1. The Global Fund Quality Assurance Policy for Pharmaceutical Products Dr Joelle Daviaud Senior Pharmaceutical Quality Assurance Officer Pharmaceutical Management Unit Global Fund Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, 23-25 September 2009

2. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 2 |2 | Outline Global Fund introduction The Global Fund Quality Assurance for Pharmaceuticals products The Global Fund Quality Control requirements Conclusion

3. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 3 |3 | What is the Global Fund? As a partnership between governments, civil society, the private sector and affected communities, the Global Fund represents an innovative approach to international health financing. As a financing mechanism, The Global Fund's purpose is to attract, manage and disburse resources to fight AIDS, TB and malaria. We do not implement programs directly, relying instead on the knowledge of local experts. The Global Fund is a financial institution, about 35 % of grant funds are for medicines and health products procurement. The GF does not conduct any procurement activities for pharmaceutical products, PR are responsible for ensuring adherence to Global Fund QA/QC requirements

4. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 4 |4 | Status of Global Fund Grants Financial StatusProposals Approved (R1-8) Grants signed US$ Money disbursed US$ Global Fund financing (US$), September 2009 16.2 billion12.2 billion8.3 billion51% Financing more than 600 grants in 142 countries (Sept 2009) Objective of the Global Fund “making a “sustainable and significant” contribution to the achievement of the Millennium Development Goals”

5. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 5 |5 | Distribution of funding 9% Others Pharmaceuticals 6% TB 20% ACT’s 65% ARV’s

6. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 6 |6 | What it can include Products Pharmaceuticals Health products Health equipment Equipment Services Registration Selection Forecasting Procurement Transport Quality control Storage Distribution Monitoring Pharmacovigilance Activities Procurement costs Distribution costs Training Technical Assistance Capacity Building

7. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 7 |7 | The Global Fund’s approach to Procurement and Supply Management Build upon National/International existing systems with no prescriptive procedures but principles and minimum standards Expanded definition of Procurement: –Getting sufficient health product of assured quality –Assessing products at reception in country –Checking the distribution chain until the end user PR procurement systems must adhere to Interagency Guidelines on Good Pharmaceutical Procurement (WHO 1999) Principal Recipient (PR) is responsible for all PSM activities (whether directly implemented or sub-contracted). –Procure quality assured products at the lowest possible price –Adhere to National and International Laws –Conduct procurement in a transparent and competitive manner

8. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 8 |8 | Country Proposal is approved for TGF Grant TGF disburses funds to Principal Recipient (PR) Patient receives drugs PR receives and checks drugs,including Quality Monitoring PR prepares PSM Plan specifying health products and quantities to order Plan is submitted to TGF/LFA for assessment and approval PR launches procurement process PR reconciles needs and funds available PR evaluates bids and awards supply contract PR places order for drugs and monitors order status PR makes payment PR distributes drugs PR collects consumption information PR reports results to TGF Suppliers submit bids The long and winding road of Procurement…

9. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 9 |9 | Global Fund Quality Assurance policy for Pharmaceuticals The Board approved the Quality Assurance Policy for Pharmaceutical Products (“QA Policy”) at its 18th Board, November 2008 The QA Policy came into effect on 1 July 2009 and is replacing the Global Fund’s previous policy for the quality assurance of pharmaceutical products Revision of the GF Policy: –concerns about the safety, stability and efficacy of products, –alignment with partner’s QA policies –market dynamics and, –lessons learned from the implementation of the existing Policy

10. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 10 | Key Elements of the revised QA policy Clinical criteria Quality criteria Selection process of FPPs New definition of SRAs Independent expert review panel Monitoring product quality

11. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 11 | Clinical criteria Medicines listed in WHO or national or institutional Standard Treatment Guidelines (STGs) Require grant applicants or PRs to provide technical justification for selection of unlisted products in one of the STGs

12. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 12 | Quality Criteria Same Quality criteria for ARVs, anti-TB and antimalarials: Authorized for use by Drug Regulatory Authority (DRA) in recipient country Selection of ARVs, anti-TB and antimalarials FPPs, either – WHO prequalified (A) or – SRA authorized (B) or – Recommended for use by an Expert Review Panel (ERP) for FPPs not yet WHO prequalified nor SRA authorized

13. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 13 | ERP recommended Product available? 2 or more A or B products Available? Procure A or B Product Yes GF request an ad Hoc ERP committee to review eligible product Product unavailability definition: Inability to supply sufficient quantity of product within 90 days from date of order Notify TGF Receive No Objection QC Testing by TGF Final letter with QC result ERP Product shipment YesNo Selection of products-flow chart

14. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 14 | The Expert Review Panel An independent technical body Hosted by WHO Department of Essential Medicines and Pharmaceutical Policies Composed of external technical experts. Purposes: – To review the potential risks/benefits associated with the use of FPPs that are not yet WHO-prequalified or SRA- authorized. –To make recommendations to the Global Fund

15. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 15 | Expert Review Panel (ERP) mechanism (1) Review – at the request of the Global Fund, or – based on manufacturer’ submissions in response to GF invitation for EoI to submit dossiers. A product is eligible for review by the ERP if: – Application to WHO Prequalification or application for marketing authorization to an SRA is accepted, and – Manufacturing site GMP compliant

16. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 16 | Expert Review Panel (ERP) mechanism (2) ERP reviews each submission to determine whether the benefits of funding the product with Global Fund resources outweigh the potential quality risks. – Manufacturers is notified of the outcome of the ERP’s review. ERP recommendations –Time limited recommendations (maximum 12 months) –Possibility of extending the recommendation period, under certain circumstances

17. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 17 | Technical Areas of ERP review Standard Product questionnaire dossier( based on Inter Agency Questionnaire): –product registration information; –regulatory (licensing) status of the FPP and manufacturing facility (GMP); –finished product specifications and information regarding compliance with international pharmacopoeia standards, if available; –stability testing data (both accelerated and real time studies) as per ICH and/or WHO Guidelines; – product labelling information; –active pharmaceutical ingredient (API) characteristics and certification; and –safety and efficacy data for innovator products, human bioequivalence data for generic products.

18. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 18 | Procurement of All Other FPPs ( non ATM drugs) All FPPs, other than antiretrovirals, anti-tuberculosis and anti-malarial FPPs, need only to comply with the relevant quality standards that are established by the National Drug Regulatory Authority (NDRA) in the country of use PRs must ensure that all FPPs are procured in accordance with principles set forth in the Interagency Guidelines: “A Model Quality Assurance System for Procurement Agencies “ (WHO, 2007)

19. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 19 | Implementation of the revised QA Policy Progress update List of 28 ERP recommended published in June 2009 Outcome of First ERP review Products dossier reviewed ERP recommended (time limited) Malaria183 Tuberculosis1210 HIV3015 No notification received for procurement of ERP recommended products since 1 July 2009 Second ERP review planned first week of October 2009

20. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 20 | Monitoring of product quality All pharmaceutical products funded by GF are subject to the monitoring of product quality Monitoring quality of products all along the supply chain Systematic random quality control testing PR to report testing results to Global Fund

21. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 21 | Quality Control of Pharmaceutical Products Quality Control of FPP All FPPsERP recommended FPPs ResponsibilityPR or sub recipient, cost may be included in the GF grant budget GF Secretariat, paid by GF secretariat ConditionIn accordance with the Good Procurement Practice Notification submission by PR to GF No Objection by GF WhenAfter receipt of drugs at country Level, along the supply chain Before any shipment of drugs to the country FrequencyAt randomMandatory for all Purchase order (PO)

22. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 22 | Quality Control: Laboratory qualification The PR responsible for the grant must select the Quality Control laboratory: –the NDRA laboratory –a QC laboratory recognized by the NDRA of the recipient country. The selected Quality Control laboratory should be: –WHO prequalified and listed in WHO website. –Quality Control laboratory complying with standards at least equivalent to WHO standards recommended for pharmaceutical quality control laboratories. –ISO/IEC 17025 certified for the required scope of drug testing It is highly recommended that the selected laboratory regularly participates in national and or international proficiency testing schemes

23. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 23 | Quality Control: Sampling PR to define with the QC laboratory –Plan of testing –Documentation to be collected –Sampling procedure –Tests to be done and timeline –Reporting process Sampling to be done –by trained staff –according to appropriate standard operating procedure –with careful attention to storage condition –at different distribution sites

24. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 24 | Quality Control: Parameters tested Appearance, Identification Related substances Assay Disintegration and or dissolution tests Uniformity of weight pH and microbial limits for solutions Sterility and bacterial endo-toxins test for injectables.

25. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 25 | Quality Control: recommended methods The laboratory should have the technical capabilities : to undertake tests as specified in the monograph of B.P, U.S.P, and Int. Pharmacopoeia. to adopt the specifications for testing as provided by the manufacturer for products that do not have monograph in B.P, U.S.P, Int. Ph. –to perform method transfer process to evaluate the correctness of the method of the manufacturer.

26. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 26 | Quality Control applicable ERP recommended FPPs: GF Secretariat responsibilities (1) Tested after notification submitted by Principal Recipient and approved by the Global Fund Secretariat Sampling at manufacturing sites by GF contracted Laboratory Testing of products in qualified laboratories: SGS Laboratory in Belgium, selected through competitive process Test methods: – Use Pharmacopoeia ( International, British or US) methods when available – Use of manufacturer’s validated methods and specifications when no monograph available in Pharmacopoeia (International, British or US). Need of method transfer à

27. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 27 | Quality Control applicable ERP recommended FPPs: GF Secretariat responsibilities (2) Items to be tested and reported: Appearance Identification, assay, and impurity control Dissolution or disintegration for tablets and capsules Content uniformity or weight variation for Tablets and capsules pH and microbial limits for the solutions ( if in the spec.) Sterility and Bacterial endotoxin test (for injectables)

28. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 28 | Quality Control applicable to ERP recommended FPPs (Ci and Cii products): GF Secretariat responsibilities Interpretation : –a lot is acceptable if the results of the testing are within the pharmacopoeia or manufacturer’s specifications –batch Pass, to be supplied, CoA issued by SGS sent to manufacturer and to PR – batch Fail, should not be supplied, manufacturer and PR informed, investigation by manufacturer and information sent to WHO  As of September 2009, Quality Control of 240 batches –QC 240 lots (ARV-114 batches; ACT-126 batches) completed: green light for the shipment of these products have been sent accordingly to manufacturer 100 % of lot tested passed the QC criteria –Results and CoAs will be soon published on GF website : avoid duplication of testing, assure full transparency

29. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 29 | QA Compliance If PRs select ERP recommended products, PRs must notify the Secretariat before procuring them. It is mandatory that procurement of ARVs, anti-TB, antimalarial products, bed nets, condoms, rapid diagnostic tests are reported in the Price Quality Reporting system (PQR) The QADM Team monitor compliance with QA Policy based on PQR data and produces: –Monthly report to Country Programs for action: notify FPMs of potential non compliance –Compliance analysis for Phase 2 Review. In case of non compliance, corrective measures applies

30. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 30 | How it works? Principal Recipient PQRPQR PQRPQR Local Fund Agent The Global Fund Partners General Public Verify Data Principal Recipients Quality Delivery Conditions Price Monitor Reports Quality Monitoring Market Information Price Comparison

31. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 31 | Conclusion (1) Uniform stringent standards All antiretrovirals, first-line anti-TB medicines and antimalarials must comply with stringent quality requirements “Other” medicines (single- and multi-source) need only be authorized in the country of use for the time being Quality monitoring at country for all FPPs funded with Global Fund ressorces to be reinforced and be strengthened – protocols and guidelines to help PR in this activity are under development in close collaboration with the WHO PQ programme

32. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 32 | Conclusions (2) NCLs’role in the Quality Monitoring at country level The Global Funds recommends to use existing system in place at country level, if system is functional and complies with GF requirements NCLs have a clear role in the quality monitoring activity of FPPS funded by the Global Fund

33. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 33 | Conclusions (3) NCLs’role in the Quality Monitoring at country level Recommendations to NCLS: –To get WHO prequalification status as soon as possible to be part of laboratory selected by the PR –To work closely with the NDRA and MOH for the development of Global Fund proposal To discuss budget implication of QC tests for FPPs funded by the Global Fund To request Technical Assistance/ Funding for improving their quality control capacities –To work closely with the PR to be an active body in the Quality Assurance process set up by the PR for the quality monitoring of FPPs funded by the Global Fund

34. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 34 |

35. Sampling and testing for Quality Control Laboratories, Nairobi, September 2009 35 | Quality Control of Pharmaceutical Products: website links For information Frequently-Asked Questions (FAQs) about Quality-Control Testing of Pharmaceutical Products http://www.theglobalfund.org/pdf/guidelines/QCTestingPharmaceuticalProducts.pdf http://www.theglobalfund.org/pdf/guidelines/QCTestingPharmaceuticalProducts.pdf WHO Prequalified Laboratories: http://healthtech.who.int/pq/lists/PQ_QCLabsList.pdf Contact for Enquiries: email: prequallaboratories@who.intprequallaboratories@who.int Model Quality Assurance System for procurement agencies, World Health Organization, WHO Technical Report Series, No. 937, 2006 Annex 6, http://healthtech.who.int/pq/info_general/documents/TRS937/WHO_TRS_937__annex 6_eng.pdf http://healthtech.who.int/pq/info_general/documents/TRS937/WHO_TRS_937__annex 6_eng.pdf