1. | Slide 1 of 34 April 2007 Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007 Pharmaceutical Development

2. | Slide 2 of 34 April 2007 Pharmaceutical Development Introduction to the Prequalification Programme Presenter: Dr AJ van Zyl vanzyla@who.int

3. | Slide 3 of 34 April 2007 Prequalification of essential medicines  The UN prequalification program is an action plan for expanding access for the hardest hit by ensuring quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM)

4. | Slide 4 of 34 April 2007 Why the prequalification is needed  Problems Millions of people living with HIV/AIDS, tuberculosis and malaria, have no or limited access to treatment Substandard and counterfeit products in different countries Weak or absent QA systems of medicines supply chain Lot of money invested in procurement  no harmonized quality assurance system available for procurement organizations/initiatives yet;  products with very different quality sourced

5. | Slide 5 of 34 April 2007 Why the prequalification is needed  Risks Sourcing of poor quality products or even counterfeit medicines  risk to patients, toxic reactions, treatment failure, resistance  bad quality (generic) products undermine public confidence

6. | Slide 6 of 34 April 2007 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 International Conference of Drug Regulatory Authorities (ICDRA) in 2002 and 2004, representing more than 100 national drug regulatory authorities; discussed also in 12 th ICDRA 2006

7. | Slide 7 of 34 April 2007 Prequalification basic principles  Transparent (all information available on the web site http://mednet3.who.int/prequal/ ) http://mednet3.who.int/prequal/  Open to both innovators and multisource / generic manufacturers  No cost for applicants as per today (in future fees considered)  Started as a Pilot Project (HIV/AIDS) – expanded…

8. | Slide 8 of 34 April 2007 Expected outcome of prequalification  Public lists of products and manufacturing units Meeting international norms and standards on quality, safety, and efficacy  Capacity building and harmonization National Drug Regulatory Authorities (DRAs), manufacturers, WHO treatment programs, NGOs, procurement organizations  Ongoing quality monitoring Ongoing monitoring of prequalified products Prequalification of quality control laboratories (pilot project, focus on AFRO at present with 3 QC labs prequalified – see web site for more information  Facilitate access to treatment Through fair procurement mechanisms (e.g. tender, competition based on the same quality standards) WHO commitment to developing better access to quality medicines

9. | Slide 9 of 34 April 2007 How prequalification is organized?  Role of WHO: Managing and organizing the project on behalf of the United Nations. Provides technical and scientific support and 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); HIV/AIDS Department Reproductive Health products

10. | Slide 10 of 34 April 2007 Prequalification Review additional data, corrective actions Changes/variations Dossier accepted and assessed Inspections performed EOI Dossier submission Listing Requalification QC

11. | Slide 11 of 34 April 2007 Prequalification PQ Reproductive health QC Labs TB (first and second line) Malaria Technical Assistance HIV/AIDS

12. | Slide 12 of 34 April 2007 How prequalification is organized?  Assessments  Mainly qualified team of assessors  Inspections  Inspectors from National DRAs (also from National Quality Control Laboratories) of ICH and associated countries, and inspectorates belonging to PIC/S plus observers

13. | Slide 13 of 34 April 2007 Assessment procedure  Assessment of products dossiers i.e. quality specifications, pharmaceutical development, bioequivalence etc.  teams of professionals from national drug regulatory authorities (DRA): Brazil, Canada, China Cuba, Denmark, Estonia, Ethiopia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe...  Copenhagen assessment week 8 to 16 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; signed by two assessors (email and post); data base generated

14. | Slide 14 of 34 April 2007 Assessment procedure- Product dossiers  Innovator products Abridged procedure if approved by stringent authorities like EMEA and US FDA Assessment report from DRAs, WHO Certificate of Pharmaceutical Product (CPP), batch certificate, update on changes Trusting scientific expertise of well-established DRAs  Multisource products Full dossier with all data and information requested Quality : information on starting materials and finished product including API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc Efficacy and safety: Bio-equivalence study or clinical study report US FDA tentative approvals for ARVs – recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO); the same approach will soon apply for EU Art58 and Canadian JCPA procedure)  Commercial sample

15. | Slide 15 of 34 April 2007 Prequalification: Generics or not? FDA requirements for generic drugs (www.fda.gov/cder/ogd)www.fda.gov/cder/ogd Generic drugs must: 1. contain the same active ingredients as the innovator drug 2. be identical in strength, dosage form, and route of administration 3. have the same use indications 4. meet the same batch requirements for identity, strength, purity and quality 5. be manufactured under the same strict standards of GMP required for innovator products. 6. be bio-equivalent Prequalification requirements for generics – fully line with major regulatory agencies

16. | Slide 16 of 34 April 2007 Prequalification: Generics or not? What if not generics – full data set to prove the safety (including preclinical toxicology) and efficacy has to be presented Not all non-innovator products in prequalification pipeline can be defined as generics – no innovator may be available

17. | Slide 17 of 34 April 2007 Inspection procedure  Inspections  Manufacturing site (final product, packaging)  Active pharmaceutical ingredient (API)  Research laboratory or Contract Research Organization (CRO)  Teamwork of inspectors WHO representative (qualified GMP inspector) Inspector from well-established inspectorate (Pharmaceutical Inspection Cooperation Scheme countries – PIC/S) National inspector(s) invited to be part of the team but have NO decision making power (different GMP standards, potential conflict of interest)  Quality control analysis  Upon need – now increased programme

18. | Slide 18 of 34 April 2007 Capacity building (Training activities) In 2005 three one week comprehensive training courses on quality of TB drugs and ARVs (Malaysia, China, Ukraine) Three GMP training courses (South-Africa, China), GMP training course in Tanzania (with PQ participation) Specific to antimalarial medicines (ACTs) training courses for regulators and industries (in 2004 - Thailand, in January 2006 – China, in August 2006 - Tanzania) Introduction to the prequalification course in Vietnam (January 2006) All training course materials are posted on the web site to assist manufacturers to prepare quality dossiers and readiness for inspections

19. | Slide 19 of 34 April 2007 Current status  Started with HIV/AIDS products in 2001 – malaria and TB products joined later  Prequalified products (Sept 2006) "Active" dossiers in pipeline (2006) 152HIV related medicines200 (April -06) 8 anti-tuberculosis medicines 65 5 anti-malarial medicines 40 134 305 Ongoing assessments and follow-up Products Manufacturing sites (both for APIs and finished dosage forms) and CROs

20. | Slide 20 of 34 April 2007 Antimalarials prequalified so far Artesunate 50mg Tablets Sanofi-Synthelabo Blister 25 blister of 12 Artemether/ 20mg Tablets Novartis Pharma Blister 30 blisters of 6, 12, 18 or 24 lumefantrine 120mg Artemotil 50mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml Artemotil 150mg/ml Sol inj ARTECEF BV 10 or 100 ampoules each of 1ml Artesunate 50mgTablets Guilin Pharmaceutical Co Ltd PVC/AI Blister 12

21. | Slide 21 of 34 April 2007 Problems encountered (artemisinin derivative containing products (I) General –Very few innovator products –Many not typical generics as well –Very few antimalarials recommended by treatment guidelines approved in ICH and associated countries –Limited DRAs and regulatory experts having experience with antimalarials –Fixed dose combinations more complicated than single component products Quality related issues –Manufacturers do not comply with GMP (even if located in the EU or EFTA countries – products not registered and produced only for export) –Many dossiers have outstanding deficiencies in proving the quality of the product – non-compliance with established specifications or poorly defined manufacturers specifications; stability data either missing or not meeting requirements; no method validation etc.

22. | Slide 22 of 34 April 2007 Problems encountered artemisinin derivatives (II) Lack of reference products for bioequivalence studies –For generic drugs safety and efficacy is proved by bioequivalence studies assuming that the same blood concentrations of active ingredient give the same safety and efficacy profile –Only exceptions are artesunate from Guilin Pharma and the Novartis FDC product (artemether+lumefantrine)

23. | Slide 23 of 34 April 2007 Problems encountered artemisinin derivatives (II) Safety and efficacy related issues –Insufficient reporting of the evidence about the clinical efficacy and safety..... No fully documented trial reports No full evaluation of published literature –No characterisation of pharmacokinetic properties of the product: for innovators and generics as well unacceptable –General statements: No interaction known -> clearly not true; No (or minimal) adverse events: information has to be provided through literature survey if no original data –Too broad efficacy claims –Galenical development history not provided -> Do results of earlier studies apply to current formulation? Many manufacturers involved have no experience in these areas

24. | Slide 24 of 34 April 2007 Measures taken to get more products prequalified General –Very limited resources –PQ programme started with only ONE professional, today it has four and by the end of 2006 it will have at least six to eight (three will be secondments from Governments) –Business plan created and funding proposals created Specific –Internal SOPs and work procedures to facilitate process created –Specific for antimalarials "Note for Applicants" prepared –Discussions with manufacturers, training workshops

25. | Slide 25 of 34 April 2007 Prequalification of national quality control laboratories in priority regions Why? –Capacity building to ensure continuous monitoring of quality How? –Auditing and assisting to get up to the standards –Linked to already existing activities, such as external quality assessment scheme (focuses on methods whereas PQ focuses on internal quality systems), International Pharmacopoeia work (monographs and international chemical reference substances) etc.

26. | Slide 26 of 34 April 2007 Prequalification of national quality control laboratories in priority regions 3 laboratories prequalified to date 2 in South Africa 1 in Algeria Another one close Several received Technical assistance

27. | Slide 27 of 34 April 2007 Other regulatory pathways EU legal basis Article 58 Regulation (EC) 726/2004 WHO as "gate keeper" Committee for Human Medicinal Products (CHMP) Scientific opinion in cooperation with WHO Part of the EU response –To the need to protect public health –To give assistance to non-EU countries –Rapid access to important medicines

28. | Slide 28 of 34 April 2007 Other regulatory pathways (2)? US FDA tentative approvals linked to PEPFAR Canadian Access to medicines scheme –WHO cooperation with the above mentioned

29. | Slide 29 of 34 April 2007 News regarding prequalification programme Programme is winning more support –UnitAID, Gates Foundation etc Expectations to the programme are increasing, includes paediatric medicines Need for more –Capacity building targeting both regulators and manufacturers –NEW things planned Technical assistance to manufacturers – need for minimizing potential conflicts of interest, setting criteria of eligibility Planned involvement of inspectors from developing countries Potential MOUs with selected national regulatory authorities...

30. | Slide 30 of 34 April 2007 Summary and conclusion  Prequalification covers e.g.:  HIV/AIDS, TB, Malaria, Reproductive health products  Dossiers, Manufacturers and CROs  QC laboratories  Training and capacity building  Technical assistance  Quality monitoring (sampling, testing, follow-up of complaints and inspections with verification)

31. | Slide 31 of 34 April 2007 Summary and conclusion  Positive message… –Relatively large number of products and suppliers comply with the standards (mostly ARVs so far) –Many potential suppliers appreciating feedback and willing to improve –Unique technical knowledge obtained about products, especially about generic antiretrovirals and antimalarials –Capacity building component a lot appreciated

32. | Slide 32 of 34 April 2007 Summary and conclusion  Challenges… –Only limited number of products have met the required standards (especially malaria and TB products) –Takes time to get into compliance Data to be generated, tests to be carried out … GMP upgrade needed –Quality has its price

33. | Slide 33 of 34 April 2007 Pharmaceutical Development For more details, guidelines, training, etc - please visit the website at www.who.int/medicineswww.who.int/medicines or http://mednet3.who.int/prequal/

34. | Slide 34 of 34 April 2007 Pharmaceutical Development Thank you Acknowledgement Dr L Rago