WHO Prequalification Team – Need and contribution Wednesday, 5 November 2014 13:35 – 15:45

1. WHO Technical Briefing Seminar 03 – 07 November 2014 WHO Prequalification Team – Need and contribution Wednesday, 5 November 2014 13:35 – 15:45 Lembit Rägo, EMP/RHT Acting Coordinator, WHO Prequalification Team ragol@who.int Presented by Deusdedit K. Mubangizi Group Leader, Inspections mubangizid@who.int

2. WHO Prequalification Team:Programme for Priority Health products and Technologies • In this presentation: • Role of PQT – towards MDGs • Reorganisation of PQ Programmes • How PQT works - operating principles • Selected focus on few areas: • Inspections • Prequalification of QCLs • Collaborative registration of WHO-PQ products • Capacity building • Frequent misunderstandings about WHO-PQ • Selected outcomes/achievements

3. WHO Prequalification Programme for Priority Health products and Technologies • Action plan of UN for expanding access to selected priority medicines • Objective • To ensure quality, efficacy and safety of Health products and Technologies procured using international funds (e.g. GFTAM, UNITAID, UNICEF) to serve patients in developing countries • Components • Evaluation of Quality, Safety and Efficacy of prioritised Health products and Technologies, 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

4. WHO-PQ contributes to the Millennium Development Goals (MDGs): • Eight international development goals that 192 United Nations member states and at least 23 international organizations have agreed to achieve by the year 2015 • Reduce child mortality • Improve maternal Health • Combat HIV/AIDs, Malaria and other diseases

5. Role of WHO prequalification Facilitate access to safe, appropriate priority diagnostics, medicines & vaccines Support two of WHO's six core functions: setting norms & standard/promoting their implementation providing technical support, catalysing change & building institutional capacity. Contribute to achieving four of WHO's impact goals: reduce under-five mortality reduce maternal mortality reduce the number of people dying from AIDS, tuberculosis and malaria eradicate polio.

6. Reorganization: single PQ programme for further impact & restructured regulatory units Consolidated prequalification programme aiming at: Enhanced management & operations e.g. quality management system e.g. administrative efficiencies, incl. financial management Better relationship with stakeholders e.g. single voice when dealing with national regulatory authorities e.g. increased transparency around processes and outcomes Cross-product stream learning e.g.extension of ERP process to new product categories e.g. bigger pool of external experts and testing laboratories e.g. PQDx benefit from medicines and vaccines experience to improve efficiency Flexibility transition business-as-usual PQ activities to NRAs WHO PQ moves into new therapeutic areas (e.g. non-communicable diseases) and/or new product types (e.g. biologicals) Improved regulatory support ― pharmacovigilance, norms & standards ―to PQ processes

7. Structure of Department of Essential Medicines & Health Products

8. Prequalification Team Structure of the Prequalification Team • Coordinator’s office • Vaccines Assessment • Medicines Assessment • Diagnostics Assessment • Inspections • Technical Assistance/Labs • Administrative team

9. How does PQT work? In the short term: assessing product dossiers, inspecting manufacturing & testing sites, organizing quality control testing of vaccines & medicines, evaluating performance of diagnostics & verifying that products are suitable for use in destination countries, facilitating regulatory approvals In the medium- and long-term by building capacity of manufacturers & regulators

10. Two routes to medicines prequalification Invitation for expression of Interest Medicine assessed by SRA Medicine not assessed by SRA Dossier and SMF submitted for assessment Valid for innovators and generics SRA registration (assessment and compliance check) WHO assessment and inspections organized Simplified review Prequalification Compliance Acceptance

11. Overview of prequalification of diagnostics

12. Steps of the Vx PQ procedure • Official request and response • Meetings with manufacturers • Product summary file (PSF) • Initial testing of vaccine samples • WHO site audits • Report and outcome of the assessment • Principles: • Reliance on the National Regulatory Authority responsible for the regulatory oversight of the vaccine. • Prerequisites: • The National Regulatory Authority responsible for the product is "functional" as per assessment performed using the WHO established indicators.

13. PQT Operating principles Acts independently Strives for innovation e.g. Expert Review Panel (1st for medicines, now for Dx) e.g. PQ of APIs e.g. Reducing time to national registration of medicines through joint assessments e.g. actively advising manufacturers how to develop unique paediatric formulations e.g. early implementation of BE study waivers for medicines to ease the regulatory burden for manufacturers e.g. Collaborative registrations for medicines and vaccines e.g. advisory visits and technical assistance for Dx innovators Seeks collaboration to enhance impacts, optimize resources, share expertise e.g. joint assessments and joint inspections with NRAs e.g. fast-track procedure for diagnostics registered by SRAs Is pro-active e.g. assists manufacturers and NMRAs e.g. monitors needs of stakeholders Seeks incremental improvements that can be sustained e.g. reduced timelines to PQ e.g. continuous process to review and refine technical guidance

14. WHO-PQT-Rx: Target Inspection Timelines • First inspection: 6 months from dossier acceptance for assessment or from site confirms it is ready. • Routine inspection: ± 3 months from due date. • Notification: 1 – 2 months before inspection. • Onsite days: 3 – 5 days. • Report: 30 days from last date of inspection. • CAPAs: 30 days from receipt of report (max 2 rounds, comprehensive, on CDs and not hard copies) • Closing of inspection: 6 months from inspection. • Follow-up inspection: 6 months from inspection • Validity of compliance: 1 to 3 year from inspection date

17. NEW SITES: Days from acceptance to first date of inspection

18. RE-INSPECTIONS: Days from acceptance to first date of inspection

19. Inspections: Worrying Trends Media is awash with NOCs, warning letters, import alerts, statements of non-compliance, complaints, recalls, etc. • Data integrity and falsification • unbalanced focus on QC (quality built in – not tested in). • « Show-case » and « shadow » industries. • « Knee-jerk » responses to inspection observations. • Many « Awaits CAPAs » on routine inspection: • poor maintenance of quality systems • work hard to pass first inspection and then go on holiday

20. Prequalification of QCLs: Objectives • Increase the access to services of QCLs that • Meet recommended standards for testing of medicines, and • Are committed to test medicines for UN agencies • Contribute to capacity building of national QCLs in developing countries (strengthening of health systems) • Technical assistance • Trainings • Guidelines

21. QCL Prequalification procedure • Established in 2004 in cooperation with UN agencies • Procedure published in 2004, revised in 2007 and 2011 • http://www.who.int/prequal/info_general/documents/TRS961/TRS961_Annex12.pdf • Participation of a QC laboratory is voluntary • Any laboratory (private or governmental) can participate • Scope - chemical and microbiological testing (including LAL test) of medicines (vaccines, biologicals not included) • Based on the following principles • Evaluation of information submitted by the laboratory • On site inspection • Monitoring of performance of prequalified laboratory

22. QCL Invitation for Expression of Interest • Previous invitations limited to QC laboratories in Africa, currently no regional limitation • 3rd EOI published in September 2007 • http://www.who.int/prequal/info_applicants/eoi/EOI-QCLabsV3.pdf • Priority in the assessment is given to • National QC laboratories and laboratories providing testing services to the governments • QC laboratories in areas where UN agencies identify the need for quality testing

23. QCLs: Steps of the procedure • Expression of interest • Currently free of charge • Submission of laboratory information file • Guidelines for preparing LIF available • Quality Manual can be submitted (amended as necessary) • Evaluation of submitted information • Assessment of laboratory's potential to pass successfully the inspection • Compliance  WHO organizes an inspection • Gaps  For a national QCL in a developing country, WHO may organize a pre-audit/ technical assistance

24. QCLs: Steps of the procedure • Site inspection • Planned and coordinated by WHO • 2-3 days, external inspectors experienced in QC appointed (preferably from MRA) • Representative of MRA of the country where the QCL is located is invited • Compliance with WHO recommended standards • WHO Good Practices for Pharmaceutical Quality Control Laboratories • http://www.who.int/prequal/info_general/documents/TRS957/GPCL_TRS957_Annex1.pdf • WHO Good practices for pharmaceutical microbiology laboratories • http://www.who.int/prequal/info_general/documents/TRS961/TRS961_Annex2.pdf • WHO Good manufacturing practices – parts relevant to QCLs • http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/index.html • Focus on the overall quality system in the laboratory and chemical and microbiological testing, not on individual methods only

25. QCLs: Steps of the procedure • Site inspection (cont) • Report communicated to the laboratory • If corrective actions to be taken by the laboratory, final decision is made after their evaluation • Audit report from another authority (e.g. EDQM) • Compliance with WHO standards is evaluated and WHO inspection may not be necessary • ISO accreditation encouraged and considered but does not cover GMP aspects • If compliant, laboratory is included in the published list and WHOPIR is published • Prequalification does not guarantee future contracts for testing for UN agencies, competitive tendering usually organized

26. QCLs: Steps of the procedure • Monitoring after prequalification • Re-inspections at a frequency based on risk assessment • At least once every 3 years • Evaluation of results from participation in proficiency testing • WHO External Quality Assurance Scheme (EQAAS), ANSM network of Francophone African countries • Brief report requested to be submitted annually • Summary of services provided to UN agencies, number of analysed samples, methods used, complaints received • Changes with significant impact to the laboratory (key personnel, facility, equipment) and update LIF • WHO may suspend or withdraw a laboratory from the list when there is evidence of noncompliance

27. Prequalified/interested QCLs(October 2014)

28. Prequalified QCLs(October 2014) • Europe • France, CHMP (2008) • Ukraine, CLQCM (2010) • Ukraine, LPA (2010) • Belgium, SGS (2011) • Netherlands, Proxy (2011) • Portugal, INFARMED (2011) • Russia-Moscow, FSBI (2012) • Belarus, RCAL (2012) • Portugal, LaboratoriosBasi (2013) • Russia-Rostov on Don, FSBI (2014) • Germany, InphA (2014) • Netherlands, Synergy Health Utrecht (2014) • Switzerland, Intertek (2014) • Eastern Mediterranean • Morocco, LNCM (2008) • Pakistan, Getz Pharma (2014) • Western Pacific • Vietnam, NIDQC (2008) • Singapore, TÜV (2009) • China, NIFDC (2012) • Africa • South Africa, RIIP+CENQAM (2005) • Algeria, LNCPP (2005) • South Africa, Adcock Ingram (2007) • Kenya, NQCL (2008) • Kenya, MEDS (2009) • Tanzania, TFDA (2011) • Zimbabwe, MCAZ (2014) • Americas • Canada, K.A.B.S. Laboratories (2010) • Peru, CNCC (2010) • Uruguay, CCCM (2010) • Bolivia, CONCAMYT (2010) • Brazil, FUNED (2011) • Mexico, CCAYAC (2013) • Brazil, INCQS (2014) • South-East Asia • India, Vimta Labs (2008) • India, SGS (2011) • Thailand, BDN (2012) • India, Stabicon (2013)

29. QCLs in the procedure – by status (October 2014)

30. QCLs in the procedure – by region (October 2014)

31. Capacity building for QCLs • Technical assistance provided to national medicines QCLs in developing countries • 46 since 2006 (14 in 2013, 7 in 2014) • Focus on implementation of quality system, microbiology testing/lab design • Training • Training in HPLC (organized with ANSM in March 2013, Tunisia) • 6 Workshops on laboratory quality control of reproductive health products (organized with UNFPA in 2011-2013 in Tanzania, Namibia, Ghana, Thailand, Fiji, Djibouti) • WHO Interregional Seminar of QCLs involved in Prequalification in South Africa, October 2014 (training focused on observations marked in red) • WHO External Quality Assurance Assessment Scheme (EQAAS) – Dr Sabine Kopp (kopps@who.int)

32. Potential benefits of PQ for QCLs • Possibility to provide testing services to UN agencies and other organizations - financial profit • Recognition as being WHO listed laboratory • Facilitated discussions with manufacturers/customers in case of non-compliant results • Learning process improving the standards of laboratory work • In case on a national QCLs in a developing country, possibility to be assisted by WHO expert consultants and participate in WHO organized trainings

33. Collaborative registration of WHO-prequalified products • To be used, prequalified medicines must be authorised for use (registered) by national regulatory authorities. • In many countries that are recipients of prequalified medicines, regulatory systems are either weak or lack capacity to manage effectively queuing applications, delaying accessibility of essential medicines. • PQT strives to facilitate the process in co-operation with involved manufacturers and regulators.

34. Principles of WHO Collaborative Procedure • Voluntary for manufacturers and NMRAs and does not interfere with national decision making process and regulatory fees • WHO-PQT shares with interested regulators detailed outcomes of its assessment and inspections to support their decision making in exchange for accelerated registration process • Product and registration dossier in countries are 'the same' as approved by PQP. Co-operation among PQ holder (manufacturer), NMRA in interested country and PQT overcomes confidentiality issues, ensures information flow and product identity • 'Harmonized product status' is monitored and maintained

35. Principles of the process • 1) • Being asked by PQ holder (manufacturer), PQT shares full PQ assessment and inspection outcomes with NMRAs participating in the scheme and provides advice to facilitate national regulatory decisions (registrations, variations, withdrawals). • - Applicable only for medicines assessed/inspected by PQP • PQ holder provides consent with information sharing • Data and product are 'same' as prequalified • - Voluntary for manufacturers and NMRAs and does not interfere with national decision making process and regulatory fees.

36. Principles of the process • 2) • It is up to discretion of participating NMRAs how to benefit from shared information. However, participating NMRAs commit to adopt registration decision within 90 days from having available full PQP assessment and inspection outcomes. NMRAs have the right to • decline to adopt procedure for individual medicines • decide differently from PQP, but keep PQP informed and clarify reasons for deviation.

37. Principles of the process • 3) • Communication continues in post-approval period to be assured that product does not 'disconnect' from prequalification status • variations are synchronized • de-listings and/or de-registrations are communicated • 4) • Participating NMRAs (countries) and registered products are posted on PQP website

38. Steps of the procedure: registration PQ product is submitted for national registration to NMRA participating in the procedure NMRA is informed about the interest to follow PQP Manufacturer informs PQP about national submission and gives consent with information sharing Participating NMRA confirms its interest to participate in procedure for specific product PQP shares with participating NMRA outcomes of assessment and inspections Participating NMRA reviews WHO PQP outcomes, decides within 90 days decides upon the national registration and informs PQP about its decision

39. Steps of the procedure: post-registration Variations NMRAs inform PQP about variations and decisions leading to inconsistency with PQP conditions PQP informs NMRAs about important variations Post-PQ and post-registration actions WHO PQP informs NMRA about withdrawals, suspensions or de-listings of prequalified medicinal products NMRAs inform PQP about national de-registration

40. Medicines: pilot initiated in June 2012, now operational process 20 participating NMRAs from 19 countries • Africa • Botswana • Burkina Faso • DR Congo • Ethiopia • Ghana • Kenya • Madagascar • Malawi • Mozambique • Namibia • Nigeria • Sierra Leone • Tanzania • Uganda • Zambia • Zanzibar • Zimbabwe • Europe/Asia • Armenia • Georgia • Kyrgyzstan • Ukraine

41. 38 registrations in 8 countries: • Zimbabwe 9 Nigeria 5 • Tanzania 7 Uganda 4 • Ghana 6 Kenya 1 • Namibia 5 Botswana 1 • 21 different prequalified products for treatment of HIV/AIDS, TB, malaria and contraceptives • 7 companies involved, • 6 from India

42. 28 (74%) approved within 4 months18 (47%) approved within 3 months

43. 72 Expressions of interest received Not accepted (13): 8 already registered or at advanced stage of normal evaluation; 3 not in line with prequalification data; 2 not in national TG

44. Win-win outcomes for all stakeholders • Manufacturers • Harmonized data for PQ and national registration • Facilitated interaction with NMRAs in assessment and inspections • Accelerated and more predictable registration • Easier post-registration maintenance • Procurers • Faster start of procurement and wider availability of PQ medicines • Assurance about 'the same' medicine as is prequalified • NMRAs • Availability of WHO assessment and inspection outcomes to support national decisions and save internal capacities • Opportunity to learn from PQP assessors and inspectors • Demonstrating NMRA efficiency • Having assurance about registration of 'the same' medicine as is prequalified • Quality control by same methods and specifications • Easier post-registration maintenance • WHO • Prequalified medicines are faster available to patients • Feed-back on WHO prequalification outcomes • Ultimate beneficiaries are patients !!! ……..Improved Access.

45. Outcomes and experience • National registrations are achieved faster • Product and registration dossier in countries are 'the same' as approved by PQP. • 'Harmonized product status' is monitored and maintained • Co-operation among PQP holder (manufacturer), NMRA in interested country and PQP is necessary to overcome confidentiality issues, assure information flow and product identity. • Avenue for learning and regulatory collaboration • Success factors: • Effective communication and good administrative practice • Involvement and training of local representatives • Dossiers in line with PQ

46. New developments • Revision of the Procedure and extension to vaccines • Draft in the first round commented by vaccine manufacturers • www.who.int/immunization_standards/vaccines_quality/expedited_review • Extended pilot for vaccines under preparation • WHO Expert Committees involved • Scheduled meeting with participating countries • Analogous process considered for in vitro diagnostics • Similar model under preparation for facilitated registrations of medicines approved by SRAs • Applicable both for innovators and generics • Process constructed in collaboration with associations of industry, relevant SRAs and companies

47. Capacity building - objectives • Good quality submissions for PQ supported by compliance with "good practices" • platform for improvement of drug development, manufacturing, documentation and quality control • Fast regulatory approvals of PQ medicines in recipient countries • technical education of regulators as a platform for strengthening expertise, regulatory efficiency and networking • Reliable quality monitoring • technical education of staff of QCLs to strengthen expertise, effectiveness of quality monitoring and networking • PQP standards and PQP example support strengthening of regulatory systems and capacity of manufacturers in general

48. Key capacity building approaches 1) Training activities of different set-up 2) Technical assistance & consultancy 3) Provision of information, standards and regulatory expertise

49. Seminars and workshops • Trainings of NRA staff and manufacturers frequently combined