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

2. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 2 |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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 3 |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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 4 |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 developing countries 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 5 |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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 6 |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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 7 |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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 8 |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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 9 |9 | I I Expression of Interest Compliance Additional information and data Corrective actions Compliance Assessment Inspections Steps in prequalification Prequalification Maintenance and monitoring Product dossier SMF

10. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 11 | Assessors participating in PQ assessment (all visits in 2001-2008, share of the WHO regions) In total 603 participations

12. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 17 | Prequalification assessment  Combined products, new dosage forms, new indications Assessment May require safety and efficacy data Monitoring after prequalification

18. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 19 | www.who.int/prequal/

20. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 22 | Prequalified priority essential medicines Prequalified priority essential medicines (July 2009)

23. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 23 |

24. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 24 | Countries where prequalified medicines are manufactured Countries where prequalified medicines are manufactured (July 2009)

25. WHO Prequalification Programme for Priority Medicines, Jakarta, October 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 26 | QCLs Prequalification Procedure (1) QCLs Prequalification Procedure (1) June 2009

27. WHO Prequalification Programme for Priority Medicines, Jakarta, October 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

28. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 28 |

29. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 29 | Topics of training workshops 2006-2008

30. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 30 |

31. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 32 | Technical assistances organized by WHO PQP 2006-2008

33. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 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. WHO Prequalification Programme for Priority Medicines, Jakarta, October 2009 34 | Thank you for attention smidm@who.int