Prequalification of Essential Medicines

1. Prequalification of Essential Medicines WHO/UNICEF Technical Briefing Seminar on Essential Medicines Policies 8 – 12 October, Geneva Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards(PSM) WHO Headquarters, Geneva, Switzerland ragol@who.int 1

2. WHO Today • Hosts three prequalification programs • 1. Prequalification of vaccines (QSS/IVB/FCH) • 2. Prequalification of diagnostics (EHT/HTP) • 3. Prequalification for priority essential medicines (QSM/PSM/HTP)

3. VACCINEShttp://www.who.int/immunization_standards/vaccine_quality/pq_system/en/VACCINEShttp://www.who.int/immunization_standards/vaccine_quality/pq_system/en/ 1

4. DIAGNOSTICS http://www.who.int/hiv/amds/diagnostics/en/ 2

5. MEDICINES http://mednet3.who.int/prequal/ 3

6. Prequalification of essential medicines • The UN prequalification program is an action plan for expanding access for patients with • HIV/AIDS • Tuberculosis • Malaria • Reproductive health • by ensuring quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID)

7. How prequalification is organized? (I) • Role of WHO: Managing and organizing the project on behalf of the United Nations. • provides technical and scientific supportand guarantee 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 (IPC group); WHO disease oriented programs

8. How prequalification is organized? (II) • Stakeholders: • Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department; other disease oriented programs • Interested Governments • Funding partners: Governments (Belgium, France, China etc.), Gates Foundation, UNITAID • Beneficiaries: • UN Procurement, Global Fund and UNITAID procurement, NGOs (e.g. MSF) • National Regulatory Agencies • Developing country industries • 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. 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 • What if not covered by these options? • Multisource products • Full dossier with all 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 • 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) • Commercial sample • Requested, but not always analysed before prequalification.

10. Prequalification: generics and not generics • Prequalification requirements for generics – fully in line with major regulatory agencies. Amultisource (generic) medicine must: 1. contain the same active ingredients as the innovator drug 2. be identical in strength, dosage form, and route of administration 3. have the same use indications 4. be bio-equivalent (as a marker for therapeutic interchangeability) 5. meet the same batch requirements for identity, strength, purity and quality 6. be manufactured under the same strict standards of GMP required for innovator products. • What if not generics – full data set to prove the 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

11. Guidance for applicants

12. Prequalification: the technical documents are WHO normative documents.When these are "silent" other guidelines such as selected ICH guidelines may be used

13. Which medicines and why PQ Programme deals with? • Application to include a product on Expression of Interest (EOI) Lists published comes from WHO disease oriented programs • Products should be of high public health value • Products must be in line with WHO treatment guidelines • Products must be in line with Essential Medicines List • Rare exceptions from these principles, if justified

14. New Product Group from 2006: Selected Reproductive Health Products

15. Current status • Started with HIV/AIDS products in 2001 – malaria and TB products joined later • Prequalified products (May 2007) "Active" dossiers in pipeline (2006) • 164 HIV related medicines60+ • 12 anti-tuberculosis medicines25+ • 8 anti-malarial medicines 30+ • 184 115+ • Ongoing assessments and follow-up • Products • Manufacturing sites (both for APIs and finished dosage forms) • CROs

16. News example

17. Transparency: WHO Pubilc Inspection Reports

21. Increased transparency about the "pipeline"

22. Problems encountered with products containing artemisinin derivatives • General • Very few innovator products • Many not typical generics as well • Very few antimalarials recommended by treatment guidelines approved in ICH and associated countries • Limited DRAs and regulatory experts having experience with antimalarials • Fixed dose combinations more complicated than single component products • Quality related issues • Manufacturers do not comply with GMP (even if located in the EU or EFTA countries – products not registered and produced only for export) • Many dossiers have outstanding deficiencies in proving the quality of the product – non-compliance with established specifications or poorly defined manufacturers specifications; stability data either 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

23. Since 2005 annual reports; 2006 annual report on the web

24. Outcome of 2006 • 44 products listed (32 in 2005) - 38% more than in 2005 • But … • No new antimalarials • No new TB drugs (but 4 new ones added in early 2007) • No new QC labs

25. Year 2006: statistics (1) INSPECTIONS • A total of 49 (2005 – 52) inspections were carried out: • 17 (20) inspections of the manufacturing sites offinished product manufacturers • 10 (10) inspections of the manufacturing sites ofactive pharmaceutical ingredients (APIs) • 15 (14) inspections of contract research organizations(CROs) • 7 (8) inspections of national pharmaceutical qualitycontrol laboratories (NPQCLs) in Africa.

26. Inspections: where? • India – 28 • China – 6 • Belgium - 1 • Canada – 1 • Malaysia - 1 • France - 1 • South Africa – 3 • Switzerland - 1 • United States – 1 • Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda – all 1

27. Year 2006: statistics (2) Assessments • During the 6 (9 - 2005) dossier assessment sessions, 334 (222 – 2005)assessment reports linked to 334HIV/AIDS-relatedproducts were written. • A total of 78 (52) assessment reports — linked to 70 (50) TB products were written • A total of 29 (73) assessment reports were written, linked to than 31 (40) malaria products • All together 75% increase in the number of assessment reports! More facts will be soon in Annual Report 2006 on the web

28. Publications 2005/2006 • New, more user friendly prequalification web site launched in November 2006, updated and improved also later: http://mednet3.who.int/prequal/ • Articles: • 3. Dekker TG, van Zyl AJ, Gross O, Tasevska I,Stahl M, Rabouhans ML, Rägo L. Ongoingmonitoring of antiretroviral products as part ofWHO’s Prequalification Programme. Journal ofGeneric Medicines, 2006, 3(2):96–105.

29. Measures taken to get more products prequalified • General • Formerly very limited resources vs huge obligations and scope • PQ programme started with only ONE professional, by the end of 2007 it may have up to 15 (three will be secondments from Governments) • Business plan and funding proposals created, funds received (Gates; UNITAID) • Specific • Internal SOPs and work procedures to facilitate process created • Specific for antimalarials "Note for Applicants" prepared • New regulatory guidance documents created and started • Specific guidance on comparator products • More direct discussions with manufacturers started • Regulatory advise on complicated cases • Additional work that could help manufacturers under way

30. Capacity building of NRAs and Manufacturers • Both remain important components and need strengthening • Both need improvement and new approaches • From 2006 one rotational post in PQ program for developing country regulators • From 2007 second will be opened • NB! In 2006 programme started to deliver in addition to general training focused to selected manufacturers technical assistance (beneficiaries in countries such as China, Ukraine, Zimbabwe …)

33. Training and related activities in 2007 • In June two days workshop in cooperation with WHO EMRO about prequalification • In June three days workshop on BE/BCS and dissolution testing (new course) in cooperation with EURO and FIP in Ukraine • In October repetition of Cape Town course on paediatric medicines development in WHO EURO • In November TBS on Medicines Quality and Prequalification • In November upon request from Chinese Gov on week training in China • Training of assessors in AFRO (planning stage) … • Training for QC lab personnel – EDQM Septmeber in Vienna

34. Prequalification of Quality Control Laboratories (1) • So far only for AFRO region, potential expansion • 3 QC Labs prequalified • South Africa, CENQAM - 6/2005 • South Africa, RIIP - 7/2005 • Algeria, LNCPP - 10/2005 • 3 QC Lab near to PQ?? • South Africa, Kenya, Tanzania • 11 QC Labs audited, corrective measures proposed • Cameroon, Mali, Madagascar, Niger, Senegal • Ghana, Etiopia, Kenya NQCL, Kenya MEDS, Uganda, Tanzania • 4 QC Labs expressed interest, but not send LIF yet • Benin, Burkina Faso, Cote d'Ivoire, Guinea

35. Prequalification of Quality Control Laboratories (2) • Technical assistance • Experts provided to 2 QC Labs : Ethiopia and Tanzania • Several in AFRO have received free of charge International Pharmacopoeia and other docs, pluss chemical reference substances for ARVs • 10 of the QC Labs were involved in Proficiency testing (Phase 3, 07/2004 - 06/2006) • Algeria, South Africa CENQAM, South Africa RIIP • Mali, Niger, Senegal • Ghana, Kenya MEDS, Tanzania, Uganda • 3 other African QC Labs took part in Proficiency testing (Phase 3, 07/2004 - 06/2006) • Morocco, Tunisia, Zimbabwe

36. Are there alternative regulatory pathwaysfor products of public health needs? • EU Article 58 • US FDA tentative approvals linked to PEPFAR • Canadian Access to medicines scheme • WHO cooperation with the above mentioned • Confidentiality agreement with US FDA in place and working; CA with Health Canada expected by March 2007 • How better use the synergies?

37. Summary and conclusion Quality can not be assessed, tested or inspected on the product, BUT It has to bebuilt into it! We have the obligation to ensure it with all the means we have in the best way we can.