PREQUALIFICATION General overview and procedures

1. PREQUALIFICATION General overview and procedures and practical implications of WHO PQ, FDA registration, registration with PICs member countries for procurement agencies involved in procurement Technical Briefing Seminar for Consultants on Procurement and Supply Management for HIV/AIDS, TB and Malaria Organized by WHO and AMDS Network Copenhagen, Denmark 31 January 2006 • Maija Hietava • M.Sci.Pharm • Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster • Tel: +41.22.791.3598 Fax: +41.22.791.4730 • World Health Organization • E-mail: hietavam@who.int

2. Prequalification of essential medicines • The UN prequalification program is an action plan for expanding access for the hardest hit by • HIV/AIDS • Tuberculosis • Malaria • for ensuring quality, efficacy and safety of medicines all the way through the medicines supply chain.

3. Why the prequalification is needed • Problems • Millions of people living with HIV/AIDS, tuberculosis and malaria, have no or limited access to treatment • Procurement and supply of substandard and counterfeit products in different countries • Weak/absent QA systems of medicines supply chain • Lot of money invested in procurement no harmonized quality assurance system available for procurement organizations • Risks • Sourcing of poor quality products or even counterfeit medicines risk to patients, treatment failure, resistance

4. Challenges of prequalification • Demand for affordable antiretrovirals, anti-malaria drugs and anti-tuberculosis drugs is increasing • Numerous generic manufacturers offering products • Challenges for UN family and procurement agencies/organizations

5. Incorrect ingredient 16% Incorrect amount 17% No active ingredient Other errors 60% 7% Is quality of pharmaceuticals a problem? Substandard drugs is a big problem - antibiotics, antimalarials, antituberculosis antiretrovirals drugs included Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database

6. Prequalification basic principles • Voluntary for participating manufacturers • Legitimate- General procedure and standards approved through WHO Expert Committee system involving all WHO Member States and WHO Governing bodies • Widely discussed • FIP Congress, Nice 2002 • Supported by ICDRA in 2002 and 2004, representing more than 100 national drug regulatory authorities • Transparent(all significant information available on the web site http://mednet3.who.int/prequal/) • Open to both innovators and multisource/generic manufacturers • No costfor applicants during pilot phase

7. Expected outcome of prequalification • List of products and manufacturers/CROs • Meeting international norms and standards on quality, safety, and efficacy (Q, S & E) • Harmonization • Co-operation, training, capacity building – NDRAs, WHO, NGOs • Facilitate access to treatment • Procurement mechanisms (e.g. tender, competition) • Ongoing monitoring of Quality, Safety & Efficacy • WHO commitment to developing

8. Objectives • Propose a list of prequalified manufacturers and products of which the quality, efficacy and safety have been assessed, inspected and controlled to meet international norms and standards. • Gives assurance that international norms and standards are applied at all the steps of the prequalification and at the process itself. • Make possible and speed up access to good quality of medicines. Fast track process for listing can take as little as two months from the date of application.

9. Objectivescont… • Follow-up and regular monitoring of the quality of manufacturers and products • Ensure re-qualification and update of the list of prequalified products and manufacturers as new products and manufacturers meet the standards • Ensure the appropriate control of variations and changes • Develop the local capacity for quality production and clinical studies. • National regulatory authorities (DRA) are involved in dossier assessment and inspections • Producers receive invaluable specific technical feedback • Help the national DRA to build up capacity in assessment, inspection and control meeting international norms and standards

10. How prequalification is organized • Role of WHO: Managing and organizing the project on behalf of the United Nations. • provide technical and scientific supportand • guarantee that international norms and standards are applied all through the process including assessment, inspection (GMP, GCP/GLP) and quality control • Partners: • UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank • Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility) • US FDA tentative approvals – recognition based on information exchange (Confidentiality agreement) • Actors: Mainly assessors and inspectors of National DRAs as well as National Quality Control Laboratories of PIC/S and ICH member countries

11. Steps of prequalification 1. Expression of interest (EOI) from a prospective supplier interested in a voluntary participation in the program. 2. Receipt of the dossier at UNICEF in Copenhagen and the Site Master File in WHO Geneva. • Explicative notes and guidelines are published on the WEB in order to explain how to bring together a product dossier meeting the requirements for prequalification. 3. Screeningof the dossier, "Quality" part, "Clinical" part and samples.  possible inspection 4. Assessment of the dossier and writing of the assessment report and assessment letter. 5. Outcome of the evaluation communicated to supplier

12. Steps of prequalificationcont… 6.Inspection of the site (s) of manufacturing and follow-up inspection when necessary  GMP compliant list of manufacturers 7.Inspection of the Research Laboratory or Contract Research Laboratory (CRO)where the bioequivalence study has been performed GCP compliant list of CROs 8.Conclusion and listingof the product in the prequalification list 9.Publication of the Public Assessment (WHOPAR) and Inspection (WHOPIR) Reports 10.Assessment of the variation when submitted, market survey, de-listing if necessary 11.Re-qualification after 3 years

13. Assessment procedure • Assessment of products dossiersi.e. quality, specifications, pharmaceutical development, bioequivalence etc. • teams of professionals from national drug regulatory authorities (DRA):Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Zimbabwe ... • Copenhagen assessment week • 8 to 12 assessors together during one week at least every two months at UNICEF in Copenhagen • Every dossier is assessed by at least two assessors. • An assessment report is issued; signed by two assessors • Letter summarizing the findings and asking for clarification and additional data if necessary. • Letter is sent first by e-mail to the applicant followed by surface mail

14. Assessment procedure-Product dossiers • Innovator products • Assessment report from DRAs • WHO Certificate of Pharmaceutical Product (CPP) • Batch certificate • Update on changes. • Multisource products (generics) • Full dossier with data and information • Quality : information on starting materials and finished product including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc • Efficacy: Bio-equivalence study or clinical study report • US FDA tentative approvals – recognition based on information exchange (Confidentiality agreement) • Commercial sample

15. Inspection procedure Inspections • Manufacturing site (FPP, packaging) • Active pharmaceutical ingredient(API) • Research laboratory/Contract Research Organization (CRO) • Teamwork of inspectors • WHO representative (qualified GMP inspector) • Inspector from well-established inspectorate (Pharmaceutical Inspection Convention Scheme PIC/S countries) • National inspector(s): Canada, India, China, France, Italy, Switzerland, South-Africa, Thailand… Quality control analysis - upon need but not always necessarily before prequalification and supply; increasingly as part of follow-up

16. Prequalification of quality control laboratories • To increase the local capacity to control the quality of pharmaceutical products • Quality Control Laboratories in sub Saharan Africa as priority • WHO norms and standards for QC laboratories • Prequalification process • Expression of Interest (EOI) • Laboratory Information File (LIF), evaluation • Inventory Audit – help/evaluate • Inspection with the team of inspectors • Prequalified laboratories list public in WHO web site (2 listed) • Reassessment system

17. Training activities • In 2005 three comprehensive 5-day training courses on quality, GMP and BE for TB drugs and ARVs (Malaysia, China, Ukraine) • Course on quality, GMP and BE planned for Jan-06 (China) • Two GMP training courses for NDRA inspectors (South-Africa, China) • Recent GMP training course in Tanzania (with PQ participation) • Training of QC lab officials • Training of PQ staff and inspectors working for WHO in BE study inspections (January-February -06)

18. Current status – December 2005 • Started with HIV/AIDS products in 2001 – malaria and TB products joined later • Prequalified products (Dec 2005) Dossiers arrived • 105 HIV related medicines - 316 (Aug-05) 343 (Dec -05) • 8 anti-tuberculosis medicines - 156 165 • 2 anti-malarial medicines - 48 49 • 115 520 557 • Ongoing assessments and follow-up • Products • Manufacturing sites • CROs

19. Current status – Manufacturers of finished products • In the prequalification list: 15 sites of generics • Asia: 9 sites • Europe: 4 sites • Africa: 2 sites

20. Ongoing monitoring and requalification • Samples taken after supply • Routine inspections and additional inspections • Changes and variations controlled • Products and manufacturers • Requalification (re-assessment) every 3 years • World Health Assembly resolution: WHA57.14 of May 2004 Public reports requested • WHOPIRs (WHO Public inspection report) and WHOPARs (WHO Public Assessment Report) are now on the prequalification web site • Increasing interest in WHO Public Inspection Reports (WHOPIR)

21. PQ web site information for procurement • List of prequalified products • List of manufacturers of manufacturers for APIs (Active Pharmaceutical Ingredient) and FFPs (Finished Pharmaceutical Product), which are GMP compliant • List of GCP compliant Contract Research Organisations (CROs), bio-equivalence centers and research laboratories, which are GCP/GLP compliant • WHOPIRs (WHO Public Inspection Report) • WHOPARs (WHO Public Assessment Report)

22. Global Fund Quality assurance policy related to procurementPractical implications of FDA registration, registration with PICs member countries for procurement • Grant funds to procure products meeting following standards • (A) such product is acceptable under the WHO Prequalification Program; or • (B) such product has been authorized for use by a stringent regulatory authority, FDA tentative approvals; • > 2 manufacturers  option A or B applies AND the product is available (conditions defined) • (C)*If the Principal Recipient determines that there is only one or no (< 2) equivalent pharmaceutical product that meets the standards of either (A) or (B) or if the Principal Recipient determines that the products that meet these standards are unavailable (Defined as inability of the manufacturer to supply a sufficient quantity of finished product within 90 days from date of order), then Grant funds may be used to procure another equivalent pharmaceutical product, provided that such product is selected in accordance with the following, in order of priority: • Application submitted to the WHO Prequalification Program or to a stringent regulatory authority and product manufactured at a GMP compliant site; or • Product manufactured at the GMP compliant site (WHO or ICH or PIC/S**) • (Random quality analysis of products being procured according to these criteria) *(C)UNTIL 30 APRIL 2005: approval by the NDRA of the recipient country. ** ICH or PIC/S countries: see next slide

23. Recommendation If products unavailable, PR informs Secretariat and then: End Option (c) on 30 April 2005  2 Equivalent products Number of equivalent products under option (a) or (b)  2 Equivalent products * Product defined as: chemical + strength + formulation **Unavailability defined as:inability of the manufacturer to supply a sufficient quantity of finished product within 90 days from date of order. The PR is required to notify GF if procuring under (i) or (ii) New Policy, Global Fund (i) In pipeline of Option (a) or (b) + Manufactured in a facility compliant with GMP following inspection by WHO or stringent regulatory authority IF NOT, THEN (ii) Manufactured in a GMP-compliant manufacturing facility

24. Global Fund Quality assurance policy related to procurementPractical implications of FDA registration, registration with PICs member countries for procurement Access to a list of countries that belong to ICH or PIC/S: http://www.theglobalfund.org/pdf/guidelines/List_of_Countries_ICH_PICS.pdf

25. PIC/S= Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme participating regulatory authorities (www.picscheme.org) Australia Austria Belgium Canada Czech Republic Denmark Finland France Germany Greece Hungary Iceland Ireland Italy Latvia Liechtenstein Malaysia Netherlands Norway Poland Portugal Romania Singapore Slovak Republic Spain Sweden Switzerland United Kingdom ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use participating regulatory authorities (www.ich.org ) European Union* Japan United States * Members include: Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Poland, Slovakia, Slovenia, Spain, Sweden, The Netherlands, United Kingdom Countries with "stringent" regulatory authorities

26. Important about Quality of Pharmaceutical Products • Building in the quality • Starts during development phase  documented evidence during the product life cycle that product used in bioequivalence studies (sometimes pilot batches) is the same as the marketed product (big production batches) • Reliable regulatory system and control for stability studies and product variationsduring the life cycle of a product (if changes are not controlled systematically, there could be a significant change during the product life cycle); capacity problems at the regulatory side

27. Important in the regulatory assessment of GENERIC pharmaceuticals • There are requirements especially for • Generics (requirements have not been harmonised yet) • Bioequivalence studies (not always a requirement as such) • Bioequivalence (guidance not harmonised yet) • Variations = changes in the product that may have effect on quality (not always strictly followed or controlled) • Stability studies (not always strictly followed or controlled) • Requirements are controlled by the authorities(capacity problems!) And…..

28. Important in the PQ process related to Quality and Efficacy • Dossier evaluation and Inspections (GMP = manufacturing and GCP for bioequivalence studies) Go hand in hand in the PQ process Sometimes "GMP compliance" alone does not tell the whole truth!! Dossier assessment Inspections GMP/GCP

29. This is misleading and/or misunderstood • WHO type certificate (by WHO Certification Scheme) is used worldwide  But it is notWHO certificate • GMP compliance?? • National GMP requirements are not always those of WHO or stringent authority requirements • Does not tell everything about the product

30. !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!This is correct!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! • WHO Prequalification does not give GMP/GCP certificates, but the GMP/GCP compliant companies are listed in our web site WHO GMP/GCP CERTIFICATE

31. Recent news and new challenges • 2005 changes in GFTAM procurement policy – challenges for prequalification • Confidentiality Agreement with the US FDA • Recognition of US FDA tentative approval process for ARVs based on the scientific assessment done by FDA • Additional fields of cooperation with European Directorate of the Quality Medicines (responsible for European Pharmacopoeia) • Jointly funded post established with UNICEF to help managing the assessment weeks in Copenhagen from Sept 2005 • Constant upgrading guidelines and guidance documents increasing workload • Building of the Quality system • Resources for 2006/2007

32. Summary and conclusion • Good news; quality of generics exists • Relatively large number of products and suppliers comply with the standards • Many potential suppliers appreciating feedback and willing to improve • Unique technical knowledge obtained of products, especially generic antiretrovirals and antimalarials • Bad news: quality assurance has the price • Only limited number of products have met the required standards • Takes time to get into compliance • Data to be generated, tests carried out • GMP upgrade needed • Bad quality generics may undermine the public confidence in generics

33. Summary and conclusion CONT… However… REMEMBER Quality can not be assessed, tested or inspected into the product, BUT has to bebuilt into the product in all the steps … development phase, production, QC, BE study etc. with the help of guidelines, regulatory requirements etc.!! More technical help to manufacturers in developing countries is needed!!

34. Summary and conclusion CONT… No more poor quality medicines for poor people! Equitable access to good quality, safe and effective medicines for all!

35. http://mednet3.who.int/prequal/

36. THANK YOU VERY MUCH FOR YOUR ATTENTION!!