1. Prequalification Programme Quality Control Laboratories Olivier Gross, Jitka Sabartova Prequalification Programme: Priority Essential Medicines HTP/PSM/QSM

2. QCL Training | 26-29 novembre 2007, Rabat, Maroc 2 |2 | UN Prequalification Programme for Priority Essential Medicines Action plan of UN from 2001 for expanding access of priority medicines to patients with –HIV/AIDS –Malaria –Tuberculosis –Reproductive health –Potentially other categories of products Antiviral medicines efficacious for avian flue Paediatric formulations

3. QCL Training | 26-29 novembre 2007, Rabat, Maroc 3 |3 | UN Prequalification Programme for Priority Essential Medicines  WHO PQ Team working in co-operation with partners –UNICEF –UN Population Fund (UNFPA) –UNAIDS –UNITAID –The Global Fund –World Bank –Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility); HIV/AIDS Department

4. QCL Training | 26-29 novembre 2007, Rabat, Maroc 4 |4 | Elements of Prequalification Programme Objective: To ensure quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM, UNITAID) Components: Evaluation of Quality, Safety and Efficacy of prioritised Essential medicines, inspections of manufacturers and monitoring of the products after their prequalification Prequalification of quality control laboratories Building capacity of regulators, manufacturers and quality control laboratories

5. QCL Training | 26-29 novembre 2007, Rabat, Maroc 5 |5 | Prequalification of QC laboratories Need to increase the access to QC laboratories that –meet recommended standards for testing of medicines –are committed to provide a service of testing of medicines, including but not limited to HIV/AIDS, Tuberculosis and Malaria products to UN agencies Procedure established in 2004 Participation of a QC laboratory is voluntary

6. QCL Training | 26-29 novembre 2007, Rabat, Maroc 6 |6 | Procedure for assessing the acceptability, in principle, of quality control laboratories for use by UN agencies Published in 2004 (WHO TRS, No. 917, Annex 4) Revision published in 2007 (WHO TRS, No. 943, Annex 5) Related documents –Good practices for national pharmaceutical control laboratories (WHO TRS, No. 902 Annex 3) –WHO GMP: main principles for pharmaceutical products. In: Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol. 2, 2nd updated edition. Good manufacturing practices and inspection (Geneva, World Health Organization, 2007) –Guidelines for preparing a laboratory information file (WHO TRS, No. 917, Annex 5)

7. QCL Training | 26-29 novembre 2007, Rabat, Maroc 7 |7 | Based on the following principles Reliance on the information supplied by the national drug regulatory authority General understanding of the quality control activities of the laboratory Evaluation of information submitted by the laboratory Assessment of consistency in quality control through compliance with GMP(s) and WHO guidelines

8. QCL Training | 26-29 novembre 2007, Rabat, Maroc 8 |8 | Invitation for Expression of Interest 3rd EOI published in September 2007 –http://www.who.int/prequal/info_applicants/eoi/EOI-QCLabsV3.pdf Previous invitations limited to QC laboratories in Africa, currently no regional limitation Priority in the assessment will be given to –National QC laboratories and laboratories providing testing services to the government –QC laboratories in areas where UN agencies identify the need for quality testing Any laboratory (private or governmental) can participate

9. QCL Training | 26-29 novembre 2007, Rabat, Maroc 9 |9 | Steps of the procedure 1.Expression of interest 2.Submission of laboratory information −Laboratory Information File - LIF needed to get basic information on laboratory's activities and suggested scope of prequalification −A good LIF makes the procedure faster −Guidelines for preparing LIF available Documentation and QA system, Personnel, Handling of samples, Materials, Premises, Equipment, Contract operations and activities, Out-of-specification investigation, Self-inspection Stability Testing, Microbiological testing, Water system, where applicable −Quality Manual can be submitted (amended as necessary) −Evidence of participation in proficiency testing schemes

10. QCL Training | 26-29 novembre 2007, Rabat, Maroc 10 | Steps of the procedure 3.Screening of submitted laboratory information −Formal completeness −Amendment requested, if necessary 4.Evaluation of the laboratory information −WHO carries out evaluation of LIFs to assess the laboratory's potential to pass successfully the inspection −If the LIF indicates that the laboratory would comply - WHO starts arranging an inspection –If the LIF is not adequate – WHO Starts arranging an inventory audit or Asks for more information or Returns the LIF

11. QCL Training | 26-29 novembre 2007, Rabat, Maroc 11 | Steps of the procedure 5.Site inspection / inventory audit −Planned and coordinated by WHO (normally for 2-3 days) −Experts appointed by WHO preferably from regulatory authority inspectorates, experienced in quality control Required to sign declaration of interest and confidentiality declaration −Compliance with WHO recommended standards Good Practices for National Pharmaceutical Control Laboratories Good Manufacturing Practices as recommended by WHO for such laboratories –ISO certification encouraged and considered –However, GMP aspects to be taken into account during inspection

12. QCL Training | 26-29 novembre 2007, Rabat, Maroc 12 | Steps of the procedure 5.Site inspection / inventory audit (cont.) −For the inspection representative(s) of the DRA of the country where the laboratory is located invited −Inventory audit less formal, combined with discussions of problems and assessment of need of technical assistance

13. QCL Training | 26-29 novembre 2007, Rabat, Maroc 13 | Steps of the procedure 6.Report and outcome of evaluation −Final Report in the established WHO format communicated to the laboratory and a copy sent to the national DRA –If corrective actions to be taken by the laboratory, WHO postpone its final recommendations until the corrective action has been evaluated and found satisfactory −In case of disagreement, possibility of an appeal −Ownership of the report lies with WHO 7.Results of assessment –Information is sent to the laboratory and national DRA –If compliant, laboratory is included in the published list and WHOPIR is published –The list will be subjected to review at least once a year

14. QCL Training | 26-29 novembre 2007, Rabat, Maroc 14 | Steps of the procedure 8.Re-evaluation after prequalification −On-going monitoring  Re-inspections at regular intervals (normally 3 years)  Evaluation of results from participation in proficiency testing schemes − WHO External Quality Assurance Scheme, AFSSAPS network of Francophone African countries −WHO may suspend or withdraw a laboratory from the list when there is evidence of noncompliance

15. QCL Training | 26-29 novembre 2007, Rabat, Maroc 15 | Steps of the procedure 9.Monitoring of complaints −WHO will investigate complaints concerning the results of analysis or service provided by the laboratory Written report and where appropriate recommendations for action Copy of the report to the laboratory, manufacturer of the product and DRA of the country where the manufacturing site is located DRA could also be invited to participate in the investigation of the complaint 10.Cost recovery –WHO reserves the right to charge for the quality assessment procedure on a cost-recovery basis

16. QCL Training | 26-29 novembre 2007, Rabat, Maroc 16 | Status of prequalification of QC Labs November 2007 4 QC laboratories prequalified –South Africa, CENQAM - 6/2005 –South Africa, RIIP - 7/2005 –Algeria, LNCPP - 10/2005 –South Africa, Adcock Ingram – 8/2007 2 QC laboratories near to PQ 11 QC laboratories audited, corrective measures proposed 6 QC laboratories expressed interest, but not send LIF yet

17. QCL Training | 26-29 novembre 2007, Rabat, Maroc 17 | Frequent deficiencies and weak points (1) Quality system –SOPs not covering, not properly maintained –No quality responsible –No or not enough self-audits Personnel –No qualification system –Not enough training, no training programmes –Responsibilities and tasks not clearly defined on personal level, vague organization Premises –Too small and unfit –Limited and unfit storage areas (lot of cupboards etc. needed) –No regular environmental (at least temperature) monitoring –Archives not good, nor secured

18. QCL Training | 26-29 novembre 2007, Rabat, Maroc 18 | Frequent deficiencies and weak points (2) Maintenance of the equipment –No proper or only partial qualifications –Documentation in general very deficient –Not adequate training by the suppliers in the beginning –No pre-maintenance programme Reference materials and reagents –Maintenance system and records not efficient, nor clear –No working standards system Instructions / methods –No clear system as to which pharmacopoeial or manufacturers' method to use –Validations/ verifications of methods not sufficient or non- existing

19. QCL Training | 26-29 novembre 2007, Rabat, Maroc 19 | Frequent deficiencies and weak points (3) Waste management –Not properly organized Safety –Fume hoods lacking or too few –No or insufficient protection of the personnel (e.g. insufficient protective garments, no training, no safety sheets of the chemicals) –No classification nor proper storage of dangerous chemical materials (e.g. toxics, caustic / volatile reagents etc.)

20. QCL Training | 26-29 novembre 2007, Rabat, Maroc 20 | Technical assistance Technical assistance provided to 5 national medicines quality control laboratories –Assistance in implementation of quality system –Assistance in microbiological testing –1 – 3 weeks Capacity building and technical assistance provided to national QC laboratories out of the scope of the prequalification procedure

21. QCL Training | 26-29 novembre 2007, Rabat, Maroc 21 | Training Participation in Quality Assurance training of OMCLs organized by EDQM –October 2005, 5 participants from AFRO and EMRO –September 2007, 12 participants from AFRO, EMRO and EURO Trainings in Quality Assurance, Quality Control and Ph.Int. under preparation –November 2007, Morocco, 40 participants from Francophone countries (AFRO, EMRO), cooperation with EDQM –December 2007, Tanzania, 40 participants from Anglophone countries (AFRO, EMRO) Trainings planned in 2008 –Market surveillance projects, Networking of African laboratories

22. QCL Training | 26-29 novembre 2007, Rabat, Maroc 22 | Sampling and Testing (1) Survey of the quality of antiretroviral medicines circulating in selected African countries –Carried out in June-December 2005, report now finalized –7 countries (Cameroon, DR of Congo, Kenya, Nigeria, Tanzania, Uganda and Zambia) –Monocomponent products (didanosine, efavirenz, lamivudine, nevirapine, stavudine, zidovudine), FDCs (lamivudine/zidovudine, stavudine/lamivudine, stavudine/lamivudine/nevirapine) –394 samples from official procurement and treatment centres, both private and public –Testing according Ph.Int., USP, Indian Pharmacopoeia, validated in-house Swissmedic methods (laboratory Swissmedic) –Tests performed - Appearance, Labelling, Identification, Uniformity of mass (capsules/tablets), Dissolution/disintegration, pH (oral solutions-depending upon the matrix), Related substances, Content of each active ingredient

23. QCL Training | 26-29 novembre 2007, Rabat, Maroc 23 | Sampling and Testing (2) Survey of the quality of antiretroviral medicines circulating in selected African countries - Findings –Very low failure of 1.8%, no critical deficiencies 1 sample with broken tablets, 2 samples insufficiently labelled, 1 sample with higher content, 1 sample failed to disintegrate in 30', 2 samples lower dissolution 53% prequalified products In 3 countries found non-registered products, mostly in private sector (12% of 394 samples) –Positive effect of common efforts of NDRAs, WHO and others involved in prequalification and purchase policies –Limited to official distribution points and treatment centres around the capital cities

24. QCL Training | 26-29 novembre 2007, Rabat, Maroc 24 | Sampling and Testing (3) Current activities –Quality survey of antimalarials ACTs, sulfadoxine-pyrimethamine in 9 African countries –Quality monitoring within UNITAID projects Paediatric ARV FDCs, cotrimoxazol, second line ARVs –Dissolution of Coartem tablets –Generic products containing nelfinavir EMS/MMS impurity, dissolution –Monitoring of quality of WHO prequalified products Verification that WHO-prequalified products procured by agencies comply with the specifications approved within PQ process –Testing on request from countries Arsuamoon tbl (co-blistered artesunate+amodiaquine), Guilin Pharma, China - from Indonesia Diethylcarbamazine citrate tbl, Asian Pharmaceutical Company, Nepal – from Nepal

25. QCL Training | 26-29 novembre 2007, Rabat, Maroc 25 | Thanks for your attention