1. WHO Prequalification of Medicines Programme Raul Kiivet, MD, PhD Manager, Prequalification of Medicines Programme Quality Assurance and Safety: Medicines (QSM) Department of Essential Medicines and Pharmaceutical Policies (EMP) 18 November 2008 1

2. 2 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Web site updated constantly – www.who.int/prequal

3. 3 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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  A UN Prequalification Program of Quality Control Laboratories exists to facilitate the quality control of the prequalified products.

4. 4 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification of Medicinal Products: Objectives - Propose a list of prequalified products and manufacturers meeting international norms and standards of which the quality, efficacy and safety has been assessed, inspected and controlled - Ensure that international 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. 5 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 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 is assessed by at least two 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 Prequalification of Priority Essential Medicines Organisation (1)

6. 6 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals  Inspections of manufacturers of Finished Products (FP) Active Pharmaceutical Ingredient (API) and also Contract Research Organizations (CRO, which carry out bioequivalence studies) Team of inspectors - WHO representative (qualified GMP inspector) - Inspector from well-established inspectorate - National inspectors invited to be part of the team but have no decision making power (different GMP standards, potential conflict of interest) - Inspector of developing countries as observer, for capacity building purpose. Prequalification of Priority Essential Medicines Organisation (2)

7. 7 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals  1. Artemisinin-based fixed dose oral combination formulations Artemether + Lumefantrine, tablet 20 mg + 120 mg; tablet 40 mg + 240 mg tablet 60 mg + 360 mg; tablet 80 mg + 480 mg  2. Artemisinin-based fixed dose combination or co-blistered oral formulations  Artesunate + Amodiaquine, tablet 25 mg + 76.5 mg; tablet 50 mg + 153 mg tablet 100 mg + 306 mg  Artesunate + Mefloquine, tablet 25 mg + 250 mg; tablet 50 mg + 250 mg tablet 100 mg + 250 mg  Artesunate + Sulfadoxine + Pyrimethamine, tablet 25 mg + 500 mg + 25 mg tablet 50 mg + 500 mg + 25 mg; tablet 100 mg + 500 mg + 25 mg  3. Artemisinin-based fixed dose combination or co-blistered oral paediatric formulations, preferably dispersible August 2008 - 6th Invitation to manufacturers of anti-malarial medicines

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

9. 9 Assessment & Inspections n Key numbers for 2007 ä 21 products prequalified (28 in 2008*), ä 90 dossiers submitted (66 in 2008*) ä 463 assessment reports (487 in 2008*) ä 46 inspections (43 in 2008*) * (8 months) ä For each prequalified product in 2007 there were: l 5-15 assessment reports l 3-7 inspections l it took 2 years in average to be prequalified

10. 10 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Currently prequalifed (15 November 2008):  162 for treatment of HIV/AIDS and related diseases  18 for treatment of tuberculosis (10 prequalified in 2007-08)  13 for treatment of malaria (8 prequalified in 2007-08) List of WHO Prequalified Medicinal Products

11. 11 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals 2005200620072008 * (8 months) HIV 67 42 25 39 TB 17 9 17 13 Malaria 3 5 7 11 Repr Health - - 10 3 New submissions to prequalification

12. 12 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals As of 1 November 2008:  120 products for treatment of HIV/AIDS and related diseases  48 products for treatment of tuberculosis  23 products for treatment of malaria  11 reproductive health products Currently under evaluation in WHO Prequalification Programme

13. 13 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Transparency – dossier status information on the web

14. 14 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Anti-malaria medicines under evaluation

15. 15 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Inspections - statistics in 2007 vs 2006 n A total of 45 (2006 – 42) inspections were carried out in 2007: ä 26 (17) inspections of the manufacturing sites of finished product manufacturers ä 6 (10) inspections of the manufacturing sites of active pharmaceutical ingredients (APIs) ä 13 (15) inspections of contract research organizations (CROs) In 2006 two inspectors in house, four in 2008

16. 16 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Transparency – Inspection outcomes on the web

17. 17 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Problems n Antimalarials and antituberculosis products – old problems but few new solutions ä No new innovator products ä Generic products with no innovator ä …or problem "new" products ä GMP (both for finished dosage form and API) ä Quality part of the dossier – specifications, stability data etc ä Safety and efficacy – poor clinical and safety data, poor quality information

18. 18 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Training activities in 2008 n In total 13 training courses of 3 to 5 days: ten courses organized and 3 co-organized n In Belgium, Brazil, China, India, Iran, Jordan, Morocco, Nicaragua, Pakistan, Tanzania n More than 500 participants - staff of regulatory authorities and pharmaceutical manufacturers n Topics: ä Development of diossiers for submission ä Asssessment of Interchangeable medicines ä Pharmaceutical Development of Paediatric Formulations ä GMP, Quality and Bioequivalence of malaria ATC products ä GMP, Quality and Bioequivalence of Reproductive Health products ä Pharmaceutical Development of Paediatric Formulations

19. 19 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Prequalification of Quality Control Laboratories n So far mainly for AFRO region, now wider scope n 6 QC Labs prequalified ä RIIP, South Africa – 07/2005 ä LNCPP, Algeria – 10/2005 ä Adcock, South Africa – 01/2008 ä National QCL, Kenya – 07/2008 ä National QCL, Marocco – 07/2008 ä Vimta Labs, India – 07/2008 n 13 QC Labs audited, corrective measures proposed ä Cameroon, Mali, Madagascar, Niger, Senegal ä Ghana, Etiopia, Kenya NQCL, Kenya MEDS, Uganda, Tanzania n 8 QC Labs expressed interest, but not send LIF yet ä Benin, Burkina Faso, Cote d'Ivoire, Guinea

20. 20 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Technical Assistance - Policy Criteria for the products in relation to which technical assistance is considered: n Inclusion in the list of expression of interest n High value for Public Health purposes n Poor representation on the Prequalification list n Manufacture has applied for PQ (exemptions can be made upon justified requests for technical assistance from regional offices) danger Criteria for the experts: n Excellent qualifications and long standing experience in the area where expertise is required n Absence of conflict of interest n Total intellectual independence from the prequalification programme, no participation in inspections or assessments.

21. 21 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Technical Assistance - Examples 2007 Manufacture of oral solid dosage forms anti TB Ukraine Technical Assistance on stability studies 06-09 February 2007 Manufacturer of sterile anti malarial API China TA on manufacture of a sterile API under aseptic conditions 05-10 March 2007 Manufacture of oral solid dosage forms anti malarial Cambodia TA on packaging of co-blisters26 March – 02 April 2007 Manufacture of oral solid dosage forms ARV Zimbabwe TA on GMP compliance01-05 May 07 Manufacturer of anti TB API India TA on manufacturing process validation and GMP 20-26 May 2007 Manufacture of oral solid dosage forms anti malarial Cambodia TA on packaging of co-blisters17-29 July 2007 Manufacture of oral solid dosage forms ARV. Bangladesh TA on GMP and engineering23–29 August 2007 Manufacture of oral solid dosage forms ARV Zimbabwe TA on GMP compliance04-09 November 2007 Manufacturer of anti TB API India TA on manufacturing process validation and GMP 17-21 December 2007 Manufacturer of sterile anti malarial API China TA on manufacture of a sterile API under aseptic conditions 17-22 December 2007

22. 22 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Revision of PQ procedure in 2008 n Reasons for revision ä 5 years experience from implementation ä discrepancies between rules and practices ä unclear responsibilities of parties n Aims of revision ä increase transparency of PQ activities ä publish more details of prequalified products ä harmonize terminology and clarify procedures ä better define responsibilities ä confidentiality agreement with applicants

23. 23 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals New PQ procedure for APIs in 2009 n until now the qualification of API source and manufacturer is the responsibility of finished product manufacturer => API manufacturer seldom inspected and API dossier commonly not evaluated n API source considered "confidential" information n Oct 2008 WHO Expert Committee on Specifications for Pharmaceutical Preparations will discuss ä Procedure for API Master File in Prequalification Programme ä PQ procedure for active pharmaceutical ingredients (APIs) – new "regulatory" approach

24. 24 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Summary remarks n 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. n The products should be submitted with technical data proving the quality of API and finished product together with necessary data on safety and efficacy n Manufacturing sites of API s and finished products should operate according to GMP principles in order to deliver consistent quality products n Technical assistance for promising manufacturers/products can be made available to achieve the goal and speed up the prequalification process. n Close cooperation with international procurement and financial institutions ä quality as prerequisite for procurement decision ä instruments to support quality production n Encourage manufacturers to invest into quality, and to apply for independent evaluation n Main aim of PQ – to increase choice and access to quality products