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 to selected priority medicines 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.

3. Categories of medicines invited • Primary categories of medicines: • HIV/AIDS • Malaria • Tuberculosis • Later added: • Reproductive health • Influenza • Acute diarrhoea • Potentially other categories of products, if there is the need

4. Scope of medicines invited • Limited to priority essential medicines • Published in invitations for Expression of Interest (EOI) on Prequalification website • EOIs include medicines that have been identified by the respective WHO disease departments as vital to effective treatment and to expanding treatment programmes

5. 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 developing countries into the project supports their capacity to produce according to international norms and standards

6. 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

7. 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)

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

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

10. Two prequalification routes Invitation for expression of Interest Medicine assessed by SRA Medicine not assessed by SRA Valid for innovators and generics Dossier and SMF submitted for assessment SRA registration (assessment and compliance check) WHO assessment and inspections organized Simplified review Prequalification Compliance Acceptance

11. 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

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 • Inspections are product oriented • APIs and Bioequivalence studies inspected based on risk assessment

13. 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

14. Prequalification assessment • Multisource products not registered by SRA 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

15. 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

16. 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

17. 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

18. Assessment actual times for 2010(median number of days) Initial screening from receipt of dossier - 10 days Dossier assessment: WHO time from acceptance of dossier to completion of assessment - 260 days Total WHO and manufacturer (stop-clock) time - 568 days Receipt of variation to completion of assessment - 36 days

19. 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, training materials

20. www.who.int/prequal/

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 IP fully in responsibility of applicant / manufacturer • Definitive negative conclusions exceptional • Technical assistance and regulatory support possible

22. Potential benefits for manufacturers • Participation in tender procedures organized by international procurers and financial profit • Recognition as being WHO listed company • Facilitated registration in some recipient countries • Reduction of inspections from recipient countries • Possibility to be assisted by expert consultants (GMP, dossier) • Learning process improving company's chance to succeed with submissions to SRAs

23. Prequalified priority essential medicines(September 2010)

25. Prequalified priority essential medicines(September 2010)

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

27. 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 17 QCLs is prequalified, 28 in process of prequalification (mostly from Africa) • More information PQP website

28. QCLs Prequalification ProcedureSeptember 2010 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) • Canada, K.A.B.S. Laboratories (2010) • Ukraine, CLQCM (2010) • Ukraine, LPA (2010) • Peru, CNCC (2010) • Uruguay, CCCM (2010) • Bolivia CONCAMYT (2010)

29. Examples of quality monitoring projects • First- and second-line anti-TB medicines • Rifampicin caps, Isoniazid tabl & inj, Rifampicin/Isoniazid tabl • Kanamycin powder for inj, Ofloxacin tabl and solution for infusion • Eastern Europe and NIS countries with high multidrug-resistant TB and extensively drug-resistant TB (Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan) • ACTs (most sold and recommended by national guidelines), sulfadoxine-pyrimethamine, oral dosage forms • Artemether/lumefantrine, artesunate/amodiaquine (both co-blistered and FDCs), sulfadoxine/pyrimethamine, sulfamethoxypyrazine/pyrimethamine • In 6 African countries (Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania)

30. 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

34. Topics of training workshops2006-2010 (VIII)

35. 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

36. TAs organized by PQP in 2006-2010(September 2010)

37. TAs organized in individual countries

38. 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.

39. Thank you for attention smidm@who.int