1. 1 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services World Health Organization's Prequalification Program for medicines Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies World Health Organization Geneva, Switzerland E-mail: ragol@who.int V Conference of the PANDRH 17 – 19 November 2008 Buenos Aires, Argentina

2. 2 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Is quality and safety of medicines still a big problem nowadays? n Panama case in 2006. It turned out the cause of death of more than forty five persons was simple. The cough syrup and potentially other medicines produced in the governmental pharmaceutical factory were contaminated. n The death were caused by diethylene glycol (DEG) found in medicines. DEG is a chemical cousin of antifreeze and used widely by various industries. It is toxic to the kidneys and can cause deadly renal failure. ä Pictures. 1. Waiting for answer. 2. A popular medicine in Panama that turned to be a killer. 3. Medicines traced down and removed from supply chain

3. 3 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Viracept (nelfinavir) saga

4. 4 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Heparin "saga" 2008 – many countries affected

5. 5 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services What is WHO doing to help the countries? n Normative functions n Capacity building n Prequalification

6. 6 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Normative functions n Nomenclatures and classifications ä International Nonproprietary (generic) Names – INNs ä Anatomical Therapeutic Chemical (ATC) classification and Daily Defined Doses (DDD) n International guidelines, standards and norms, mostly in the area of quality assurance ä International Pharmacopoeia ä WHO GMP, interchangeability, fixed dose combinations, variations, stability guidelines etc.

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9. 9 New Specifications adopted by 41 st WHO Expert Committee - examples ä Abacavir oral solution ä Abacavir sulfate tablets ä Didanosine tablets ä Didanosine oral solution (adult formulation) ä Lamivudine oral solution ä Lamivudine tablets ä Stavudine capsules ä Zidovudine capsules ä Zidovudine IV injection ä Zidovudine oral solution ä Zidovudine and Lamivudine tablets ä Zidovudine, Lamivudine and Abacavir tablets

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11. 11 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Prequalification of essential medicines  The UN prequalification program is an action plan for expanding treatment access for patients with  HIV/AIDS  Tuberculosis  Malaria  … and includes also selected products for reproductive health and Avian flu (oseltamivir)  by ensuring quality, efficacy and safety of medicines procured using international organizations and funds (e.g. UNICEF, Global Fund, UNITAID)

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13. 13 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Why the prequalification is needed?  Risks Sourcing of poor quality products or even counterfeit medicines  risk to patients, toxic reactions, treatment failure, resistance  bad quality (generic) products undermine public confidence  Problems Millions of people living with HIV/AIDS, tuberculosis and malaria, have no or limited access to treatment Substandard and counterfeit products in different countries Weak or absent QA systems of medicines supply chain Lot of money invested in procurement  products with very different quality sourced

14. 14 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Prequalification basic principles  Legitimate - General procedure and standards approved through WHO Expert Committee system involving all WHO Member States and WHO Governing bodies  Voluntary for participating manufacturers  Widely discussed FIP Congress, Nice 2002 Supported by International Conference of Drug Regulatory Authorities (ICDRA) in 2002, 2004 and 2006 representing more than 100 national drug regulatory authorities;  Transparent (all information available on the web site http://mednet3.who.int/prequal/ ) http://mednet3.who.int/prequal/  Open to both innovators and multisource/generic manufacturers  No cost for applicants as per today (in future fees considered)  Capacity building important part of it

15. 15 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Expected outcomes of prequalification  Public lists of products and manufacturing sites Meeting international standards on quality, safety, and efficacy  Capacity building and harmonization National Drug Regulatory Authorities (DRAs), manufacturers, WHO treatment programs, NGOs, procurement organizations  Ongoing quality monitoring Ongoing monitoring of prequalified products  Facilitate access to treatment Through fair procurement mechanisms (e.g. tender, competition based on the same quality standards) WHO commitment to developing better access to quality medicines

16. 16 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services How prequalification is organized?  Role of WHO: Managing and organizing the project on behalf of the UN provides technical and scientific support and 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 Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department  Actors: Qualified assessors and inspectors from National DRAs of ICH and non-ICH countries, and inspectorates belonging to PIC/S

17. 17 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services 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 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 apply for EU Art 58 and Canadian access procedure)

18. 18 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Inspections and QA analysis  Inspections  Manufacturing site (final product, packaging)  Active pharmaceutical ingredient (API)  Research laboratory or Contract Research Organization (CRO)  Teamwork of inspectors WHO representative (qualified GMP inspector) Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S) National inspector/s invited to be part of the team but have NO decision making power (different GMP standards, potential conflict of interest)  Quality control analysis - upon need, but not always necessarily before prequalification and supply, increasingly as part of proactive follow-up

19. 19 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Prequalification: the technical documents are WHO normative documents n The Expert Committee documents pass wide international consultation and are finally adopted by the Committee composed of outstanding international technical experts n In case WHO standards are "silent" other applicable standards such as ICH and national standards are used n New TRS No 943 with 41 st Report from 2007 ä Updated PQ general procedure ä PQ of QC labs procedure

20. 20 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Current status  Started with HIV/AIDS products in 2001 – malaria and TB products joined later  Prequalified products " Active" dossiers in pipeline 171HIV related medicines 65 17anti-tuberculosis medicines 25 10 anti-malarial medicines 32 184 115+

21. 21 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Transparency: WHO Public Inspection Reports (WHOPIR) and WHO Public Assessment Reports (WHOPAR) on web * WHOPAR – structure and amount of information the same as in European Public Assessment Report (EPAR)

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24. 24 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services News example: latest 9 products listed

25. 25 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Inspections 2005-2007 n Inspections of finished products (FP) manufacturers in 2007 reaching 26 n Active pharmaceutical ingredients (API) manufacturers in 2007 – 6 n Contract Research Organizations (CRO) for BE studies in 2007 - 13

26. 26 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Dossier assessment – number of assessment reports generated for different product groups n In 2007 total 511 assessment reports were generated

27. 27 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Publications 2005-2007 n Prequalification of medicines. WHO Drug Information, 2005, 19:1. n WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2. n 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 n Survey of the Quality of Antiretroviral Medicines Circulating in Selected African Countries, WHO/PSM/QSM/2007.9 (September 2007)

28. 28 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Capacity building: Examples of trainings organized by in 2007 n Workshop on Pharmaceutical Development with a Focus on Paediatric Medicines ä Cape Town, South Africa, 16 - 20 April 2007 n Training Workshop on Dissolution, Pharmaceutical Product interchangeability and Biopharmaceuticals Classification System (BCS) ä Kiev, Ukraine, 25 - 27 June 2007 n Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence with a Focus on TB products ä Jiaxing, China, 5 - 9 November 2007 n Training Seminar for Quality Control Laboratories on Quality Assurance, Prequalification and Development of Standards ä Rabat, Morocco, 27 - 29 November 2007 n Training Workshop on WHO Good Manufacturing Practices ä Dakar, Senegal, 11 - 14 December 2007

29. 29 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP/IUPHAR Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

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32. 32 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Other specific regulatory pathways for products of public health needs n EU Article 58 n US FDA tentative approvals linked to PEPFAR n Canadian Access to medicines scheme ä WHO cooperates with all the above mentioned ä Confidentiality agreement with US FDA in place and working; CA with Health Canada in progress ä MoU (including confidentiality arrangements) under developemnt with European Commission

33. 33 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services Summary  Not so good news  Only limited number of products have met the required standards (especially malaria and TB products)  Takes time to get into compliance Data to be generated, tests to be carried out … GMP upgrade needed  Quality has its price  Good news ä Relatively large number of products and suppliers comply with the standards (mostly ARVs so far) ä Many potential suppliers appreciating feedback and willing to improve ä Unique technical knowledge obtained about products, especially about generic antiretrovirals and antimalarials ä Capacity building component appreciated a lot ä Working together – way to learn to recognize each others work and work for reducing duplicative efforts

34. 34 Department of Essential Medicines and Pharmaceutical Policies, Health Systems and Services n Prequalification - a good engine to pull quality of medicines into international agenda n It challenges the still existing reality - "poor quality medicines for poor" n How best keep it going as huge unfinished agenda is ahead?