1. Global Fund Quality Assurance for Health Products LFA PSM Expert workshop 28 - 30 January 2014

2. Outline of the Presentation General Procurement and QA Principles Quality Assurance Policies for Health Products  Pharmaceutical Products  Diagnostics Products  Condoms  LLINs and Insecticides

3. Global Fund’s PSM Principles  Procure quality assured products  in a transparent and competitive manner  In the most adequate form to support adherence (fixed dose combinations, children forms)  At the lowest possible price  In adherence to applicable National Laws and international agreements  Supply Systems: capacity to ensure an uninterrupted supply of health products while minimizing risk of wastage and diversion General principles while executing procurement: o Best value for money o Fairness, Integrity, Transparency o Effective competition

4. Health Products Management Good Procurement Practices Principal Recipients must procure all products in accordance with principles set out in the interagency guidelines “A Model Quality Assurance System for Procurement Agencies”.A Model Quality Assurance System for Procurement Agencies Objective of Quality Assurance : T o ensure safe, effective health products and acceptable to end users. 1- Prequalification of products and manufacturers 2- Purchase 3- Storage 4- Distribution 4 critical functions

5. Pharmaceutical Products (since December 2010) Condoms WHO Procurement Guidelines Diagnostic Products (since March 2011 ) Long Lasting Insecticidal Nets, IRS WHOPES recommendations 2012 WHO Public Health Pesticides Procurement guidelines Global Fund Quality Assurance for Health Products

6. QUALITY ASSURANCE FOR PHARMACEUTICAL PRODUCTS

7. QA Policy for Pharmaceutical Products 1. Clinical Criteria Medicines listed in WHO or national or institutional Standard Treatment Guidelines Require applicants/ recipients to provide justification for selection of unlisted products in one of the STGs 2. Quality Criteria For all products: Authorization for use in the recipient countries 3. Monitoring Quality Monitoring quality of products all along the supply chain Systematic random quality control testing Recipients report testing results to Global Fund selection GMP assessment and dossier review For ARVs, anti-TB and anti- malarial products WHO-prequalified (PQ) or authorized by a Stringent Regulatory Authority (SRA); ---or--- Found eligible for use by the Expert Review Panel, (only if <2 WHO PQ or SRA authorized products available) ++ Selection ProcurementIn-country management

8. A panel of experts hosted by WHO Assesses the potential risks/benefits associated with the use of FPPs that are not yet WHO-prequalified or SRA- authorized Eligibility criteria for dossier submission: product manufactured in GMP site and dossier already submitted to and accepted for review by WHO PQ program or a SRA Assesses abbreviated product dossiers submitted by manufacturers (questionnaire + annexes) Makes time limited recommendations: validity maximum 12 months Expert Review Panel (ERP): to extend the pool of quality products

9. Procuring products reviewed by ERP: Notification and QC process PR has to notify the GF Secretariat Non Objection/ Objection  GF letter If Non Objection  QC testing initiated by GF QC result:  GF approval letter to PR/ Mfr  shipment of the product Contracts with Supplier of products reviewed by ERP: maximum 12 months No Objection letter valid for 12 months PO( Purchase orders) could be issued during full validity of the Non Objection letter

10. Procurement of second line anti-TB products Submission to Global Fund: -details MDR-TB expansion plan -List and quantification of medicines Procurement Directly through GDF Special conditions PR to budget $50,000 or lower amount, each year for GLC support

11. P rocurement of other pharmaceutical products Selection done according to MQAS principles According the national applicable laws Recommended to select products manufactured in GMP- compliant site when available on the market

12. Quality Control Activities ERP-reviewed products Pre-Shipment All Pharmaceuticals: Post-Shipment Responsibility Global Fund Secretariat,Principal Recipients WhenBefore shipment to country, for ERP products notified After receipt in country, all along the supply chain FrequencyMandatory for all PurchasesRandomly according to testing plan defined by the country (risk based approach) LaboratoryWHO PQ lab ISO 17025 lab WHO PQ lab ISO 17025 lab MethodsInt.Ph, US or Brithish Ph, when possible Int.Ph, US or Brithish Ph, when possible

13. Which QC monitoring systems are in-place in-country? 1.Do PRs perform in-country QC testing for pharmaceuticals products procured with grant funds ? 2.What criteria are used to send a product for testing? 3.Do they consider a risk approach all along the supply chain? 4.Is there a QC testing plan in place? 5.Is this done with the NRA? 6.Name and qualification of QC laboratory performing the QC testing: 7.What products are being tested? How often? 8.Has any product failed the control? What action have been taken? 9.If no quality testing in place, is such activity currently under development? Document available: In-country quality monitoring of pharmaceutical products in Global Fund supported programs

14. Conclusions Grant recipients have purchased increasing amounts of stringently quality-assured products with grant resources : almost 100% for ARVs 68% for first-line anti-TB products 89% for antimalarials Time-limited use of ERP- reviewed products is still needed in TB and malaria Harmonization of QA policies with GDF and UNITAID increase access of assured QA medicines Market shaping impact Remaining challenges Not enough quality assured finished products available for certain pediatric formulations, second-line anti-TB products and fixed- dose combinations Changes in API sources are a challenge for consistent product quality Lack of qualified API sources causes price increases (artemisinin-based products, anti-TB products)

15. QUALITY ASSURANCE FOR DIAGNOSTIC PRODUCTS

16. Global Fund QA policy for Diagnostics principles Products subject to the policy: All durable and non-durable In Vitro Diagnostic Products and important for diagnosis Rapid diagnostic tests Equipment/consumables Reagents, Calibrators, Software Microscopes Imaging equipment, for example X-ray machines Not subject to this policy: Products for general laboratory use: gloves, syringes, needles, general reagents, test tubes Main principles Clinical criteria Quality criteria Quality monitoring at country level Ensuring quality of use Monitoring of compliance of POs with GF QA policy requirements 16

17. (a) Clinical Criteria Product types must be selected in compliance with: National guidelines WHO guidance (a) Clinical Criteria Product types must be selected in compliance with: National guidelines WHO guidance (b) Quality Criteria Manufacturing site for all products: compliant with ISO 13485 (except for microscopes for which ISO9000 applies) Product standards for Malaria and HIV RDTs as detailed later (b) Quality Criteria Manufacturing site for all products: compliant with ISO 13485 (except for microscopes for which ISO9000 applies) Product standards for Malaria and HIV RDTs as detailed later + QA Policy for Diagnostic Products (March 2011 ) (c) Monitoring Quality and Ensuring Adequate Use Adequately trained staff Adequate storage and distribution Lot testing Reporting of failures (c) Monitoring Quality and Ensuring Adequate Use Adequately trained staff Adequate storage and distribution Lot testing Reporting of failures

18. Quality criteria Quality Standards: For Malaria RDTS : Approved by WHO after technical assessment, After positive advice received from WHO when assessed according to requirements of authorities member of GHTF For HIV RDTs, ELISA, WB: Approved by WHO after technical assessment or Assessed according to requirements of authorities members founder of GHTF List of Malaria RDTs List of Malaria RDTs (WHO evaluations and information note) List of HIV RDT (WHO eligible for procurement) + “GHTF”-approved + USAID waiver list Phased implementation of criteria 4 on Quality Standards HIV RDTs : applicable since March 2011 CD4, VL, EID : in discussion to be introduced early 2014 v v

19. Recipients must : 1.follow WHO guidance for good practice in storage and distribution of diagnostic products, 2.ensure that diagnostic products are only used by appropriately trained and qualified staff in adequate settings, 3.use best efforts to participate in External Quality Assessment (EQA) programs, 4.organize calibration and maintenance of equipment, 5.arrange for systematic reporting of defects. Ensuring quality of use 19

20. Procurement principles (1) 20 Procurement principles according to the local context, in a competitive and transparent manner, according to the following recommendations. Malaria RDTs meeting Antwerp Dec 2013 For Malaria RDTs: Recipients might continue to procure a selected RDT/from a short list of RDTs provided 1.a competitive selection process had been performed within, at least, the previous 3 years, and 2.evidence of:  continued compliance of the product with the quality criteria defined in the Global Fund QA Policy ;  evidence of adequate performance in WHO-FIND Lot testing;  absence of reports of failure in the field.

21. Procurement principles (2) For HIV RDTS: 2 situations 1.One or several testing algorithm(s) for the diagnosis of HIV infection defined and validated within the last 5 years Products selected as part of the validated national testing algorithm(s), compliant with the QA criteria PR to follow the recommendations of the validated algorithm(s) to order the products without competition, for the validity period of the algorithm Products selected as part of the validated national testing algorithm(s), not compliant with the QA criteria defined in the Global Fund QA policy PR inform the National HIV Programme and request a replacement HIV assay. Selection through competitive process 2. No testing algorithm defined and validated: selection through competitive process

22. Procurement process (3) Selecting appropriate Diagnostic Test Kits In country-studies to determine performance (sensitivity specificity) of the RDTs are not recommended as a primary basis for product selection. Ease of use assessments in local conditions may be highly relevant in informing procurement decisions within a short list of RDTs. Procurement of RDTs In line with national guidelines Guided by programmatic needs: training requirements for health workers, completeness of the kits, and ease of use, previous experience in use of RDTs, and level of deployment in the country

23. Procurement process (4) Cost of RDT/ Total Cost of ownership 23 Expected additional costs must be compared against estimated procurement cost : unit price of eligible RDTs, including all the components needed to preform the test Additional costs linked to the introduction of a new RDT: re-training, or re-design of job aids.

24. Lot Testing 1.Routine lot testing : not mandatory Pre-shipment lot testing: check a QC lot release certificate issued by the manufacturer or an independent regulatory body, Through lot-testing using the WHO-FIND Lot Testing of Malaria Rapid Diagnostic Tests and its recognized laboratories. 2. In case of suspected quality problem Quarantine suspected faulty Diagnostic Test Kits, Inform the national reference laboratory for preliminary investigation, Inform Global Fund PSM and WHO for guidance. 24

25. Providing the means for QA system 1. Each Recipient must develop and maintain a QA system for the PSM and use of Diagnostics 2. Principal Recipients should budget and consider the total cost associated with a specific product, including for example:  (Re-)design of guidelines, job aids etc. and (re-)training of staff if introduction of a new product,  Maintenance of equipment and costs of consumables, and reagents for durable products. It is strongly recommended that Recipients refer to WHO Good Practices for selecting and procuring rapid diagnostic tests for malaria and HIV 25

26. Implementation challenges Difficulty in getting appropriate information on products status, lack of transparency on origin of rebranded products, same product code used for different manufacturing site Selection of appropriate products and definition of requirements for tenders/request for quotations, Non-availability/lack of registrations of tests compliant with QA policy in some countries/regions Lack of interchangeability (or transparency on interchangeability): challenge when product not available or in case of failures Quality monitoring at pre shipment and post shipment level: reference materiel to use? Country capacity? Countries did not systematically report on quality failures 26

27. A compilation of relevant guidance is available on Global Fund website  Global Fund’s QA policy for Diagnostic Products  List of Malaria RDTs / List of HIV Diagnostics tests  Price and quality reporting  Guidance for best practice  Quick Facts on Procuring Malaria Rapid Diagnostic Test Kits  Global Fund Guidance for Procurement and Use of HIV Diagnostic Test Kits with Global Fund Grants http://www.theglobalfund.org/en/procurement/quality/diagno stics / 27

28. CONDOMS AND LLINS QA criteria for other Health products

29. Quality Standards for Other Health Products “ Grant funds may only be used to procure Health Products other than Finished Pharmaceutical Products or long- lasting insecticidal mosquito nets, if they are selected from lists of pre-qualified products, if any, and comply with quality standards applicable in the Host Country where such products will be used, if any.”

30. Procurement of Condoms Procure from UNFPA/WHO prequalified manufacturers Pre-shipment testing by an independent QC laboratory of all batches Highly recommended Sampling to be done by an independent sampling agent (ISO 2859-1) QC testing is done by ISO 17025 certified laboratory (ISO4074: 2002 standards) Reference guidelines WHO/UNFPA Standards and Guidelines for Condoms Procurement “, Male Latex Condom: Specifications, Prequalification and Guidelines for Procurement, 2010”. http://www.unfpa.org/webdav/site/glo bal/shared/procurement/malecondo ms_specs_procurement_2010.pdf

31. Quality Standards for LLINs/ Pesticide products Quality Standards : Grant funds may only be used to procure long-lasting insecticidal mosquito nets that are recommended for use by the WHO Pesticide Evaluation Scheme (WHOPES) Reference Guidelines: Guidelines for procuring public health pesticides on our web page at http://www.who.int/whopes/resources/ en/ http://www.who.int/whopes/resources/ en/ Select WHOPES prequalified manufacturers Systematic Manufacturers CoA review at pre-shipment and random pre-shipment testing by an independent QC lab  Sampling to be done by an independent sampling agent  QC testing by ISO 17025 certified laboratory, WHO Collaborating Centre for QC of Pesticides  According to WHO Methods and Specifications Pre-shipment testing highly recommended / Post shipment testing only if risk identified

32. Challenges faced when procuring LLINS and IRS

33. Case 1: LLINS Post Marketing Quality Control in country 1 LLIN selection : Each LLIN type (brand name) ordered for the mass campaign and still on stock Based on the information submitted by the PR Sampling: 5 districts selected, based on the quantity on stock By an independent party, SGS, contracted by the Global Fund for pre-shipment inspection and sampling of Health Products submitted to QC testing Quality Control Tests: Performed by Wallon Agricultural Research Centre ( CRA-W), laboratory ISO 17 025 certified and Reference Laboratory for WHOPES (WHO Pesticide Evaluation Scheme) According to the WHOPES recommended methods for each concerned insecticide

34. Case 1 Results 5 brands tested Brands 1 and 2 : 100% samples tested were consistent with the results expected Brand 3 : 95% of nets tested were not impregnated Brand 4: 70% of samples tested showed an insecticide content inferior to content specifications Brand 5 : 33% of samples tested showed an insecticide content inferior to the specifications 1.Only 2/5 marks show 100% of compliance with specifications for insecticide content even before the LLINs distribution to the users 2.All the districts “tested” are impacted by quality issues in the LLINs tested

35. Case 2: Pre-shipment quality control of IRS -Early 2012 : UNDP reported to the Global Fund that eight orders of insecticides for IRS out of eight tender processes were not compliant with WHOPES standards the manufacturers agreed to replace the sub-standard batch by a compliant one significant delay in the supply of IRS insecticides to national malaria programs serious concern as it may have great public health significance, in particular by contributing to insecticide resistance.

36. Case 2: Results Country/ case reference Product Total batches produced Total batches failed % of failures 1 A105 27 34.5 % 1 B33100% 1 B111100% 1 A55o0% 2 C33100% 3 D22 4 E11 5 F33

37. Case 3: VPP pre-shipment testing of IRS in 2012 Country/ case reference Produc t Total batches produced Total batches failed % of failures 1 A 161063% Discussion between the manufacturer and WHOPES lab on methods used 100 0% 2 A14 0% B 6350% 23 100% Investigation and exchange between the manufacturer and WHOPES lab on methods used 2300% Lessons learned: A thorough review of manufacturers QC methods with WHOPES laboratory can prevent futures failures Need for a strict application by manufacturers of the WHOPES published methods on all the parameters.

38. The way forward: How to prevent such quality issues? Increase Pre shipment QC of Pesticides : the Global Fund Secretariat is developing a plan for systematic pre-shipment quality control of pesticides, by WHOPES QC laboratory Procured from WHOPES recommended sources and Systematic Manufacturers CoA review at pre-shipment level All parameters listed in WHOPES published methods to be reported and Random pre-shipment testing by an independent QC laboratory, QC testing is done by ISO 17025 certified laboratory, WHO collaborating Centre for QC of Pesticides According to WHOPES published Methods and Specifications Sampling to be done by an independent sampling agent The process is already followed for all VPP procurements; For others mechanisms, procurement guidance to be finalized in the coming weeks

39. Conclusion Safe use and efficiency of the pesticides is critical for Health and environmental impact - The lack of pesticides quality has delayed the use of LLINs and IRS by countries and in some cases for more than one year: no spraying before the raining season great public health significance in particular by contributing to insecticide resistance. - Quality of Pesticides cannot be compromised: The Global Fund is increasing the quality monitoring of pesticides, including its control on pesticides at pre and post shipment level - The Global Fund is working in close collaboration with WHO, Partners and Manufacturers to identify solutions to increase access to additional assured quality pesticides

40. COMPLIANCE MONITORING THROUGH PQR

41. Compliance monitoring through the PQR It is mandatory to report procurement transactions for ARVs, anti-TB, antimalarial products, bed nets, condoms, diagnostic tests, CD4, Viral load Genexpert machines and associated consumables in the Price Quality Reporting on line system (PQR) http://www.theglobalfund.org/en/procurement/pqr/ http://www.theglobalfund.org/en/procurement/pqr/ The Secretariat monitors compliance with QA requirements: –Compliance criteria Procurement of WHO-PQ, SRA authorized or ERP products Notification request sent/ Non Objection for ERP products procured –Monthly compliance review In case of non-compliance, follow up and potential corrective measures

42. PQR : Data Quality ? Period Total number of entries Number of entries wrongly reported: Potential non complaint Ratio over total wrong entries 201251601597245.3% 201368052468534.6% Entries wrongly reported: Manufacturer's name Product name Packing Dosage form No manufacturer's name

43. http://www.theglobalfund.org/en/procurement/quality/pharmaceutical

44. Model Quality Assurance System for procurement agencies

45. MQAS: Goal and objectives “ This Model is intended to assist organizations purchasing pharmaceutical products, vaccines, or other health sector goods or which are otherwise involved in the prequalification, purchasing, storage and distribution of such products, hereafter referred to as procurement agencies, to procure safe, effective pharmaceuticals of suitable quality” ( MQAS) 2000: clear need identified by WHO and partners for establishing, harmonizing and implementing a quality assurance system for prequalification purchasing storage distribution of pharmaceuticals/diagnostics/ health goods

46. Quality Assurance for Health Products Good Procurement Practices Principal Recipients must procure all products in accordance with principles set out in the interagency guidelines ( GF QA policy) “A Model Quality Assurance System for Procurement Agencies”.A Model Quality Assurance System for Procurement Agencies To ensure safe, effective health products and acceptable to end users. 1- Prequalification of products and manufacturers 2- Purchase 3- Storage 4- Distribution 4 Critical function s

47. MQAS Structure : A quality assurance system should be in place to ensure that transactions ultimately result in procuring pharmaceutical products of the best possible quality. 6 modules: Module I: General requirements for Procurement Agencies Organization and management Personnel Quality systems Documentation Counterfeit products Self-inspection Complaints Recalls 6 Modules

48. Module II Module III Module IV Module V Module VI Prequalificati on PurchasingReceiving and dispatch Distribution of purchased products (Packaging – transport) Re- assessment Prequalification procedure EOI Product information, screening and evaluation Inspections Prequalification outcome Purchasing Monitoring of performance of prequalified manufacturer s Receiving Quality control Storage Stock control Containers and labelling Dispatch Transport Transit Re- assessment of manufacturers Re-evaluation of products Monitoring of contracted-out services

49. Harmonized Tool for Assessment of PA Harmonized tool developed by partners and PAs to align the assessment criteria Submitted to WHO Expert Committee in October 2013 for discussion/ approval? Tool can be used by PA for self assessment Tool to be used by an Independent Party to perform PA assessment Development of the harmonized tool for assessment of PA based, on MQAS principles, using transparent processes and common tool, should lead To work towards mutual recognition of PA assessment findings. To ensure better use resources by coordinating PA assessments

50. What it means for manufacturers Clear information available to manufacturers on how to prequalified products, quality control performed, inspection criteria followed, expectations for transport conditions… - manufacturers can build in advance the processes to comply with these requirements Common Product Dossier : –all information submitted clearly defined, helping manufacturer to submit in one hand all the expected information –same dossier can be submitted to different PAs, facilitate the manufacturer work, no duplication of work Site Inspection: –Based on clear principles and reference, PAs are working more and more developed joint on site inspection –Simplification of processes

51. WHO guidance: www.who.int/medicines/areas/quality_safety/quality_ass urance/guidelines/en/index.html see under "Current projects" (MQAS is under revision) THANK YOU