Pre-qualification of products and manufacturers

1. Pre-qualification of products and manufacturers Technical Briefing Seminar 30 September 2003 WHO, Geneva Andre van Zyl, M. Pharm. Project Manager Health Technology and Pharmaceuticals Cluster, Essential Drugs and Medicines Policy, Quality Assurance and Safety: Medicines Tel: +41.22.791.3598 Fax: +41.22.791.4730 World Health Organization E-mail: vanzyla@who.int

2. Challenges for WHO and procurement agencies/organizations • Which way to go to get the best possible protection of public health with the resources available?

3. Quality Assurance System Pre-qualification Access to Products of Acceptable Quality

4. WHO/HTP/EDM/QSM Pre-qualification • What is the problem? • Sub-standard drugs purchased • weak or absent quality assurance systems • Lot of money invested in procurement • no harmonized quality assurance system available for procurement organizations/initiatives • Duplication of work • lack of harmonized standards (GMP inspections) • Risk: Sourcing sub-standard drugs, waste of money and, health risks to patientshe from:

5. WHO/HTP/EDM/QSM Pre-qualification • What should be done? • Pre-qualification: • Specifications of products submitted by suppliers • Unified principles: Evaluation of information on quality • Creating uniform standards: Inspection • Model QAS: • existing quality assurance systems, • creating a single, harmonized quality system and pre-qualification program for use by WHO and its partners

6. Quality Assurance System Pre-qualification Pre-qualification

7. WHO/HTP/EDM/QSM Pre-qualification • Quality Assurance System (QAS) • QSM • Model QAS for UN Procurement organizations • NGOs • Other interested organizations • Informal discussion and first draft • Second draft in progress from: • General Procedure: Pre-qualification • Drafting of the GENERAL PROCEDURE • Comment, amendments, Expert Committee • Pre-qualification: HIV/AIDS drugs • Pilot project

8. WHO/HTP/EDM/QSM General procedure: Pre-qualification • PLANNED ... • General Procedure • Purpose: To verify that products meet - Specifications set - Requirements for multi-source products - Manufactured in compliance with GMP from:

9. WHO/HTP/EDM/QSM General procedure: Pre-qualification Steps of the Procedure • 1. Invitation for EOI • 2. Guidelines for product dossier compilation • 3. Receiving submissions (dossiers) • 4. Screening of dossiers • 5. Dossier evaluation • 6. Site inspection • 7. Reports and outcome • 8. Pre-qualification results • 9. Testing of samples

10. WHO/HTP/EDM/QSM General procedure: Pre-qualification Steps of the Procedure • 1. Invitation for EOI • Wide publication • Open, transparent • Specify products required • 2. Guidelines for product dossier compilation • Multi-source products? • Innovator products?

11. WHO/HTP/EDM/QSM General procedure: Pre-qualification • Guidelines: • Innovator products manufactured and registered in USA, EU, Japan • WHO type CPP • Assessment report by the DRA • Batch certificate • If different information: Stability data and reasons from: • Multi-source products • Dossier with required data as in WHO Manual

12. WHO/HTP/EDM/QSM General procedure: Pre-qualification • What will be required (1) ? • 1. Details of the product • 2. Regulatory situation in other countries • 3. Active pharmaceutical ingredient (s) (API) • 3.1 Properties of the active pharmaceutical ingredient(s) • 3.2 Sites of manufacture • 3.3 Route(s) of synthesis • 3.4 Specifications • API described in a pharmacopoeia: • API not described in a pharmacopoeia: • 3.5 Stability testing • WHO Expert Committee on Specifications for Pharmaceutical Preparations, Thirty-fourth report. Geneva, World Health Organization, 1996: 65-79(WHO TRS, No 863) http://www.ifpma.org/ich5q.html#stability

13. WHO/HTP/EDM/QSM General procedure: Pre-qualification • What will be required (2)? • 4. Finished product • 4.1. Formulation • 4.2. Sites of manufacture • 4.4. Manufacturing procedure • 4.5 Specifications for excipients • 4.6 Specifications for the finished product • 4.7 Container/closure system(s) and other packaging • 4.8 Stability testing

14. WHO/HTP/EDM/QSM General procedure: Pre-qualification • What will be required (3)? • 4.9 Container labelling • 4.10 Product information • 4.11 Patient information and package inserts • 4.12 Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s) • 4.13 Interchange-ability (bio-equivalence studies) • 4.14 Summary of pharmacology, toxicology and efficacy of the product

15. WHO/HTP/EDM/QSM General procedure: Pre-qualification • 3. Receiving of dossiers • 4. Screening of dossiers • Screen for completeness • Inform supplier • Listed for a possible site inspection • 5. Dossier evaluation • Team of experts (pharmaceutical development, bio-equivalence etc) • From Drug regulatory Authorities • Standard: WHO Manual and guidelines " Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority, WHO/DMP/RGS/98.5) • Outcome of the evaluation communicated to supplier

16. WHO/HTP/EDM/QSM General procedure: Pre-qualification • 6. Site inspection • WHO GMP • Inspection team: • Appointed inspector • Experience, qualification, preferably from DRA • Local, national inspectorate • WHO representative • 7. Report and outcome • Reports on dossier evaluation and site inspection • Communicated to supplier/manufacturer • Compliance? Additional information to be submitted?

17. WHO/HTP/EDM/QSM General procedure: Pre-qualification • 8. Pre-qualification results • Meeting standards = Pre-qualified suppliers’ list • WHO Web page • Meeting WHO standards/requirements/recommendations /guidelines • Product and manufacturing site specific • Outcome communicated to supplier/manufacturer and DRA from: • 9. Testing of samples • Samples submitted with product dossier • Random samples of products supplied after pre-qualification and inspections - batch verification • Failure: Investigation and communication to supplier/manufacturer

18. WHO/HTP/EDM/QSM General procedure: Pre-qualification • Other aspects: • Confidentiality undertaking - Signed by evaluators and inspectors • Conflict of interest: • Re-evaluation (re-qualification?) • At regular intervals • Changes made to product by supplier/manufacturer • Manufacturing sites: 2 to 5 years • Dossiers: 5 years or sooner • Other instances (misconduct, complaints, suspension of supply)

19. WHO/HTP/EDM/QSM General procedure: Pre-qualification • Complaints • Investigated • Written report and action to be taken • DRA involvement : • Cost recovery • Possibility for the future

20. Pilot project WHO Pilot Project: Procurement, Quality and Sourcing • HOW DID IT START? • Preparation of quality specification requirements (guidelines) started without project being funded • Two experts (from developed and developing country) working on draft January/February 2001 • Drafts received by 28.02, revised, discussed and combined into single draft document by internal QSM WG, e-mail consultations with limited number of outside experts • Then: As described in the General Procedure

21. Pilot project Pilot Procurement, Quality and Sourcing Project • WHAT DID WE DO… • Pilot Procurement, Quality and Sourcing Project: Access to HIV/AIDS drugs (and diagnostics) of assured quality • Establish and implement the QSM QAS • Test the General Procedure for Pre-qualification • What is the current status, outcome, lessons learnt?m:

22. Pilot project WHO Pilot Project: Procurement, Quality and Sourcing • Partners • UNAIDS • UNFPA • UNICEF • WHO • Supported by the World Bank from: • WHO role • Provide technical assistance in quality related issues

23. Pilot project WHO Pilot Project: Procurement, Quality and Sourcing • EXPECTED OUTCOME... • List with pre-qualified suppliers • Operation of harmonized quality assurance system and pre-qualification program by WHO and other UN organizations • Agreement among interested organizations on: coordination of inspections; evaluation of product quality; training of inspectors; and exchange of inspection reports • Increased collaboration between WHO regions and National Drug Regulatory Authorities (NDRAs)

24. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • Process and history so far … • Invitation EOI (first) published in October 2000, letters received in December 2000 • Guidelines for product dossiers sent to interested suppliers in March 2001 • Given 2 months to submit product file - end May 2001 • Preparing for evaluation (identifying available experts, identifying QC laboratories, providing the background information to experts, preparing TORs for experts etc • Convene an international group of evaluators to evaluate all the files received (beginning June 2001) • Suppliers informed of outcome, additional data requested to be submitted in 60 days.

25. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • Process and history so far … (continued) • Evaluators reviewed additional data in September 2001 • Manufacturing site inspections started • Publication of EOI (second) in October 2001 • Ongoing assessment of dossiers (2001 - current) • Ongoing inspections (2001 - current) • Samples submitted to QC laboratories for analysis • Now fourth EOI • 243 product dossiers assessed

26. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • What are the technical difficulties and problems experienced or revealed as a result of pre-qualification? • Quality of product dossiers varied • Lack of information regarding API, validation, specifications, bio-equivalence • DRAs not applying same standards as recommended by WHO, yet products are registered and used • Very few substances and products have Pharmacopoeia monographs • Dilemma: new drugs or generics? • What standards to apply? If standards not available - full assessment necessary

27. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • Difficulties and problems (cont) Manufacturing site inspections • Manufacturers not ready • Upgrading of facilities to comply with WHO GMP • DRAs issued CPP – yet non-compliance • Inspections reveal non-compliance, e.g. antibiotics (penicillin), hormones and other products manufactured in the same site • No validation • Time needed to respond to report • “double standards” – local vs. international market

28. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • To be noted: • Time is needed to address the shortcomings • Importance of appropriate pre-qualification should not be under- estimated • ? % of drugs in the World are suspected to be counterfeit • Can procurement organizations afford to procure low quality or sub-standard products? • Is it important for WHO (and other UN organizations, interested partners) to ensure a harmonized approach to pre-qualification? • What are the benefits of pre-qualification and a harmonized procedure?

29. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • Results: • First list of products and manufacturers (March 2002) • Now 9th edition of the list with various ARVs and other products including innovator and generic products • Purchasing already took place (tender) • Re-qualification due • Batch verification and ongoing monitoring done • Comparative dissolution planned

30. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • Expanded • Tuberculosis products: First line as well as second line treatment • 119 Product dossiers • Several inspections in various countries • List of products and manufacturers not yet published • Malaria • 27 Product dossiers, mainly artimesinin and combination products • List of product(s) published in August 2003

31. Pilot project Access to HIV/AIDS Drugs and Diagnostics of Acceptable Quality • Expansion? • Planned: • Prequalification of QC laboratories • standards and procedure • Prequalification of procurement agencies • standards and procedure drafted • Other products?