Supply and quality of antimalarial medicines and diagnostics: introduction of issues Dr Andrea Bosman Global Malaria Programme Geneva, 9 July 2009 RBM Case Management Working Group (CMWG) of

9 July | GLOBAL MALARIA PROGRAMME The built-in chemical instability of artemisinin and its derivatives, necessary for their biological action, causes pharmaceutical problems both in the manufacturing process and in the co-formulation with other compounds. The problems of instability are accelerated under tropical conditions. The requirement for observing stringent quality manufacturing standards are particularly important for these compounds, for which manufacturers and national regulatory authorities have limited experience. Differences in product quality selection criteria create opportunities for sub-standard artemisinin-based antimalarial medicines to access international funds for procurement, and discourage compliance with more stringent quality standards. Quality requirements of artemisinin-based antimalarial medicines

9 July | GLOBAL MALARIA PROGRAMME UNICEF/WHO tender criteria Inter-agency harmonized criteria for the selection of artemisinin-based antimalarials GFATM QAP criteria Restricted annual joint tender 1. WHO Treatment Guidelines 2. PQ approved or SRA-registered 3. Dossier accepted by PQ or SRA 4. GMP compliance after inspection by WHO PQ or SRA Dossier submission only to SRA Inclusion only in National Treatment Guidelines Evaluation of IPPQ: - registration information, - regulatory (licensing) situation, - finished product specifications and compliance with International Pharmacopoeia standards, - stability data (in Zone IV), - labeling information, - API characteristics and certification. Review of efficacy and safety

9 July | GLOBAL MALARIA PROGRAMME New GFATM QA policy and selection of finished pharmaceutical products PRs may procure a FPP recommended by the ERP For ARVs, antimalarial and anti-TB FPPs Number of FPPs WHO prequalified or SRA authorized If 2 or more FPPs WHO prequalified or SRA authorized If 1 or 0 FPPs WHO prequalified or SRA authorized PR has to procure one of these FPPs If product not available° ° Inability to supply sufficient quantity of product within 90 days from date of order Courtesy of Dr Sophie Logez, The Global Fund

9 July | GLOBAL MALARIA PROGRAMME Artemisinin-based antimalarial Medicines on WHO/UNICEF procurement lists (updated: ) International Non-Proprietary Name (INN) of product StrengthDosage formSupplierPresentationPackaging Artemether / lumefantrine20mg/120mgFixed dose tabletsAjanta, India 6x1 30 blisters / box 6x2 6x3 6x4 Cipla, India 6x1 30 blisters / box 6x2 6x3 6x4 Ipca, India 6x1 Single blisters 6x2 6x3 6x4 Novartis, 6x1 30 blisters / box China/USA 6x2 6x3 6x4 Artesunate + amodiaquine25mg+67.5mgFixed dose tabletsSanofi Aventis325 blisters / box 50mg+135mg 100mg+270mg 6 50mg + 150mg (base)Co-blistered tabletsGuilin, China3+325 blisters / box mg + 153mg (base) Co-blistered tabletsCipla, India3+325 blisters / box Ipca, India3+310 or 100 treatments / box or 100 treatments / box or 100 treatments / box Strides, India treatments / box Artesunate + mefloquine200mg + 250mgCo-blistered tablets Mepha, Switzerland 3+6Single blisters Artesunate + 50mg + 500/25mgCo-blistered tabletsCipla, India 3+1 Single blisters sulfadoxine / pyrimethamine Artemether20mg/mlInjection Dafra, Belgium 3 3 Ampoules / pack 1010 Ampoules / pack 80mg/ml 5 5 Ampoules / pack Prequalified

9 July | GLOBAL MALARIA PROGRAMME Antimalarials recommended by ERP (with effect on ) Artemether/Lumefantrine20mg/120mgTAB Ipca Laboratories Ltd, Plot No. 255/1, Village Athal, Dadra and Nagar Haveli(U.T), Silvassa , India. Al/PVC/PVDC blister(pack of 1x6's, 2x6's, 3x6's, 4x6's and 3x8's) Artemether/Lumefantrine40mg/240mgTAB Cipla Limited, MIDC, Patalinga, Plot A-33, -42 MIDC, Dist Raigad, Maharashtra, India Al/Al blister(pack of 3's, 6's and 12's) Artesunate+ Sulphadoxine/ Pyramethine 50mg + (500 mg+25mg) TAB Cipla Limited, MIDC, Patalinga, Plot A-33, -42 MIDC, Dist Raigad, Maharashtra, India CO BLISTER- PVC/PE/PVDC film blister with (12 Art+ 3 SP tabs), (6 Art+ 2 SP tabs),(3 Art+ 1SP tab)

Quality Control of Pharmaceutical Products Quality Control TestMulti Source Single and limited source products complying with option A or B Single and limited source products complying with option C ResponsibilityPR or sub recipientGF Secretariat Condition (s)In accordance with the Good Procurement Practice Notification submission by PR to GF No Objection by GF WhenAfter receipt of drugs at country level Before any shipment of drugs to the country FrequencyAt random, to be determined by the PR Mandatory for all Purchase Order LaboratoryTo be selected by PR, laboratory recognized by NDRA, WHO prequalified lab when possible SGS laboratory, contracted by GF Procedures and AssaysTo be defined by the PR and selected laboratory Listed in SGS/GF Contract All details in FAQ:

9 July | GLOBAL MALARIA PROGRAMME ACT Prices for procurement by WHO (last updated ) Price per unit treatment (USD) Price per unit treatment (USD) Age-groups AL AS+AQ ASAQ AS+SP Fixed-Dose Combinations Co-blistered Combinations

9 July | GLOBAL MALARIA PROGRAMME Adoption, deployment, past procurement and 2009 forecast of ACTs Millions of ACT treatment courses Cumulative number of countries Forecast 6-24 months from adoption to implementation

9 July | GLOBAL MALARIA PROGRAMME Price reduction of artesunate + amodiaquine over 6 UNICEF/WHO joint tenders Price per adult treatment course (USD) Not co-blistered 14-38% 4-28% 10% 5-10% 0- 12%

9 July | GLOBAL MALARIA PROGRAMME Price reduction of Coartem® (artemether-lumefantrine): Price per adult treatment course (USD) 25 % 22 %

9 July | GLOBAL MALARIA PROGRAMME Price variations relating to production and demand of artemisinin Global shortage Relative over-supply USDUSD Cost of production Cost of production Spot prices of artemisinin USD/kg

9 July | GLOBAL MALARIA PROGRAMME Complex SCM of ACTs: example of AL Seedling, nursery, plantation, growth and harvest (7 months) Extraction (1 month) Extraction (1 month) Derivatisation (2 months) Derivatisation (2 months) Co-formulation, tabletting, packaging and shipping (4 months) Co-formulation, tabletting, packaging and shipping (4 months) Growers API suppliers API suppliers Manufacturers of finished pharmaceutical products Manufacturers of finished pharmaceutical products Extractors

9 July | GLOBAL MALARIA PROGRAMME ACT demand and artemisinin supply Forecast of ACTs (in millions) ACTs for public sector ACTs for private sector through AMFm 1045 ACT in private sector105 total ACTs Artemisinin forecast (in tonnes)° °2m treatments = 1 ton of artemisinin Artemisinin supply (in tonnes) Secured for ACT production Requirements to meet ACT demand Artemisinin stocks available/gap

9 July | GLOBAL MALARIA PROGRAMME Revolving fund to artemisinin extractors Artemisinin extractors API suppliers/ACT manucatures Development Bank

Malaria Rapid Diagnostic Tests (RDTs)

Malaria Diagnostics June Malaria RDTs in context of overall Round 8 portfolio Source: TRP Report on recommended proposals, sampling of detailed budgets for largest HIV and malaria grants, and procurement reported planned in proposal Attachment B’s. Note that applicants were inconsistent in where freight, insurance, distribution, etc. costs were allocated. In most cases, it appears that these costs were included under “PSM Costs” but requires further review. ESTIMATES RDTs account for est. $45M or 3% of R8 Malaria portfolio Courtesy of Dr Joelle Daviaud, GFATM

Malaria Diagnostics June Malaria RDTs in approved proposals for Rounds 6-8 Source: Sampling and analysis of proposal documents for R6-8. ESTIMATES Significant increase in value of procurement proposed for malaria RDTs over Rounds 6-8 As percentage of total malaria proposal budgets, RDTs have accounted for 3-6% over last three rounds Significant increase in value of procurement proposed for malaria RDTs over Rounds 6-8 As percentage of total malaria proposal budgets, RDTs have accounted for 3-6% over last three rounds Courtesy of Dr Joelle Daviaud, GFATM

Product lists and manufacturing quality Submission to Product Testing 2008 ALL 60+ Manufacturers ~200 products ISO13485: Manufacturers 112 products Evaluated Manufacturers 41 products ~ 60+ million tests procured in 2008

9 July | GLOBAL MALARIA PROGRAMME New Developments in : The WHO Malaria RDT Evaluation Programme, jointly coordinated by WPRO, TDR, FIND and US CDC, completed Round 1 product testing in 2009 and publication of results allows comparative assessment of RDTs in relation to parasite detection thresholds, stability, false positivity rate, invalid test results and ease of use. Product testing, together with pre/post-shipment lot-testing, allows informed decisions for procurement agencies to take place. New WHO guidelines for Quality Assurance of Malaria Microscopy have been published and provide new and practical approaches for QA in malaria microscopy, including methods for accreditation of national expert microscopists, and routine validation of slide examination. International QA systems in place

9 July 2009 Product testing 2008 Pre-qualification 2010 Lot testing 2007 International Quality Assurance Systems for Malaria Rapid Diagnostic Tests Dossier review and manufacturer inspections 2009

9 July para/ul x para/uL x1 x12 Negative x10 Report in 5 wk days Procurement Release to field 200 para/ul x para/uL x1 x6 Negative x2 Report every 3 months 125 RDTs Country programmeLot-testing lab Requirements: 125 Pf RDTs 175 Pf-pan RDTs Failures: Follow re-testing algorithm Confirm at second lab End of shelf life Incubate QC Lot-testing of Malaria RDTs Courtesy of Dr Jennifer Juchavez, RITM

9 July 2009 Summary of RDT lot testing performed at RITM ( ) lots, from 27 manufacturers, >400 reports, 2-4 lots/month TOTAL QC Testing Result Pass (%) Deferred/Failed Pf (%) Non-Pf (%) 2003*6 2 (33.3) 4 (66.7) 0 (0.0) (72.0) 4 (16.0) 3 (12.0) (65.5) 3 (10.3) 7 (24.1) (92.3) 1 (3.8) 1 (3.8) (91.7) 1 (2.1) 3 (6.3) TOTAL (79.9) 13 (9.7) 14 (10.4) * Initial development of SOPs for QC lot testing. Courtesy of Dr Jennifer Juchavez, RITM

Phase 2 P. vivax detection

Combo tests with high detection rate of both P. falciparum and P. vivax at 200 parasites/µl Combo tests with high detection rate of both P. falciparum and P. vivax at 200 parasites/µl

WHO procurement criteria for malaria RDTs: evolution over time Criteria for inclusion: 2006: ISO13485:2003 or ‘sufficient equivalence’ * 2007: ISO13485:2003 or US FDA 21 CFR 820 * 2008: Only Products submitted to WHO Product- Testing Programme 2009: RDTs with good performance in product testing * Plus credible heat-stability protocol

9 July | GLOBAL MALARIA PROGRAMME Select RDTs with: – high detection rate, – low false positive rate, – low invalid rate. In populations with low immunity, higher detection of low parasitaemia is important

9 July | GLOBAL MALARIA PROGRAMME Price per test (USD) n=3 n=8 n=10 RDTs eligible for procurement by WHO and UNICEF RDTs eligible for procurement by WHO and UNICEF USD Current WHO/UNICEF prices of malaria RDTs eligible for RFP RDTs with highest detection at 200 parasites/µl RDTs with highest detection at 200 parasites/µl