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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 1 Overview of presentation • • • • • • Introduction Determinants of quality/QA GFATM policy on QA WHO prequalification project QC Conclusion 2 What is quality? • Fitness for purpose • Fulfilling of needs • Compliance with specifications 3 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 “ 4 Determinants of Product Quality • Product manufacture • Active ingredients • Equipment and maintenance • Inactive ingredients • Plant environment • Packagingimmediate and external • Manufacturing process • Labeling./packet inserts/ • Quality control program • Product formulation Product information • Handling and storage conditions Product=specific medicine manufactures at a specific site Product=medicine in container with label, packaging insert and information 5 GMP, inspection and licensing Evaluation of product dossier Product Selection Use Storage/handling QA Procurement Prod.Specs. Prequalification Tender contract Storage/distribution GSP,GDP Monitoring of supplier performance 6 Inspections/licensing Critical Elements in QA for Procurement • Product selection • Inspection of shipments • Supplier prequalification • Laboratory testing • Product certification • Appropriate storage, transport, dispensing, and use procedures • Contract specifications • Product monitoring/ reporting system 7 Guide to the Global Fund’s Policies on Procurement and Supply Management Building on: Interagency Guidelines: Operational Principles for Good Pharmaceutical Procurement. WHO, Geneva, 1999. WHO/EDM/PAR/99.5. 8 Guide to the Global Fund’s 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 !! 9 Guide to the Global Fund’s 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. 10 Guide to the Global Fund’s Policies on Procurement and Supply Management 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. 11 Guide to the Global Fund’s Policies on Procurement and Supply Management Multi-source pharmaceutical products 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 recipient’s country. 12 Guide to the Global Fund’s Policies on Procurement and Supply Management Single and limited-source pharmaceutical products 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. 13 Guide to the Global Fund’s Policies on Procurement and Supply Management Single and limited-source pharmaceutical products Grant funds may be used to procure a single- or limitedsource 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 recipient’s country, provided that this clause shall only apply until April 30, 2005. 14 Countries with stringent regulatory authorities Pharmaceutical Inspection Cooperation Scheme (PIC/S) participating regulatory authorities Australia Austria Belgium Canada Czech Republic Denmark Finland France Germany Greece Hungary Iceland Ireland Italy Latvia Liechtenstein Malaysia Netherlands Norway Portugal Romania Singapore Slovak Republic Spain Sweden Switzerland United Kingdom European Union Member States, Japan and United States 15 Guide to the Global Fund’s 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 16 purchase under clause c) prior to April 30, 2005. 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 DRA’s are encourages to expedite registration by accepting the above •Fast track registration •Provisional registration •Waive registration 17 Guide to the Global Fund’s Policies on Procurement and Supply Management Single and limited-source pharmaceutical products Recommendation Number of equivalent products under option (a) or (b) 2 Equivalent products 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) which should be time-limited until products under option a) and b) are available (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 If products unavailable, PR informs Secretariat and then: Evidence of application submitted and GMP compliance IF NOT, THEN (ii) Manufactured in a GMP-compliant manufacturing facility Evidence of GMP compliance 18 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 19 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 20 http://mednet3.who.int/prequal 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 2nd line ARVs 8 paediatric formulations 35 other products for HIV-care (non-ARV) 6 originator products 29 generics hiv_suppliersJune05.pdf 21 WHO Prequalification Project Malaria As of 2005: Malaria products: 2 products only: Artesunate 50 mg tablets Arthemeter/Lumefantrine 20/120mg tablets mal_suppliers.pdf 22 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 23 WHO Prequalification Project TB As of 2005: TB products: 7 products only: tub_suppliers.pdf 24 WHO Prequalification Projectwithdrawals Withdrawals from of products because of : non-compliant with international standards of Good Clinical Practice and Good Laboratory Practice 25 WHO Prequalification Projectwithdrawals 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. 26 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” 27 GMP, licensing Evaluation of product dossier Product Selection QC Use Storage/handling Inspections/licensing QA Procurement Prod.Specs. Prequalification Tender contract QC Storage/distribution QC GSP,GDP 28 Inspections/licensing QC of “new” ARVs WHO Monographs: WHO Draft monographs for comment: •Didanosine •Stavudine •Indinavir sulfate •Lamuvidine •Nelfinavir mesilate •Nelfinavir mesilate tablets •Nevirapinhe •Nelfinavir mesilate oral; powder •Ritonavir • Saquinavir mesilate capsules •Saquinavir •Saquinavir mesilate 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 29 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 d’Ivoire 30 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 31 Counterfeit malaria medicines • Recent reports of counterfeit antimalarials : – – – – – – – – – – Chloroquine Quinine Sulphadoxine-pyrimethamine (Fansidar TM) Metakelfin TM Mefloquine Halofantrine Primaquine Artesunate Intramuscular artemether Dihydroartemisinin ? 32 Fake artesunate in mainland SE Asia 2000-1 • 38 % of shop bought artesunate counterfeit, containing no active drug 33 Paul Newton, Welcome Foundation 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 34 Paul Newton, Welcome Foundation Genuine Hologram Fake Artesunate Type 2 35 Genuine Hologram Fake Artesunate Type 3 36 Genuine Hologram Fake Artesunate Type 4 37 Genuine Hologram Fake Artesunate Type 5 38 Genuine Hologram Fake Artesunate Type 6 39 Genuine Hologram Fake Artesunate Type 7 40 Rapid Alert System on combating counterfeit drugs http://218.111.249.28/ras 41 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 42 • Increase awareness of the problems 43 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 44