Prequalification Programme

1. Prequalification Programme QualityControl Laboratories Testing Projects Jitka Sabartova Prequalification Programme: Priority Essential Medicines HSS/PSM/QSM

2. Prequalification Programme for Priority Essential Medicines • A United Nations Programme managed by WHO • Action plan of UN from 2001 for expanding access of patients to priority medicines for treatment of • HIV/AIDS • Malaria • Tuberculosis • Reproductive health • Potentially other categories of products • Antiviral medicines efficacious for avian flu • Paediatric formulations

3. 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. Prequalification Programmefor Priority Essential Medicines 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 • 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 • Possibility to recognize the outcome of an inspection done by another authority/organization? • Detailed comparison of standards • Availability of the audit report • Case by case consideration

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 postpones its final conclusion until evaluation of corrective actions • 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 • WHO External Quality Assurance Scheme, AFSSAPS network of Francophone African countries • Brief report to be submitted annually • Overview on number of analysed samples, methods used, services provided to UN agencies • Outcomes from proficiency testing • Changes to key personnel, facility or other significant impact to the laboratory • Update of LIF, in case of changes with significant impact on LIF content • 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 • 12 QC laboratories audited, corrective measures proposed • 8 QC laboratories expressed interest, but not send LIF yet • Not audited yet, information not complete or recent interest expression

17. Frequent deficiencies and weak points (1) • Quality system • SOPs not covering, not properly maintained • No quality responsible • No or not enough internal 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 • 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 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 • Capacity building and technical assistance provided to national QC laboratories • Out of the scope of prequalification procedure • Technical assistance provided to 5 national medicines quality control laboratories • Assistance in implementation of quality system • Assistance in microbiological testing • 1 – 3 weeks

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, 47 participants from Francophone countries (AFRO, EMRO), cooperation with EDQM • December 2007, Tanzania, 50 participants from Anglophone countries (AFRO, EMRO, AMRO/PAHO) • Trainings planned in 2008 • Market surveillance projects, Networking of African laboratories

22. Sampling and testing of medicines • Policy • To monitor quality of supplied prequalified products • Required by the procedure for products prequalification • To contribute to quality control of other products procured by UN agencies • To contribute to quality control of products, if requested by Member States • Prequalified laboratories used for testing, if available

23. Survey of the quality of antiretroviral medicines circulating in selected African countries (1) • Carried out in June-December 2005, report finalized this year • 42 collection sites in 7 countries • Cameroon, DR of Congo, Kenya, Nigeria, Tanzania, Uganda and Zambia • Monocomponent products (didanosine, efavirenz, lamivudine, nevirapine, stavudine, zidovudine) and FDCs (lamivudine/zidovudine, stavudine/lamivudine, stavudine/lamivudine/nevirapine) • 394 samples from official procurement and treatment centres, both private and public, around capital cities • Good logistic organization, no deterioration of samples, no expired sample sent for testing

24. Survey of the quality of antiretroviral medicines circulating in selected African countries (2) • Testing • Samples tested in Swissmedic – official medicines control laboratory of Switzerland • According to Ph.Int., USP, Indian Pharmacopoeia, validated in-house Swissmedic methods • 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

25. Survey of the quality of antiretroviral medicines circulating in selected African countries(3) • Findings • Very low failure of 1.8%, no critical deficiencies • 1 sample broken tablets, 2 samples insufficiently labelled, 1 sample higher API 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 • Positive outcome cannot be generalized to the entire territories of the countries surveyed

26. Current sampling and testing activities (1) • Comparative dissolution study of Coartem tablets • Artemether / lumefantrine innovator - problems with dissolution reported from various sides • 5 batches manufactured in different manufacturing sites and collected in Tanzania tested in RIIP, South Africa • Dissolution profiles of compared to the mean of all data  SIMILAR • Generic products containing nelfinavir • Test on EMS/MMS impurity using Roche method • Search for manufacturers placing product on markets – 2 in India, 1 in Thailand • Samples collected from manufacturers, as well as from markets • For the purposes of Ph.Int. monograph dissolution study added • Testing on-going in Swissmedic

27. Current sampling and testing activities (2) • Testing samples on request from countries • Arsuamoon tablets (co-blistered artesunate+amodiaquine), Guilin Pharma, China • Request from Indonesia, local procurement by donors, concerns about authenticity • 2 batches tested in RIIP, South Africa  artesunate tablets compliant with Ph.Int., amodiaquine tablets compliant with USP • Diethylcarbamazine citrate tablets, Asian Pharmaceutical Company, Nepal • Request from Nepal, serious adverse events reported, MoH asked for independent testing before distribution of further batches • 4 batches tested in RIVM, Netherlands  compliant with USP

28. Current sampling and testing activities (3) • Quality survey of antimalarials • Most sold and recommended by national guidelines ACTs (co-packed and FDCs) and sulfadoxine-pyrimethamine, oral dosage forms • In 9 African countries (Cameroon, Ethiopia, Ghana, Kenya, Madagascar, Nigeria, Senegal, Tanzania, Uganda) • Covering whole distribution chain (private and public) and informal market throughout the country • First testing using GPHF-Minilab, part of samples then tested in a laboratory (identification, dissolution/disintegration, content of APIs) • Collection of samples in countries being prepared in extensive cooperation with WHO country offices and NDRAs • Assessment of quality of product information (Labelling and PIL)

29. Current sampling and testing activities (4) • Quality monitoring within UNITAID projects • Strengthening of quality control of products as close to patients as possible, in close cooperation with NDRAs (capacity building) • Pilot phase under preparation - paediatric ARV FDCs, cotrimoxazol, second line ARVs in Kenya, Tanzania, Uganda and Zambia • Framework protocol supplemented by country specific sampling and testing plans • Assessment of quality of product information (Labelling and PIL) • Monitoring of quality of WHO prequalified products • Verification that WHO-prequalified products procured by agencies comply with the specifications approved within PQ process • In cooperation with NDRAs

30. Systematic approach to sampling and testing of medicines • Objectives • Products which are prequalified and procured using international funding are subject to systematic risk based quality testing • Probability of poor quality, severity of health risk, size of exposed population, … • Urgent testing is organized, if needed • Member States are supported in quality testing, if requested • Outcomes of testing are reflected in appropriate measures • Quality team • Assessor/s, inspector/s, PhV expert, pharmacopoeial expert, QCL coordinator, external expert/s (if needed) • Discussion of project proposals and immediate signals, application of risk analysis, projects outcomes, actions needed

31. Sampling and testing projects Commitments (PQ procedure, Agreements) Reports Actions Inspections Assessment PhV Entry information (Quality concerns, complaints/defects, signals) Plan +updates P1-out P2-out P3-out P1 P3 P2 Conduct of projects

32. Thanks for your attention www.who.int/prequal prequallaboratories@who.int