE (QA) CONTAMINATION, ISSUES QUALIFICATION, VALIDATION OTHERS MARKETING AUTHORIZATION ANALYTICAL METHODS DEVELOPMENT PHARMACEUTICS COMPOSITION OF PIVOTAL BATCHES OTHERS

12. 2005.02.28. Dr. Pogány - WHO, Shanghai 12/62 Regulatory quality assurance  The former slide emphasizes an integrated approach to QA based on scientific risk management of the:  manufacturing authorization based on GMP design and construction,  marketing authorization (assessment of product dossiers), and  inspections,

13. 2005.02.28. Dr. Pogány - WHO, Shanghai 13/62 http://mednet3.who.int/prequal/  GMP : main principles for pharmaceutical products  GMP: starting materials  Active pharmaceutical ingredients (bulk drug substances)  Pharmaceutical excipients  GMP: specific pharmaceutical products  Sterile pharmaceutical products

14. 2005.02.28. Dr. Pogány - WHO, Shanghai 14/62 WHO GMP - General considerations Licensed pharmaceutical products (marketing authorization) should be manufactured only by licensed manufacturers (holders of a manufacturing authorization) whose activities are regularly inspected by competent national authorities, p.9.

15. What data and information needs to be submitted in a dossier for the assessment of a generic product? MULTISOURCE (GENERIC) FPPs

16. 2005.02.28. Dr. Pogány - WHO, Shanghai 16/62 EOI criteria for quality assessment  Valid manufacturer’s license for production  Product registered or licensed in accordance with national requirements  Products manufactured in compliance with GMP as certified by the national regulatory authority and/or certified GMP inspectors

17. 2005.02.28. Dr. Pogány - WHO, Shanghai 17/62 EOI criteria for quality assessment  Certificate of Pharmaceutical Product exist in accordance with the WHO certification scheme on the quality of pharmaceutical products moving in international commerce  Product dossiers of acceptable quality are to be submitted and assessed with regard to the pre- qualification requirements and approved  Outcome of the GMP inspection performed by or on behalf of WHO, UNICEF, UNAIDS and UNFPA

18. 2005.02.28. Dr. Pogány - WHO, Shanghai 18/62 http://mednet3.who.int/prequal/ Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: A Manual for a Drug Regulatory Authority (The so-called blue book) Regulatory Support Series, No. 5 WHO, Geneva, 1999

19. 2005.02.28. Dr. Pogány - WHO, Shanghai 19/62 Initial decisions on options for premarket evaluation by a NDRA Blue book, p. 21:  Prepare its own reports;  Rely on evaluation reports prepared by other national authorities;  Rely on decisions made by other national authorities;  Use some permutation of these approaches.

20. 2005.02.28. Dr. Pogány - WHO, Shanghai 20/62 Domestically manufactured products  If the FPP has been locally developed and manufactured, the national drug regulatory authority (NDRA) must evaluate the data set itself ( Blue book, p. 23 ).  If an evaluation report —critical summary and interpretation of the data, with conclusions— is not available, it is not possible to seek a WHO- type certificate ( Blue book, p. 23 ).

21. 2005.02.28. Dr. Pogány - WHO, Shanghai 21/62 Blue book, Annex 7: Detailed Advice on Evaluation of Data by the Drug Regulatory Authority Example: Specifications for the finished product, p.153 Provide a list of tests and limits for results for the finished product, including sufficient detail of test methods for them to be replicated by another laboratory. If the product is tested on the basis of a monograph in a pharmacopoeia, it is sufficient to provide a copy of the monograph together with any test methods referenced but not duplicated in the monograph. Provide details of any specifications additional to those in the pharmacopoeia. Provide both release and expiry limits for results. Provide the results of validation of the assay method for this formulation. For pharmacopoeial methods, provide data which demonstrate that the method is applicable to this formulation.

22. 2005.02.28. Dr. Pogány - WHO, Shanghai 22/62 http://mednet3.who.int/prequal/ 1.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 2.Guide on Requirements for Documentation of Quality pharmaceutical products manufactured in and approved by stringent drug regulatory authorities including inter alia EU, Japan and USA (not discussed in this presentation) 3.Other WHO guides 4.International Conference on Harmonization (ICH) guidelines

23. 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 Assessors’ Guide – Generic FPPs

24. 2005.02.28. Dr. Pogány - WHO, Shanghai 24/62 Section 1. CHARACTERISTICS OF THE FPP 1.1 Details of the product 1.1.1 Name, dosage form and strength of the product 1.1.2 Approved generic name(s) [use International Non- proprietary Name (INN), if any] 1.1.3 Visual description of the FPP 1.1.4 Visual description of the packaging 1.2 Sample 1.3 Regulatory situation in other countries

25. Section 2. Active Pharmaceutical Ingredients Separate presentation on Tuesday, 1 March 2005 Just one point...

26. 2005.02.28. Dr. Pogány - WHO, Shanghai 26/62 Tablet Manufacturing Starts with the Purification/Crystallization of API Isolation and purification of API Physical processing and packaging of API GranulationCompression

27. 2005.02.28. Dr. Pogány - WHO, Shanghai 27/62 Tablet Manufacturing Starts with the Purification/Crystallization of API Attributes with potential impact on processability:  existence/absence of polymorphs and water/solvent of crystallization/solvatation  particle size  bulk density (tapped and untapped)  flowability (flowing properties)  hygroscopicity

28. Section 3. Finished Pharmaceutical Products ILLUSTRATIVE EXAMPLES OF REQUIREMENTS

29. 2005.02.28. Dr. Pogány - WHO, Shanghai 29/62 Section 3. FPP(s) 3.1Manufacturing and marketing authorization 3.2 Pharmaceutical development 3.2.1Company research and development 3.2.2 Information from literature 3.3Formulation 3.4Sites of manufacture

30. 2005.02.28. Dr. Pogány - WHO, Shanghai 30/62 Pharmaceutical development This section should contain information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the purpose specified in the application. The studies described here are distinguished from routine control tests conducted according to specifications.

31. 2005.02.28. Dr. Pogány - WHO, Shanghai 31/62 Pharmaceutical development Illustrative examples:  Compatibility of APIs with each other [fixed-dose combinations (FDCs)]  A [discriminating (in the case of FDCs)] dissolution method should be developed and integrated in the quality control and stability programs  Packaging should be selected to ensure the quality of the FPP throughout its shelf life.

32. 2005.02.28. Dr. Pogány - WHO, Shanghai 32/62 Part 3. FPP(s) 3.5Manufacturing process 3.6Manufacturing Process Controls of Critical Steps and Intermediates 3.7Process Validation and Evaluation 3.7.1New generic FPPs 3.7.2Established generic FPPs

33. 2005.02.28. Dr. Pogány - WHO, Shanghai 33/62 Validation - new generic FPPs  The progress from pre-formulation → formulation → pilot manufacture → industrial scale manufacture should be shown in the dossier submitted for prequalification to be logical, reasoned and continuous.  Full validation studies should be completed for each FPP at the production scale.

34. 2005.02.28. Dr. Pogány - WHO, Shanghai 34/62 Validation - new generic FPPs  Short description of the process with a summary of the critical processing steps or critical parameters to be monitored during validation.  Interim in-process controls proposed with acceptance criteria.

35. 2005.02.28. Dr. Pogány - WHO, Shanghai 35/62 Validation - new generic FPPs  Additional testing, e.g., failure mode analysis, intended to be carried out  Sampling plan — where, when and how the samples are taken.  Details of methods for recording and evaluation of results.  Proposed timeframe.

36. 2005.02.28. Dr. Pogány - WHO, Shanghai 36/62 Validation – established generics Annual quality review data and analysis to prove that the manufacturing processes —including equipment, buildings, personnel and materials— are capable of achieving the intended results on a consistent and continuous basis.

37. 2005.02.28. Dr. Pogány - WHO, Shanghai 37/62 Part 3. FPP(s) 3.8Specifications for excipients 3.8.1Excipients not described in Int.Ph., JP, BP, Ph.Eur., or USP 3.8.2Excipients described in Int.Ph., JP, BP, Ph.Eur., or USP 3.9Control of the FPP 3.9.1Specifications for the FPP 3.9.2 Analytical procedures 3.9.3 Validation of analytical procedures 3.9.4 Batch analysed 3.10Container/closure system(s) and other packaging

38. 2005.02.28. Dr. Pogány - WHO, Shanghai 38/62 Specifications for the FPP Illustrative issues:  The maximum acceptable deviation in the API content of the FPP shall not exceed ±5% of the label claim at batch release.  Degradation products, synthesis impurities (typically not applicable) and residual solvents (rarely applicable).  Dissolution versus disintegration time.  All analytical methods should be validated or verified (system suitability).

39. 2005.02.28. Dr. Pogány - WHO, Shanghai 39/62 Part 3. FPP(s) 3.11Stability testing 3.11.1 Stability-indicating quality parameters 3.11.2 Photostability Testing 3.11.3 Selection of Batches 3.11.4 Container Closure System 3.11.5 Testing Frequency 3.11.6 Storage Conditions 3.11.7General case 3.11.8Finished products packaged in impermeable containers 2.11.9Finished products packaged in semi-permeable containers 2.11.10Evaluation 2.11.11Extrapolation of data 2.11.12Core Storage Statements

40. 2005.02.28. Dr. Pogány - WHO, Shanghai 40/62 Stability of FPPs  Characteristics studied should be those in the FPP specification that are likely to be affected by storage and/or not monitored routinely at the time of manufacture.  Analytical procedures should be fully validated and stability indicating. Whether and to what extent replication should be performed will depend on the results of validation studies.  It may be appropriate to have justifiable differences between the shelf life and release acceptance criteria based on the stability evaluation and the changes observed on storage.

41. 2005.02.28. Dr. Pogány - WHO, Shanghai 41/62 Stability of FPPs  A systematic approach should be adopted in the presentation and evaluation of the stability information, which should include, as appropriate, results from the physical, chemical, biological and microbiological tests, including particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms, hardness, LOD, etc.).  An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 ± 2 o C / 60 ± 5 % RH (2 years) and 40 ± 2 o C / 75 ± 5 % RH (6 months).

42. 2005.02.28. Dr. Pogány - WHO, Shanghai 42/62 Part 3. FPP(s) 3.12Container labelling 3.12.1 Outer packaging or, where there is no outer packaging, on the immediate packaging 3.12.2 Blisters and strips 3.13Product information for health professionals 3.14Patient information and package leaflet 3.15Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s).

43. 2005.02.28. Dr. Pogány - WHO, Shanghai 43/62 Labelling - blisters and strips  Name, strength and pharmaceutical form of the FPP  Name of the manufacturer, company or person responsible for placing the product on the market.  The batch number assigned by the manufacturer.  The expiry date in an uncoded form.

44. 2005.02.28. Dr. Pogány - WHO, Shanghai 44/62 WHOPAR  Propose a copy of the Summary of Product Characteristics (SmPC) aimed at medical practitioners and other health professionals and approved by the competent authority at the time of licensing. The SmPC is an essential part of pre- qualification and it can only be changed with the consent of WHO.  Provide copies of all package inserts distributed to the patients. The package leaflet should be in conformity with the SmPC. It should be written in English, should be legible and comprehensible.

45. Other WHO guides on quality of FPPs AN ILLUSTRATIVE EXAMPLE

46. 2005.02.28. Dr. Pogány - WHO, Shanghai 46/62 Animal Spongiform Encephalopathy Agents Products with risk of transmitting agents of animal spongiform encephalopathies are those derived from tissues or secretions of animals susceptible to transmissible spongiform encephalopathies. This definition applies to all substances or preparations obtained from such animals and to all substances or preparations where products obtained from such animals are included as active substances or excipients or have been used during production, e.g. as raw or source materials, starting materials or reagents. WHO Technical Report Series, No. 908, 2003

47. International Conference on Harmonization guides AN ILLUSTRATIVE EXAMPLE

48. 2005.02.28. Dr. Pogány - WHO, Shanghai 48/62 Impurities in New Drug Products -Q3B(R) Illustrative excerpts:  This guideline addresses only those impurities in new drug products classified as degradation products of the API or reaction products of the API with an excipient and/or immediate container.  Generally, impurities present in the API need not be monitored or specified in the FPP unless they are also degradation products.  The specification for a FPP should include a list of degradation products expected to occur during manufacture of the commercial product and under recommended storage conditions.

49. Guidance on variations in a dossier submitted within the prequalification program GENERAL OVERVIEW

50. 2005.02.28. Dr. Pogány - WHO, Shanghai 50/62 Minor changes  MINOR CHANGE is a change concerning an amendment to the contents of the documents such as they existed at the time when the product was listed as prequalified.  PRIOR EVALUATION of the submitted documentation amended as a result of the variation is required for minor changes.  41 minor changes are listed in the document.

51. 2005.02.28. Dr. Pogány - WHO, Shanghai 51/62 Example of minor change: Replacement or addition of a manufacturing site for part or all of the manufacturing process of the FPP – cont. Conditions  Site appropriately authorised by the relevant competent authority for the packaging or manufacturing of the pharmaceutical form and product concerned.  New site must be approved by WHO as complying with WHO GMP, a satisfactory inspection of the manufacturing site has been performed in the last three years by WHO or a competent authority of a ICH region country.  Product concerned is not a sterile product.  Validation scheme is available or validation of the manufacture at the new site has been successfully carried out according to the current protocol with at least three production scale batches.

52. 2005.02.28. Dr. Pogány - WHO, Shanghai 52/62 Example of minor change: Replacement or addition of a manufacturing site for part or all of the manufacturing process of the FPP – cont. Documentation  Proof that the proposed site is authorised by the relevant competent authority as complying with WHO GMP within the prequalification project for the packaging or manufacturing of the pharmaceutical form and product concerned.  The batch numbers of not less than 3 batches used in the validation study should be indicated and related validation protocol (scheme) to be submitted.  The variation application should clearly outline the “present” and “proposed” finished product manufacturers.

53. 2005.02.28. Dr. Pogány - WHO, Shanghai 53/62 Example of minor change: Replacement or addition of a manufacturing site for part or all of the manufacturing process of the FPP – cont. Documentation  Copy of approved release and end-of-shelf life specifications.  Batch analysis data on three production batches and comparative data on the last three batches from the previous site.  For semisolid and liquid formulations in which the API is present in non-dissolved form, appropriate validation data including microscopic imaging of particle size distribution and morphology.

54. 2005.02.28. Dr. Pogány - WHO, Shanghai 54/62 Example of minor change: Replacement or addition of a manufacturing site for part or all of the manufacturing process of the FPP Documentation  For solid dosage forms a comparative dissolution test data on the last 3 batches from the previous site and the 3 first batches for the new site including not less than 6 time points should be provided.  Statement as when the change will be effective should be submitted.  Submit updated section 3.4 of the product dossier.

55. 2005.02.28. Dr. Pogány - WHO, Shanghai 55/62 Major change A MAJOR CHANGE is a change to the documentation which can neither be deemed to be a minor variation within the meaning of preceding definition (therefore exceeding the frame of a minor change) nor to be a change for which the submission of a new application would be necessary.

56. 2005.02.28. Dr. Pogány - WHO, Shanghai 56/62 Major changes  Change in the manufacturing process of the API  Change in the composition of the finished product  Change of immediate packaging of the FPP

57. 2005.02.28. Dr. Pogány - WHO, Shanghai 57/62 New dossier Certain changes are so major that they are considered to fundamentally alter the terms of a prequalification and consequently cannot be considered as a change. For these changes a new dossier must be submitted.

58. 2005.02.28. Dr. Pogány - WHO, Shanghai 58/62 New dossier Changes to the API (self-evident examples):  Change of the API to a different API  Inclusion of an additional API to a multi- component product  Removal of one API from a multi- component product  Change in the dose of one or more APIs

59. 2005.02.28. Dr. Pogány - WHO, Shanghai 59/62 New dossier Changes to the pharmaceutical dosage form:  Change from an immediate release product to a slow- or delayed-release dosage form and vice versa  Change from a liquid to a powder for reconstitution, or vice versa  Changes in the route of administration

60. 2005.02.28. Dr. Pogány - WHO, Shanghai 60/62 Additional stability studies In all cases of changes the supplier of the dossier has to investigate whether or not the intended change will have an impact or not on the quality of the API and the FPP and consequently on their stability. For all changes that require the generation of stability data, the first three production scale batches manufactured following notification/approval of the change should be placed on long term stability testing using the same stability testing protocols as described in the assessment guide. The results of the stability studies when available should be submitted within the prequalification program.

61. 2005.02.28. Dr. Pogány - WHO, Shanghai 61/62 Main points again 1. Only ARV FPPs included in MLEM and EOI are prequalified. 2. WHO manuals and guides were prepared with well-established, compendial, multisource FPPs in mind but ARV FPPs rarely meet these criteria. 3. Prequalification guides permit the assessment of non-compendial, multisource FPPs, as well. 4. ICH guidelines are used, when a quality issue cannot assessed by WHO guides. 5. Changes to prequalified FPPs are also controlled in the evaluation process.

62. 2005.02.28. Dr. Pogány - WHO, Shanghai 62/62 THANK YOU 谢谢 !