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

2 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals Web site updated constantly –

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

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

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 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 )  13 for treatment of malaria (8 prequalified in ) List of WHO Prequalified Medicinal Products

11 Department of Medicines Policy and Standards, Health Technology and Pharmaceuticals * (8 months) HIV TB Malaria Repr Health New submissions to prequalification

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

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

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

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 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 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 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 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 February 2007 Manufacturer of sterile anti malarial API China TA on manufacture of a sterile API under aseptic conditions 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 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 December 2007 Manufacturer of sterile anti malarial API China TA on manufacture of a sterile API under aseptic conditions December 2007

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 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 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