Prequalification Programme

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

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. 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. 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. 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. 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. 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. 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. Steps of the procedure • Expression of interest • 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. Steps of the procedure • Screening of submitted laboratory information • Formal completeness • Amendment requested, if necessary • 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. Steps of the procedure • 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. Steps of the procedure • 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. Steps of the procedure • 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 • 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. Steps of the procedure • 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. Steps of the procedure • 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 • Cost recovery • WHO reserves the right to charge for the quality assessment procedure on a cost-recovery basis

16. Status of prequalification of QC LabsNovember 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. 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. 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. 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. 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. 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. 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. 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. 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. Thanks for your attention