1. 1 QA /QC including issues related to GF policies and prequalification :general principles Truls Eriksen Technical Officer HIV/AIDS and STI WHO Western Pacific Regional Office

2. 2 Overview of presentation Introduction Determinants of quality/QA GFATM policy on QA WHO prequalification project QC Conclusion

3. 3 What is quality? Fitness for purpose Fulfilling of needs Compliance with specifications

4. 4 What is quality assurance? QA is the sum total of the organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use; Quality assurance is about getting it right

5. 5 Determinants of Product Quality Active ingredients Inactive ingredients Packaging immediate and external Labeling./packet inserts/ Product information Handling and storage conditions Product manufacture Equipment and maintenance Plant environment Manufacturing process Quality control program Product formulation Product=specific medicine manufactures at a specific site Product=medicine in container with label, packaging insert and information

6. 6 Product Selection Procurement Storage/distribution Use Prod.Specs. Prequalification Tender contract Monitoring of supplier performance GSP,GDP Inspections/licensing QA Storage/handling GMP, inspection and licensing Evaluation of product dossier

7. 7 Critical Elements in QA for Procurement Product selection Supplier prequalification Product certification Contract specifications Inspection of shipments Laboratory testing Appropriate storage, transport, dispensing, and use procedures Product monitoring/ reporting system

8. 8 Guide to the Global Funds Policies on Procurement and Supply Management Building on: Interagency Guidelines: Operational Principles for Good Pharmaceutical Procurement. WHO, Geneva, 1999. WHO/EDM/PAR/99.5.

9. 9 Guide to the Global Funds Policies on Procurement and Supply Management Before May 2005: Products bought using GF must be: WHO prequalified; or Approved by Stringent Regulatory Authority; or Approved by National Regulatory Authority After May 2005: WHO prequalified; or Approved by Stringent Regulatory Authority Quality standard has been raised !!

10. 10 Guide to the Global Funds Policies on Procurement and Supply Management Quality assurance refers to the management activities required to ensure that the medicines (or other health products) that reach patients are safe, effective and acceptable to the patient. These activities may include, but are not limited to, (drug) registration, pre-qualification and quality control.

11. 11 Pharmaceuticals procured with Global Fund resources are subject to authorization by the National Drug Regulatory Authority (NDRA) in the country in which they are used, following its standard practices for drug registration (or other forms of authorization, such as authorizations for special use) for pharmaceutical products. Guide to the Global Funds Policies on Procurement and Supply Management

12. 12 Multi-source pharmaceutical products are off-patent products that have a prior history of safe and efficacious use. Multi-source pharmaceutical products tend to be available from a wide range of manufacturers around the world. For such multi-source products, there are no additional requirements other than verification of compliance with quality standards must be conducted in accordance with relevant requirements of the NDRA in the recipients country. Guide to the Global Funds Policies on Procurement and Supply Management Multi-source pharmaceutical products

13. 13 Products that are available only from a single supplier, normally the originator company, are referred to as single source products. If in addition to the single supplier there are a limited number of other suppliers, the product is referred to as a limited-source product. Many of the antiretrovirals and antimalarials belong to the latter category. Guide to the Global Funds Policies on Procurement and Supply Management Single and limited-source pharmaceutical products

14. 14 Grant funds may be used to procure a single- or limited- source pharmaceutical product provided that such product meets one of the following standards: a) Have been found to be acceptable by the UN Procurement Quality and Sourcing Project (also known as the WHO Prequalification Project ); or b) Have been authorized for consumption in their country by a stringent regulatory authority c) Have been authorized by the NDRA in the recipients country, provided that this clause shall only apply until April 30, 2005. Guide to the Global Funds Policies on Procurement and Supply Management Single and limited-source pharmaceutical products

15. 15 Countries with stringent regulatory authorities Pharmaceutical Inspection Cooperation Scheme (PIC/S) participating regulatory authorities Australia Greece Norway Austria Hungary Portugal Belgium Iceland Romania Canada Ireland Singapore Czech Republic Italy Slovak Republic Denmark Latvia Spain Finland Liechtenstein Sweden France Malaysia Switzerland Germany Netherlands United Kingdom European Union Member States, Japan and United States

16. 16 Guide to the Global Funds Policies on Procurement and Supply Management Single and limited-source pharmaceutical products After April 30, 2005, Grant funds may only be used to procure single- or limited-source pharmaceutical products that meet the requirements of the two standards set out in a) and b), provided that:. (1)Contracts entered into by the Principal Recipient on or before April 30, 2005 with suppliers for products that qualified for purchase under clause c) may be honoured until such contracts expire or otherwise terminate. (2) After April 30, 2005, the Principal Recipient may not enter into any new contracts, nor extend any existing contracts, for the supply of products that would have qualified for purchase under clause c) prior to April 30, 2005.

17. 17 NDRA marketing authorization (registration) for new products For products that have passed the WHO Prequalification Project review, or have been authorized by stringent regulatory authority DRAs are encourages to expedite registration by accepting the above Fast track registration Provisional registration Waive registration

18. 18 2 Equivalent products Number of equivalent products under option (a) or (b) Recommendation (a), (b) End Option (c) on 30 April 2005 (i) In pipeline of Option (a) or (b) + Manufactured in a facility compliant with GMP following inspection by WHO or stringent regulatory authority 2 Equivalent products If products unavailable, PR informs Secretariat and then: * Product defined as: chemical + strength + formulation ** Unavailability defined as: i nability 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) which should be time-limited until products under option a) and b) are available Guide to the Global Funds Policies on Procurement and Supply Management Single and limited-source pharmaceutical products Evidence of application submitted and GMP compliance Evidence of GMP compliance IF NOT, THEN (ii) Manufactured in a GMP-compliant manufacturing facility

19. 19 Use of option i) or ii) QC of samples is required and GF will contract an independent third-part to conduct random quality analysis In general QC should be carried out for quality monitoring Laboratories used must meet the following criteria 1.Be prequalified 2.ISO17025 or EN45002 Accreditation 3.Acceptance by stringent regulatory authority

20. 20 WHO Prequalification Project I. Assessment of products dossiers i.e. quality specifications, pharmaceutical development, bioequivalence etc. : teams of professionals from national drug regulatory authorities: Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Zimbabwe... II. Manufacturing site inspections: teamwork of inspectors: WHO representative (qualified GMP inspector), inspector from well-established inspectorate (Pharmaceutical Inspection Convention Scheme countries) and national inspector(s): Canada, France, Italy, Switzerland, The Netherlands … Quality control analysis - upon need but not always necessarily before prequalification and supply, increasingly as part of follow-up http://mednet3.who.int/prequal

21. 21 WHO Prequalification Project HIV/AIDS As of June 2005: 88 HIV/AIDS products 53 ARVs 34 originator products (30single, 4FDCs) 19 generic products (15 single, 4 FDCs) 14 2 nd line ARVs 8 paediatric formulations 35 other products for HIV-care (non-ARV) 6 originator products 29 generics hiv_suppliersJune05.pdfhiv_suppliersJune05.pdf

22. 22 WHO Prequalification Project Malaria As of 2005: Malaria products: 2 products only: Artesunate 50 mg tablets Arthemeter/Lumefantrine 20/120mg tablets mal_suppliers.pdf

23. 23 WHO Prequalification Project Malaria However, 25 products are currently being evaluated 4 artemether capsules/tablets 7 artemether inj. 5 artesunate tablets 3 artesunate rectal 3 artesunate+ amodiaquine tablets 3 artesunate+sulfadoxine+pyrimethamine tablets 1 Dihydroartemesinine/piperaquine phosphate tablets

24. 24 WHO Prequalification Project TB As of 2005: TB products: 7 products only: tub_suppliers.pdf

25. 25 WHO Prequalification Project- withdrawals Withdrawals from of products because of : non-compliant with international standards of Good Clinical Practice and Good Laboratory Practice

26. 26 WHO Prequalification Project- withdrawals WHO's advice to countries is that, in principle, patients should suspend the use of de-listed medicines and switch to other prequalified products. The risk of withholding treatment is higher than that of providing medicines whose bioequivalence is not proven but which have demonstrated quality and safety. A switch to non-prequalified products is not recommended, as their quality has not been documented by WHO. However, if it is difficult to obtain alternative prequalified products immediately, it is recommended that patients continue the use of de-listed products.

27. 27 Quality Control (QC) Part of quality assurance Testing to confirm compliance with specification QC useful in monitoring product quality during storage/distribution/use Screening for Counterfeit medicines Quality needs to be built into a product during design, formulation and manufacture Can not test quality into a product

28. 28 Product Selection Procurement Storage/distribution Use Prod.Specs. Prequalification Tender contract GSP,GDP Inspections/licensing QA Storage/handling Inspections/licensing GMP, licensing Evaluation of product dossier QC

29. 29 QC of new ARVs WHO Monographs: Didanosine Indinavir sulfate Nelfinavir mesilate Nevirapinhe Ritonavir Saquinavir Saquinavir mesilate WHO Draft monographs for comment: Stavudine Lamuvidine Nelfinavir mesilate tablets Nelfinavir mesilate oral; powder Saquinavir mesilate capsules The Int. Chem. Ref substances required for the monograph for Didanosine and Nevirapine are available. Those required for the other monographs are in preparation and notification will be given (on this website) when they are available

30. 30 Counterfeit ARVs Information Exchange System Alert No. 110 Counterfeit triple antiretroviral combination product (Ginovir 3D) zidovudine (200 mg), lamivudine (150 mg) and indinavir (40 mg). detected in Côte dIvoire

31. 31 WHO Definition of a counterfeit medicine A product that is deliberately and fraudulently mislabeled with respect to source and/or identity. Counterfeiting can apply to both generic and branded products. Counterfeit products may include: –products with the correct ingredients –with wrong ingredients –without ingredients –with incorrect quantities of active ingredients –with fake packaging

32. 32 Counterfeit malaria medicines Recent reports of counterfeit antimalarials : –Chloroquine –Quinine –Sulphadoxine-pyrimethamine (Fansidar TM ) –Metakelfin TM –Mefloquine –Halofantrine –Primaquine –Artesunate –Intramuscular artemether –Dihydroartemisinin ?

33. 33 Fake artesunate in mainland SE Asia 2000-1 38 % of shop bought artesunate counterfeit, containing no active drug Paul Newton, Welcome Foundation

34. 34 Repeat artesunate survey 2002-3 In the same areas, by Dondorp et al. 188 artesunate samples 58 % artesunate blisterpacks contained no artesunate. All labelled as made by Guilin Pharma 9 % of mefloquine was substandard and probably fake No counterfeit artesunate injection or oral artemether, dihydroartemisinin were found Paul Newton, Welcome Foundation

35. 35 Genuine Hologram Fake Artesunate Type 2

36. 36 Genuine Hologram Fake Artesunate Type 3

37. 37 Genuine Hologram Fake Artesunate Type 4

38. 38 Genuine Hologram Fake Artesunate Type 5

39. 39 Genuine Hologram Fake Artesunate Type 6

40. 40 Genuine Hologram Fake Artesunate Type 7

41. 41 Rapid Alert System on combating counterfeit drugs http://218.111.249.28/ras

42. 42 Rapid Alert System Information System for reported cases Repository of reports and response data Alert mechanism enhancing process flow Platform for communication & collaboration Objectives: To transmit alerts on counterfeit medicines Support professional assessment Improve national & international smart partnership & networking Reduce the incidence of counterfeit medicines Increase awareness of the problems

43. 43

44. 44 Conclusion - Quality can be assured through: Prequalification of products/manufacturers WHO Prequalification Project Prior registration in countries with stringent regulatory authority National Registration by DRA (fast track) Maintaining product quality through: Proper storage (GSP) Proper distribution (GDP), dispensing and use Monitoring of quality through out the distribution chain