Prequalification of Medicines

1. Prequalification of Medicines Dr Lembit Rägo, Coordinator Quality Assurance and Safety: Medicines (QSM) Department of Essential Medicines and Pharmaceutical Policies (EMP) Geneva, Switzerland

2. Web site updated constantly – www.who.int/prequal

3. Prequalification of Medicines Programme • The UN Prequalification Programme is ensuring that medicines procured with international funds are of assessed and inspected quality, efficacy and safety. • The Prequalification Programme is an action plan for expanding access to priority essential medicines in the following four areas: - HIV/AIDS - Tuberculosis - Malaria - Reproductive Health - Selected individual products for other diseases such as oseltamivir and Zinc sulphate • A UN Prequalification Program ofQuality Control Laboratories exists to facilitate the quality control of the prequalified products.

4. Prequalification of Medicinal Products: Objectives - Propose a list of prequalified productsand manufacturers meeting international norms and standards of which the quality, efficacy and safety has been assessed, inspected and controlled - Ensure thatinternational norms and standards are applied at all the steps of the Prequalification Programme. - Make sure re-evaluation and maintenance of the list are performed and that variations and changes are correctly controlled. - Help the national drug regulatory authorities to build up capacity in assessment, inspection and control meeting international norms and standards. - Develop the local possibilities of production and clinical studies by offering customized technical assistance.

5. Medicines Prequalification Process Expression of Interest Product dossier SMF Inspections Assessment Additional information and data Corrective actions Compliance Compliance Prequalification Dossier maintenance (variations) Handling of complaints Monitoring

6. Prequalification of Priority Essential Medicines Organisation (1) Assessment of the product dossier i.e. quality specifications, pharmaceutical development, stability, bioequivalence… • Copenhagen assessment week - 15 to 20 assessors during one week at least every two months - Every dossier part (mostly Q and BE) is assessed by at least 2 assessors including one senior assessor for the second assessment - An assessment report is issued - Letter summarizing the findings and asking for clarification and additional data if necessary; sent first by e-mail to the applicant followed by surface mail • Handling of variations of already prequalified products - Done in house and during Copenhagen-week

7. Variations – 2009 (as of 30 October)

8. Prequalification of Priority Essential Medicines Organisation (2) • Inspections of manufacturers of • - Finished Products (FPP) • - Selected Active Pharmaceutical Ingredient (API) and also • - Selected Contract Research Organizations (CRO, which carry out clinical/bioequivalence studies) Team of inspectors • - WHO representative (qualified GMP inspector) • - Inspector from well-established inspectorate • - National inspectors invited to be part of the team as observers but have no decision making power (different GMP standards, potential conflict of interest) • -Inspector of potential target countries (and other countries in need for capacity building)as observers, for capacity building purpose.

9. Assessment & Inspections • Key numbers for 2008 • 40 products prequalified (21 in 2007), • 92 dossiers submitted (90 in 2007) • 732 assessment reports (463 in 2007) • 52 inspections (45 in 2007) • For each prequalified product there were: • 5-15 assessment reports • In most cases, at least 1 inspection (may be more e.g. API, FPP, CRO) • 2 years total time on average to get prequalified (the clock stops for PQ when request for additional information/corrective actions is sent to the applicant)

10. Product dossiers accepted for evaluation 2005200620072008 HIV 67 42 25 42 TB 17 9 17 12 Malaria 3 5 7 9 Repr Health - - 10 4

11. Currently under evaluation in WHO Prequalification Programme As of 31 January 2009 : • 68 products for treatment of HIV/AIDS and related diseases • 41 products for treatment of tuberculosis • 17 products for treatment of malaria • 11 reproductive health products • Total 137

12. Transparency – dossier status information on the web

13. Inspections - statistics in 2008 vs 2007 • A total of 62 (2007 – 46) inspections were carried out in 2008: • 27 (26) inspections of the manufacturing sites offinished product manufacturers • 11(6) inspections of the manufacturing sites ofactive pharmaceutical ingredients (APIs) • 14 (13) inspections of contract research organizations(CROs) • 10 (1) Quality control laboratories • In 2008 four/three inspectors in-house

14. Prequalification Programme:Transparency - WHOPIRs and NOCs • These are published in response to the WHA Resolution WHA57.14 of 22 May 2004, which requested WHO, among other actions: • "3. (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;" • A WHO Public Inspection Report (WHOPIR) provides a summary of the inspection (where found to be GMP complaint) • A Notice of Concern (NOC) is a letter reflecting areas of concern where the non-compliances require urgent attention and corrective action by the manufacturer or research organization.

15. Transparency – Inspection outcomes on the web

16. Suspension of some TB medicines in 2009 APRIL 28, 2009, 12:32 P.M. ET WHO To Avoid Tuberculosis Drugs Made By Wyeth In Pakistan By Jared A. Favole Of DOW JONES NEWSWIRES WASHINGTON (Dow Jones)--The World Health Organization, saying it can't assure the quality of several tuberculosis products made at a Wyeth (WYE) plant in Pakistan, will suspend recommending purchases of the drugs. Wyeth Pakistan Ltd., a unit of Wyeth, introduced new active ingredients into the medications and changed the storage conditions without getting approval of the WHO, according to a letter the agency sent the company on Monday. The letter was posted online Tuesday. The suspension affects four drugs manufactured at the plant that are used to treat tuberculosis, a deadly infectious disease that commonly affects the lungs.

17. Products included in the WHO List of Prequalified Medicines

18. Products included in the WHO List of Prequalified Medicines by Therapeutic Area (cumulative numbers)

19. Capacity building: whom it affects? • WHO support to the generation of expertise for development, manufacture, control and regulation of medicines Manufacturers Clinical Research Organizations (CROs) Quality control laboratories (QCLs) National Regulatory Authorities (NRAs)

20. Rotational Position at WHO HQ • Since November 2006 – present • 8 fellows – from Zimbabwe, Uganda, Tanzania, Ethiopia and Ukraine • More fellows to join in 2009 including GMP inspectors • 3-months hands-on experience in everyday work of the PQ Program team • Optional participation as observer in inspections • Follow-up plan for implementation at home NMRA upon return

22. Trainings organized or supported byQSM in 2009 (I-IX)(1) • Assessment of pharmaceutical quality in PQP • Copenhagen, Denmark, January 14-16, 2009 • WHO Prequalification programme and requirements • Damascus, Syria, February 8-9, 2009 • WHO Prequalification programme and requirements • Cairo, Egypt, February 11-12, 2009 • Training workshop on ACTs • Kampala, Uganda, February 23-27, 2009 • Training workshop on the Assessment of Multisource Interchangeable Medicines • Mombasa, Kenya, July 10-14, 2009 • Interregional seminar for Quality Control Laboratories • Nairobi, Kenya, September 23-25, 2009 • Quality of Active Pharmaceutical Ingredients (APIs) • Hyderabad, India, September 5-7, 2009

25. Other Benefits • Stimulates harmonization among • NMRAs • group assessments pass on skills • readily available, user friendly guidelines - easy to adopt/adapt • Building trust among regulatory staff from same region e.g. EAC • Manufacturers • Gives access to certain market free of charge • Improve dossiers by use of WHO guidelines for markets that do not have own guidelines yet • Experience in submitting PQ dossiers improves appreciation of regulatory requirements in other regions • Reduced cost – same dossiers to PQP and to NMRAs

27. QCLs Prequalification Procedure(1)September 2009 Prequalified QCLs: • South Africa, RIIP+CENQAM (2005) • Algeria, LNCPP (2005) • South Africa, Adcock Ingram (2007) • Morocco, LNCM (2008) • Kenya, NQCL (2008) • India, Vimta Labs (2008) • France, CHMP (2008) • Vietnam, NIDQC (2008) • Kenya, MEDS (2009) • Singapore, HSA (2009) • Singapore, TÜV (2009)

28. Capacity building • Technical assistance provided to 8 national medicines QC laboratories • Focus on implementation of quality system and microbiological testing, inventory audits • Trainings in Quality Assurance, Quality Control and Ph.Int. under preparation (2007) • Morocco, 44 participants from 16 Francophone countries (AFRO, EMRO), cooperation with EDQM and AFSSAPS • Tanzania, 46 participants from 23 Anglophone countries (AFRO, EMRO, PAHO/AMRO) • Seminar on rational sampling and testing in quality control of medicines (2009) • Kenya, 45 participants from 21 countries (AFRO, EMRO, WPRO) • Participation in EDQM Quality Assurance training for OMCLs • 2005, 5 participants from AFRO and EMRO • 2007, 12 participants from AFRO, EMRO and EURO

29. Sampling and testing projects in 2008 • Quality survey of antimalarials (ACTs and sulfadoxine-pyrimethamine) • Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Madagascar, Nigeria, Senegal, Tanzania, Uganda • 936 samples collected and screened by Minilab, 299 selected for full testing in laboratory (testing ongoing) • Assessment of quality of product information (Labelling and PIL) • Quality monitoring of products funded by UNITAID • Pilot phase (paediatric and second-line antiretrovirals) in cooperation with NDRAs in Kenya, Tanzania, Uganda, Zambia • 378 samples collected and tested in laboratory (testing ongoing) • Assessment of quality of product information (Labelling and PIL) • Quality survey of anti-TB medicines in Eastern Europe • Cooperation with NDRAs in Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan; Focused on Rifampicin, Isoniazid, Rifampicin/Isoniazid, Ofloxacin, Kanamycin (360 samples planned)

30. Technical Assistance - Policy Criteria for the products in relation to which technical assistance is considered: • Inclusion in the list of expression of interest • High value for Public Health purposes • Poor representation on the Prequalification list • Manufacture has applied for PQ (exemptions can be made upon justified requests for technical assistance from regional offices) danger Criteria for the experts: • Excellent qualifications and long standing experience in the area where expertise is required • Absence of conflict of interest • Total intellectual independence from the prequalification programme, no participation in inspections or assessments.

31. Experts participating in TAs

32. Revision of PQ procedure in 2008 Reasons for revision • 5 years experience from implementation • Differences between procedure and actual activities practices • unclear responsibilities of parties Aims of revision • increase transparency of PQ activities • publish more details of prequalified products • harmonize terminology and clarify procedures • better define responsibilities • confidentiality agreement with applicants

33. Problems • Antimalarials and antituberculosis products – old problems but few new solutions • Immature submissions – takes time to get to the maturity needed • Relative lack of motivation from applicants • Relative lack of new innovator products • Generic products with no innovator • …or problem "new" products • GMP non compliance (both for finished dosage form and API) • Quality part of the dossier – specifications, stability data etc incomplete • Bioequivalence – failures in studies (from design to GCP compliance) • Safety and efficacy – poor clinical and safety data, poor quality information, poor information for users

34. Summary remarks • International buyers – increasing quality requirements, new QA policies (e.g. GFTAM) • The purpose of the prequalification programme is to list good quality, safe and effective medicinal products in the interest of public health in resource-limited countries. • The products should be submitted with technical data proving the quality of API and finished product together with necessary data on safety and efficacy (quality submissions in demand) • Manufacturing sites of API s and finished products should operate according to GMP principles in order to deliver consistent quality products • CROs should conduct studies in compliance with GCP / GLP as appropriate

35. Summary remarks (2) • Technical assistance for promising manufacturers/products can be made available to achieve the goal and speed up the prequalification process. • Close cooperation with international procurement and financial institutions • quality as prerequisite for procurement decision • instruments to support quality production • Encourage manufacturers to invest into quality, and to apply for independent evaluation • Main aim of PQ – to increase choice and access to quality products without compromising requirements for quality, safety and efficacy should remain unchanged