WHO Prequalification Programme

1. WHO PrequalificationProgramme Milan Smid, M.D., Ph.D. Prequalification Programme: Priority Essential Medicines

2. UN Prequalification Programme for Priority Essential Medicines • Action plan of UN from 2001 for expanding access of priority medicines to patients with • HIV/AIDS • Malaria • Tuberculosis • Reproductive health • Influenza • Acute diarrhoea • Potentially other categories of products, if there is the need

3. Elements of Prequalification Programme Objective: • To ensure quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID) Components: • Evaluation of Quality, Safety and Efficacy of prioritised Essential medicines, inspections of manufacturers and monitoring of the products after their prequalification. • Prequalification of quality control laboratories. • Building capacity of regulators, manufacturers and quality control laboratories.

4. How prequalification is organized? • WHO manages and organizes the programme on behalf of the United Nations: • provides technical and scientific support to assessment, inspections (GMP, GCP, GLP) and quality control (GPCL) • involvement of qualified assessors and inspectors mostly from NRAs of ICH and associated countries and PIC/S inspectorates • guarantees that international norms and standards are applied all through the process • supports capacity of NRA in developingcountries to evaluate, inspect and control the quality of medicines • involvement of qualified assessors and inspectors from NRAs in developing countries • by involvement of manufacturers from development countries into the project supports their capacity to produce according to international norms and standards

5. How prequalification is organized? • WHO PQT working in co-operation with partners • UNICEF • The Global Fund to Fight AIDS, Tuberculosis and Malaria • UN Population Fund (UNFPA) • UNAIDS • World Bank • Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department

6. Essential steps of PQ evaluation procedure • Need is specified and agreed by WHO treatment programmes • Invitation for Expression of interest (EOI) is published • Interested parties submit dossiers • Dossiers receive initial screening • Full dossiers are assessed • Inspections are conducted at manufacturing sites and at CROs • Samples are tested, if needed • If outcome is positive, pharmaceutical product is listed on the website, including product information (SPC, PIL), assessment report (WHOPAR) and inspection report (WHOPIR)

7. Essential steps of monitoring of PQ product • Variations to the dossier of prequalified product • Sampling and Testing • Reinspections • Requalification • De-listing or suspension (if and when appropriate)

8. Standards • WHO standards as defined in WHO guidelines and International Pharmacopoeia are applied in prequalification process • If these not exist, ICH guidelines are applied • In case of need, guidelines of stringent regulatory authorities, which are involved in ICH process

9. I Steps in prequalification Expression of Interest Product dossier SMF Inspections Assessment Additional information and data Corrective actions Compliance Compliance Prequalification Maintenance and monitoring

10. Evaluation procedure • Assessment of product dossiers (Quality specifications, pharmaceutical development, production, control, stability, bioequivalence etc). • Teams of professionals from national Drug Regulatory Authorities (DRA):Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe ... • Copenhagen assessment week • 8 to 20 assessors together during one week at least every two months at UNICEF in Denmark • Every dossier is assessed by at least four assessors. • An assessment report is issued - signed by assessors • Letter summarizing the findings and asking for clarification and additional data if necessary is sent first by e-mail to the applicant followed by surface mail

11. Assessors participating in PQ assessment (all visits in 2001-2008, share of the WHO regions) In total 603 participations

12. Inspections: • Team of inspectors for each inspection • WHO PQ inspector plus PIC/S member country plus local country inspector (observer) • Some cases – capacity building (recipient country) • Preparation includes SMF, product information, inspection reports, complaints etc • APIs, Finished products • Clinical studies: Mostly Bioequivalence studies (generic products

13. Prequalification assessment • Innovator products • Accepted, if approved by stringent authorities like US FDA and EMEA • Based on availability of assessment reports, WHO Certificate of Pharmaceutical Product (CPP), batch certificate • Continuous update on product changes after prequalification • Confidence in scientific expertise of well-established RAs

14. Alternative regulatory pathways • USA FDA tentative approvals linked to PEPFAR • Included in WHO PQ List • Confidentiality agreement with US FDA in place • EU Article 58 • For products exclusively to be used outside EU • Canadian Access to medicines scheme • WHO cooperation with the above mentioned • Confidentiality agreement in preparation

15. Prequalification assessment • Multisource products Assessment • Quality: information on starting materials and finished product, (API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc.) • Interchangeability with reference product (efficacy and safety):Report of bio-equivalence, biovaiwer or clinical study demonstrating interchangeability with reference product • Inspection of manufacturers and CROs • Laboratory analysis in case of need Monitoring after prequalification

16. Simplified assessment • Prequalification of Multisource (generic) Finished Pharmaceutical Products approved by Stringent Regulatory Authorities • Assessment report (waived for anti-TB or antimalarial medicines with 30 years of therapeutic experience - including 15 years in ICH region) • 5 years of continuous manufacturing experience • last Annual Product Report

17. Prequalification assessment • Combined products, new dosage forms, new indications Assessment • May require safety and efficacy data Monitoring after prequalification

18. Outcomes of PQ procedure Information in public domain: http://who.int/prequal/ • Lists of PQ medicinal products • WHOPAR (SPC, PIL, labelling) • WHOPIR (both FPP and API) • Notices of Concern and Suspension • Information on progress of assessment procedure and inspections • Supportive documents: WHO guidelines, description of PQ procedure

19. www.who.int/prequal/

20. Same principals applied in prequalification as valid for national regulatory approvals by stringent authorities • Benefits prevail the risks at a time of regulatory approval and nothing indicates that benefits will not prevail also during use of product in normal medical practice • Available data about quality (Dossier) • Available data about efficacy and safety or interchangeability (Dossier) • Available data are credible and were eticaly obtained • Good practices (GLP, GCP, GPhVP, …) • Existing reassurance about production in stable quality and quality assurance mechanisms • GMP • Way of use of medicine characterized for physicians and patients • Data sheets, SPCs, PILs, package labeling • Lack of knowledge is be properly manged • Pharmacovigilance, risk management programmes • Evaluations and inspections follow WHO and/or ICH standards

21. Difference between PQP and national approval procedures • Only certain categories of products are accepted • Voluntary - no direct legal implications • Free of charge (yet) • Assessment and inspections done by multinational teams • Assessment and inspection outcomes are publicly available, no negative conclusions and findings published (yet) • Issues of IPP fully in responsibility of applicant / manufacturer • Definitive negative conclusions exceptional • Technical assistance and regulatory support possible

22. Prequalified priority essential medicines(July 2009)

24. Countries where prequalified medicines are manufactured (July 2009)

25. Prequalification of Quality Control Laboratories • Invitation for expression of interest issued by WHO • Laboratory Information File submitted by interested QCLs • If needed, technical assistance is provided • Inspection is organised • Currently 10 QCLs is prequalified, 25 in process of prequalification (mostly from Africa) • More information PQP website

26. QCLs Prequalification Procedure (1)June 2009

27. Contribution of PQ to capacity building • Organization of trainings • general and problem specific (HIV/AIDS, TB and antimalarial products, pediatric dosage forms, BE, BE/BCS, GMP) • Trainings of NRA staff and manufacturers frequently combined • Involvement of assessors from NRAs into PQ assessment • Involvement of inspectors from NRAs into PQ inspections • 3 months rotations of experts from NRAs in WHO HQ – PQT

29. Topics of training workshops2006-2008

31. Technical Assistance • Provision of expert consultants to • Manufacturers • Quality control laboratories • Regulators • Assistance focuses on • GMP, GCP or GLP compliance • Regulatory guidance • Assistance is separated from the assessment / inspections and may be followed by specific trainings

32. Technical assistances organized by WHO PQP 2006-2008

33. Conditions for provision of technical assistance Manufacturers: • Participation in the prequalification programme, • Found to be capable and willing to improve • Location in a developing country Products: • Inclusion in the list of expression of interest • High value for Public Health purpose • Poor representation on the Prequalification list.

34. Thank you for attention smidm@who.int