Prequalification Programme: Priority Essential Medicines

1. Prequalification Programme: Priority Essential Medicines Training Workshop on Pharmaceutical Development with a focus on Paediatric Formulations 15 October 2007 Tallinn, Estonia Dr A J van Zyl Technical Officer HTP/PSM/QSM World Health Organization (WHO) Geneva, Switzerland vanzyla@who.int 1

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

3. What is WHO doing to help the countries? • Normative functions – setting norms and standards • Including GMP • Capacity building • Prequalification Programme: Priority Essential Medicines • "Three in one" – more tuned to real public health problems, immediate feedback, better quality, higher efficiency

4. In this presentation… • What is "prequalification" and how does it work • Steps in prequalification • Norms and standards used • Evaluations (dossiers and site inspections) • Outcome of assessment • Capacity building and improvements

5. 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)

6. How prequalification is 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

9. Steps in prequalification I Expression of Interest Product dossier SMF Assessment Inspections Additional information and data Corrective actions Compliance Compliance Prequalification Monitoring

10. 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)

11. Product dossier assessment

12. Reproductive Health Products

13. 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

14. 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)

15. Prequalification: generics and not generics • 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 • Prequalification requirements for generics • Fully in line with major regulatory agencies • What if not generics • Full data to prove safety (including preclinical toxicology) and efficacy has to be presented • Not all non-innovator products in prequalification pipeline can be defined as generics – no innovator may be available • See also FDA requirements for generic drugs (www.fda.gov/cder/ogd)

16. Norms and standards used

18. Prequalification: where the technical documents come from? • International consultation process • The WHO Expert Committee – review and adopts • Executive Board • World Health Assembly • Printed in respective TRS and WHO web site

22. Publications 2005/2006 • New, user friendly prequalification web site launched in November 2006: http://who.int/prequal/ • Articles: • 1. Prequalifi cation of medicines. WHO DrugInformation, 2005, 19:1. • 2. WHO and its Prequalification Programme:an Overview. WHO Pharmaceuticals Newsletter,2005, No. 2. • 3. Dekker TG, van Zyl AJ, Gross O, Tasevska I,Stahl M, Rabouhans ML, Rägo L. Ongoingmonitoring of antiretroviral products as part ofWHO’s Prequalifi cation Programme. Journal ofGeneric Medicines, 2006, 3(2):96–105.

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

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

25. Inspection of sites

26. Inspections: • Team of inspectors for each inspection • WHO PQ inspector plus PIC/S member country plus local country inspector (observer) • Some cases – capacity building (recipient country) • Preparation includes SMF, product information, inspection reports, complaints etc • APIs, Finished products • Clinical studies: Mostly Bioequivalence studies (generic products

27. Inspections: Assess compliance with WHO norms and standards: • GMP • GCP • GLP • GSP • GDP… • Organizations conducting clinical trials • WHO training materials

28. Where are the inspections performed? • India, Bangladesh, Pakistan • China • Belgium • Canada • Malaysia • France • South Africa • Switzerland • United States • Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda …

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

30. Inspections: • Bio-equivalence studies • GCP and GLP • About 2 days per study including • Clinical part • Clinic, Pharmacy and related areas, data verification • Bio-analytical part • Laboratory and data verification • Statistical analysis

31. Problems identified in GMP inspections: Various including validation, ventilation, equipment, quality risk management… • Validation and qualification work was often incomplete • Validation Master Plans (VMP) lacked details • Validation policies as defined in the VMPs were not implemented • Process validation was lacking • Validated procedures (e.g. environmental monitoring) were lacking

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

33. Wrong sequence of components (e.g. after filtration) Inappropriate AHU for equipment e.g. coaters, FBD Claim "wet scrubbers" – but not functional Inappropriate change control No quality risk management documented Problems identified in GMP inspections:

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

35. Outcome

36. 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

37. List of prequalified products

38. Examples of Antimalarials prequalified so far • Artesunate 50mg Tablets Sanofi-Synthelabo Blister 25 blister of 12 • Artemether/ 20mg Tablets Novartis Pharma Blister 30 blisters of 6, 12, 18 or 24 lumefantrine 120mg • Artemotil 150mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml • Artesunate 50mg Tablets Guilin Pharmaceutical Co Ltd PVC/AI Blister 12 • Some other manufacturers may have also achieved GMP level but GMP alone is not enough for prequalification

39. Monitoring… • Ongoing assessments and follow-up • Products • Manufacturing sites (both for APIs and finished dosage forms) • CROs • Sampling and testing • Data verification inspections

40. Since 2005: PQ Annual report

41. Capacity building and improvement

42. Capacity building of DRAs and Manufacturers • Both remain important components and need strengthening • Both need improvement and new approaches • From 2006 - in addition - provide (to selected manufacturers): Technical Assistance

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

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

45. Alternative regulatory pathways • USA FDA tentative approvals linked to PEPFAR • Included in WHO PQ List • Confidentiality agreement with US FDA in place • EU Article 58 • For products exclusively to be used outside EU • Canadian Access to medicines scheme • WHO cooperation with the above mentioned • Confidentiality agreement in preparation

46. Thank you