1. Prequalification Programme: Priority Essential Medicines QUALITY, GOOD MANUFACTURING PRACTICE AND BIOEQUIVALENCE WITH A FOCUS ON ANTITUBERCULOTICS 5-9 November 2007 Jiaxing, China 1

2. 2 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification Programme: Priority Essential Medicines Presented by: Dr A J van Zyl 安德李 Technical Officer WHO HTP/PSM/QSM vanzyla@who.int

3. 3 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals In this presentation… n Why prequalification? What is prequalification? How does it work? n Steps in prequalification n Norms and standards used n Evaluations (dossiers and site inspections) n Outcome of assessment n Capacity building and improvements

4. 4 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Quality of medicines remains a problem in many countries n Oct 2006. Panama: More than 30 died - cough syrup containing diethylene glycol – industrial solvent (in antifreeze) – kidney failure n 1999. Belgium: Two babies died. Injected KCl (supposed to be glucose) n 2000. USA: 17 children died. No active ingredient in inhalers ä Picture. New York Times 2007 ä Death by GMP: MH Anisfeld. GMP Review. Vol 4 No 4 2006

5. 5 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals What is WHO doing to help the countries? n Normative functions – setting norms and standards ä Including GMP n Capacity building n Prequalification Programme: Priority Essential Medicines ä "Three in one" – more tuned to real public health problems, immediate feedback, better quality, higher efficiency

6. 6 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification of essential medicines The UN prequalification program:  Is an action plan for expanding access to medicines for patients with:  HIV/AIDS  Tuberculosis  Malaria  And access to Reproductive Health Products  Ensures quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM)

7. 7 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals How is prequalification organized?  Role of WHO: Managing and organizing the project on behalf of the United Nations. Provides technical and scientific support Ensures that international norms and standards are applied all through the process including assessment, inspection (GMP, GCP, GLP) and quality control  Partners: UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department  Actors: Mainly qualified assessors and inspectors from National DRAs (also from National Quality Control Laboratories) of ICH and associated countries, and inspectorates belonging to PIC/S

8. 8 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

9. 9

10. 10 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals I Expression of Interest Product dossier SMF Compliance Additional information and data Corrective actions Compliance Assessment Inspections Steps in prequalification Prequalification Monitoring

11. 11 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Quality Assurance (QA) of WHO prequalification process PQ team has its own Quality Assurance system:  Quality Assurance and Safety: Medicines (QSM)  Standard Operating Procedures (SOPs)  Manuals and guidelines  General Procedure for Prequalification  Norms and standards (product dossiers, manufacturers etc)

12. 12 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Product dossier assessment

13. 13 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Anti-Tuberculosis Products 7th Invitation to manufacturers of antituberculosis medicines to submit an Expression of Interest (EOI) for product evaluation to the WHO Prequalification Programme (June 2007) Interested manufacturers are encouraged to submit documentation for recommended dosage forms and strengths, as specified below, of medicinal products in the following categories. 1. Single ingredient first-line antituberculosis medicines - Ethambutol, tablet 400 mg - Isoniazid, tablet 300 mg - Pyrazinamide, tablet 400 mg - Rifampicin, capsule 150 mg; 300 mg - Streptomycin, powder for injection 1g (vial) 2. Fixed dose combination products of first-line antituberculosis medicines - Isoniazid + Rifampicin, tablet 75 mg + 150 mg; tablet 150 mg + 150 mg - Ethambutol + Isoniazid, tablet 400 mg + 150 mg - Ethambutol + Isoniazid + Rifampicin, tablet 275 mg + 75 mg + 150 mg - Ethambutol + Isoniazid + Pyrazinamide + Rifampicin, tablet 275 mg + 75 mg + 400 mg + 150 mg

14. 14 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Anti-Tuberculosis Products 3. Single ingredient second-line antituberculosis medicines - Amikacin, 250 mg/ml (vial 2 ml, 4 ml); powder for injection 1g (vial) - Capreomycin, powder for injection 1g (vial) - Cycloserine, capsule 250 mg - Ethionamide, coated tablet 125 mg; 250 mg - Kanamycin, powder for injection 1g (vial) - Levofloxacin, tablet 250 mg - Moxifloxacin, tablet 400 mg - Ofloxacin, tablet 200 mg; 400 mg - Prothionamide, coated tablet 250 mg - P-aminosalicylic acid, granules 4g - P-aminosalicylic sodium, granules 100 g 4. Scored solid dosage formulations for children, preferably dispersible - Ethambutol, tablet 100 mg - Isoniazid, tablet 50 mg; 100 mg - Isoniazid + Rifampicin, tablet 60 mg + 60 mg; tablet 30 mg + 60 mg - Isoniazid + Pyrazinamide + Rifampicin, tablet 30 mg + 150 mg + 60 mg - Pyrazinamide, tablet 150 mg

15. 15 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Evaluation procedure  Assessment of product dossiers (Quality specifications, pharmaceutical development, production, control, stability, bioequivalence etc).  Teams of professionals from national Drug Regulatory Authorities (DRA): Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe...  Copenhagen assessment week 8 to 20 assessors together during one week at least every two months at UNICEF in Denmark Every dossier is assessed by at least four assessors. An assessment report is issued - signed by assessors Letter summarizing the findings and asking for clarification and additional data if necessary Letter is sent first by e-mail to the applicant followed by surface mail

16. 16 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Assessment procedure- Product dossiers  Innovator products Abridged procedure if approved by stringent authorities like EMEA and US FDA Assessment reports from Drug Regulatory Authorities (DRSs), WHO Certificate of Pharmaceutical Product (CPP), batch certificate, update on changes Trusting scientific expertise of well-established DRAs  Multisource (generic) products  Full dossier with all the data and information requested Quality: Information on starting materials and finished product, including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc Efficacy and safety: Bio-equivalence study or clinical study report  Commercial sample  Requested, but not always analysed before prequalification. US FDA tentative approvals for ARVs – recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO); the same approach will soon apply for EU Art58 and Canadian JCPA procedure)

17. 17 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification: generics and not generics n Generic medicines: 1. To contain the same active ingredients as the innovator drugs as the innovator drug 2. To be identical in strength, dosage form, and route of administration 3. To have the same indications for use 4. To meet the same batch requirements for identity, strength, purity and quality 5. To be manufactured under the same strict standards of GMP required for innovator products. 6. To be bio-equivalent n Prequalification requirements for generics ä Fully in line with major regulatory agencies n What if not generics ä Full data to prove safety (including preclinical toxicology) and efficacy has to be presented n Not all non-innovator products in prequalification pipeline can be defined as generics – no innovator may be available l See also FDA requirements for generic drugs (www.fda.gov/cder/ogd)www.fda.gov/cder/ogd

18. 18 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Norms and standards used

19. 19 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

20. 20 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification: where the technical documents come from? n International consultation process n The WHO Expert Committee – review and adopts n Executive Board n World Health Assembly n Printed in respective TRS and WHO web site

21. 21 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

22. 22 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

23. 23 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

24. 24 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Publications 2005/2006 n New, user friendly prequalification web site launched in November 2006: http://who.int/prequal/ n Articles: ä 1. Prequalifi cation of medicines. WHO Drug Information, 2005, 19:1. ä 2. WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2. ä 3. Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalifi cation Programme. Journal of Generic Medicines, 2006, 3(2):96–105.

25. 25 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems encountered with product dossiers n General ä HIV/AIDS: Initially – few monographs (Official Pharmacopoeia) ä Malaria - very few innovator products, many not typical generics as well l Very few antimalarials approved in ICH and associated countries ä Limited DRAs and regulatory experts having experience ä Fixed dose combinations more complicated than single component products ä TB: Old products, low profits – lack of data meeting current requirements n General Quality related issues ä Manufacturers do not comply with GMP ä Products not controlled - registered and produced only for export ä Lack of specifications or poorly defined manufacturers specifications ä Stability data missing or not meeting requirements ä No method validation etc. l Mostly manufacturers can overcome these problems if motivated. However, it may take a lot of time

26. 26 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems encountered with product dossiers n Lack of reference products for bioequivalence studies ä For generic products: Bioequivalence studies to show the same blood concentrations (assume same safety and efficacy profile) ä Often unclear which comparator product to be used ä BE not a requirement in all countries n Safety and efficacy related issues ä Insufficient data submitted l Incomplete protocols and trial reports l Incomplete evaluation of published literature ä No characterisation of pharmacokinetic properties of the product ä General statements made: No interaction known (clearly not true); No (or minimal) adverse events (literature survey if no original data) ä Too broad efficacy claims ä Galenical development history not provided

27. 27 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Inspection of sites

28. 28 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Inspections: n Team of inspectors for each inspection n WHO PQ inspector plus PIC/S member country plus local country inspector (observer) n Some cases – capacity building (recipient country) n Preparation includes SMF, product information, inspection reports, complaints etc n APIs, Finished products n Clinical studies: Mostly Bioequivalence studies (generic products

29. 29 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Inspections: Assess compliance with WHO norms and standards: n GMP n GCP n GLP n GSP n GDP… n Organizations conducting clinical trials n WHO training materials

30. 30 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Where are the inspections performed? n India, Bangladesh, Pakistan n China n Belgium n Canada n Malaysia n France n South Africa n Switzerland n United States n Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda …

31. 31 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Inspections: Production and control activities: n Normally over 3 days n Covers all aspects of GMP ä Quality management, Quality assurance, Premises, Equipment, Documentation, Validation, Materials, Personnel, Utilities (e.g. HVAC, water)... n Also data verification (dossier) including stability data, validation (process), development batches and bio batches n Quality control laboratory – specifications, reference standards, methods of analysis, validation and qualification...

32. 32 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Inspections: n Bio-equivalence studies ä GCP and GLP n About 2 days per study including n Clinical part ä Clinic, Pharmacy and related areas, data verification n Bio-analytical part ä Laboratory and data verification n Statistical analysis

33. 33 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems identified in GMP inspections: Various including validation, ventilation, equipment, quality risk management… n Validation and qualification work was often incomplete n Validation Master Plans (VMP) lacked details n Validation policies as defined in the VMPs were not implemented n Process validation was lacking n Validated procedures (e.g. environmental monitoring) were lacking

34. 34 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems identified in GMP inspections: n No URS for HVAC, water and computer systems n Incomplete (not detailed) or "no" qualification of HVAC / water / computers n Insufficient filtration of air to production areas n No prevention of possible cross-contamination and contamination. n No authorized schematic drawings n "As built" AHUs lacked components reflected in the schematic drawings, including filters n Temperature and RH mapping studies incomplete, or results not applied n HVAC systems not controlled or monitored n Filters: ä not planned, classified, tested (including installed filter leakage test), monitored n Pressure differential gauges not controlled, including calibration and zero checks

35. 35 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems identified in GMP inspections: n Wrong sequence of components (e.g. after filtration) n Inappropriate AHU for equipment ä e.g. coaters, FBD ä Claim "wet scrubbers" – but not functional n Inappropriate change control n No quality risk management documented

36. 36 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems identified in GCP inspections: n Volunteers ä Number of volunteers in a study ä No control for participating in several studies in a short period ä Supportive documentation – DOB, identification, ECGs ä Screening ä ICF n Ethics committee ä Independence ä Supportive documentation n Clinic n Archives n Pharmacy ä Documentation, randomization, dispensing n CRFs n Analytical method validation n Stability (stock solutions, samples) n Source data including chromatograms

37. 37 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Outcome

38. 38 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Transparency: WHO Public Inspection Reports

39. 39 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

40. 40 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

41. 41 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals

42. 42 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Increased transparency about the "pipeline"

43. 43 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Outcome  List of prequalified products New and revised guidelines, norms and standards Monographs International Chemical Reference standards Sampling and testing of products on the market Training Capacity building... See also Annual Report

44. 44 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals List of prequalified products Disease2001200220032004200520062007 HIV/ AIDS ……………25 (excluding US FDA, Canada) 19 (excluding US FDA) TB…(5)2104 Malaria02303

45. 45 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Monitoring…  Ongoing assessments and follow-up Products Manufacturing sites (both for APIs and finished dosage forms) CROs Sampling and testing Data verification inspections

46. 46 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Since 2005: PQ Annual report

47. 47 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals n Capacity building and improvement

48. 48 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Capacity building of DRAs and Manufacturers n Both remain important components and need strengthening n Both need improvement and new approaches n From 2006 - in addition - provide (to selected manufacturers): Technical Assistance

49. 49 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Measures taken to get more products prequalified n Action taken... ä Formerly very limited resources vs huge obligations and scope l Initially only ONE professional - today at least 15 (including 4 secondments from Governments such as France and China) ä Business plan and funding proposals – now funds received (Gates) and (UNITAID) ä Internal SOPs and work procedures ä "Note for Applicants" (anti-malaria products) ä New regulatory guidance documents created and started ä Specific guidance on comparator products ä More direct discussions with manufacturers started ä Regulatory advice on complicated cases including BE ä Pharmaceutical development, technology transfer, paediatric formulations "Notes to consider"

50. 50 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Measures taken to get more products prequalified n Action taken (2)... ä Additional funding (e.g. Gates, UNITAID) ä Additional training workshops ä Additional staff to be recruited ä Communication to be improved l Regulators l Manufacturers l Donors and partners ä More proactive approach towards potential suppliers – new elements l Regulatory advice l Technical assistance ä Strengthening links with WHO regions ä Taylor made approach to different regions ä Building capacity in countries

51. 51 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Alternative regulatory pathways n USA FDA tentative approvals linked to PEPFAR ä Included in WHO PQ List ä Confidentiality agreement with US FDA in place n EU Article 58 ä For products exclusively to be used outside EU n Canadian Access to medicines scheme ä WHO cooperation with the above mentioned ä Confidentiality agreement in preparation

52. 52 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 谢谢