1. WHO and its activities in quality assurance of medicines Sabine Kopp, PhD Quality Assurance and Safety: Medicines Essential Drugs and Medicines Policy World Health Organization

2. 2 WHO - EDM SK 2003 n 1. What is WHO? n 2. How does WHO work and for whom? n 3. Details on WHO activities in the areas of quality assurance, including: ä - INN ä - Int. Ph. ä -GMP ä -Stability ä -pre-qualification project... n 4. Summary

3. 3 WHO - EDM SK 2003 1. What is WHO? Some basic facts n 192 Member States n Two governing bodies: - World Health Assembly - Executive Board n WHO Secretariat: - HQ - six Regional Offices - WHO Expert Panels (e.g... on the International Pharmacopoeia and Pharmaceutical Preparations) Constitution 1946, in force since 7 April 1948 (World Health Day)

4. 4 WHO - EDM SK 2003 2. How does WHO work and for whom? n WHO’s main functions: inter alia n - To act as the directing and coordinating authority on international health work n - To encourage technical cooperation for health with Member States

5. 5 WHO - EDM SK 2003 --> WHO responsibilities (inter alia) n To assist governments, upon request, in strengthening health services n To provide information, counsel and assist in the field of health n To stimulate eradication of epidemics, endemics and other diseases n To promote cooperation among scientific and professional groups which contribute to the enhancement of health n To promote international conventions and agreements in health matters n To promote and conduct research in the field of health n To develop, establish and promote international standards for food, biological and pharmaceutical products n........

6. 6 WHO - EDM SK 2003 Access gap - financing, delivery and other constraints still limit access to essential drugs n >1/3 of world’s population lacks regular access n 320 million in Africa have <50% n Problem worsens with economic pressures Percentage of populations and number of countries with regular access to essential drugs: 1 = <50% (43) 2 = 50-80% (64) 3 = 80-95% (30) 4 = >95% (41) 5 = No data available (1) Pharmaceutical gaps Source: WHO/DAP 1998

7. 7 WHO - EDM SK 2003 What are the priorities for WHO’s medicines strategy? n Access to essential drugs ä for priority health problems (malaria, TB, childhood, HIV/AIDS) ä for poor and vulnerable populations n Quality and safety of all medicines ä creating and maintaining global guidelines and standards ä supporting effective drug regulation & quality assurance n Rational use of medicines ä by health professionals ä by households n National drug policies ä integrated in national health policies and systems ä emphasis on implementation and monitoring WHO medicine strategy

8. 8 WHO - EDM SK 2003 WHO medicine strategy What guides and anchors WHO’s work in drugs and medicines policy? n Global norms, standards, guidelines, nomenclature ä Expert Committees and Expert Panels ä WHO Collaborating Centres n Essential drugs and national drug policies ä 1975 resolution introducing essential drugs concept ä Revised drug strategy (1986) and subsequent WHA resolutions n WHO medicines work today ä Governing bodies - Assembly, Executive Board, Regional Committees ä Meeting of Interested Parties - MIP ä --> changes as from 21 July 2003

9. 9 WHO - EDM SK 2003 Challenges: past and present… n Past: ä Manufacture direct from API -> finished product ä Manufacture of API in sites close to or same as product ä Experience and long-standing knowledge of production, product and manufacture of parties involved ä Few intermediates in sales chain ä Usually stable trade and sales connections

10. 10 WHO - EDM SK 2003 Challenges: past and present… n Present: ä Rationalization of drug production ä Contracting-out of many steps in manufacture ä Many intermediates in trade and sales chain ä Trade, shipping, long distances involved ä Increase of risks… ä Increase of requirements and documentation ä Increase of national control mechanisms

11. 11 WHO - EDM SK 2003 Global challenges … n National vs international requirements n Number of requirements n Application and interpretation of requirements n Import vs export control on national level n Quality assurance systems applied n Knowledge of product by parties involved in manufacture n Cross-border promotion and sale n Free trade zones

12. 12 WHO - EDM SK 2003 Global challenges… n Number of national and international inspections by same party n Number of inspections in same site by different parties n Applicability of new technologies in different settings n Contracts, agreements, MRAs….. n Risks of mistakes, accidents, human errors etc n Counterfeit drugs n …...

13. 13 WHO - EDM SK 2003 National regulatory and inspection systems ä --> approx. 1/3 of WHO Member States have well developed regulatory systems, approx.. 1/3 have none n In developed countries ä well organized, controlling national market ä dossiers evaluation and inspections ä different approaches used, few MRA n In developing countries ä often difficulties of resources ä capacity? ä application of national and international guidelines… ä --> or non-existent ….

14. 14 WHO - EDM SK 2003 Experience from WHO's pre-qualification project - example ARVs ä Inspections and dossiers evaluation can differ from country to country ä Small percentage of products and manufacturers participating in the project comply internationally ä Time needed from some manufacturers to get into compliance l data to be generated l GMP upgrade ä Quality Assurance at a price!

15. 15 WHO - EDM SK 2003 WHO’s global guidelines and strategies n Requirements for drug registration and model legislation n Networking among and with regulatory authorities n International alerts n Counterfeit network n Global norms and standards in production, inspection, quality control, good storage practices and nomenclature (INN) …..

16. 16 WHO - EDM SK 2003 WHO has a constitutional mandate to n "develop, establish and promote international standards with respect to biological, pharmaceutical and similar products” n (Article 2(u) of WHO's Constitution) --> Good Manufacturing Practices, stability guidelines, …… INN Programme …….

17. 17 WHO - EDM SK 2003 WHO Procedure for the preparation of guidelines n Preliminary consultation and drafting n Draft guidelines n Circulation for comments n Revision process n.......... n WHO Expert Committee n WHO Governing bodies n Recommendation to governments for implementation --> publication in Technical Reports

18. 18 WHO - EDM SK 2003 WHO’s global guidelines and strategies - quality control - ä International specifications (Int.Ph., screening tests..) ä WHO Model Certificate of Analysis (COA) for use in trade and procurement ä Considerations for requesting analysis of drug samples ä Quality control laboratories  good practices for national control labs  list of equipment  External qc assessment scheme for labs

19. 19 WHO - EDM SK 2003 International Pharmacopoeia Historical overview  1874Discussion on Unification of terminology and composition of drugs  1902 First Conference organized by Belgian Government  1906Agreement on Unification of the Formulae of Potent Drugs ratified by 19 states  1925 Brussels agreement (signed 1929)  League of Nations: “international pharmacopoeia”

20. 20 WHO - EDM SK 2003 International Pharmacopoeia Historical overview - 2 -  1937 First meeting (experts from B, DK, F, NL, CH, UK, USA) - League of Nations  1947 Interim Commission of WHO takes up health related work of League of Nations  1948 First World Health Assembly established Expert Committee on Unification of Pharmacopoeia

21. 21 WHO - EDM SK 2003 International Pharmacopoeia Historical overview - 3 -  1950 WHA approved publication of Pharmacopoeia Internationalis  1951 named: Expert Committee on International Pharmacopoeia  1959 named: Expert Committee on International Pharmacopoeia and Pharmaceutical Preparations --> to date

22. 22 WHO - EDM SK 2003 International Pharmacopoeia  current: Third edition  implementation: “ready for use” by Member States  Scope since 1975:  Model List of Essential Drugs and  Drugs recommended by WHO Specific disease programmes, e.g. Malaria, TB, HIV/AIDS

23. 23 WHO - EDM SK 2003 WHO’s strategy for quality control  Step-wise approach: - Basic tests (identification) - Screening tests (TLC) - International Pharmacopoeia + International reference materials (ICRS and IR reference spectra)

24. 24 WHO - EDM SK 2003 IntPh and links to other WHO activities  Establishment of monographs for antiretrovirals, HIV medicines - collaboration with other pharmacopoeias, including PDG, Ph.Eur. USP, JP, IP - collaboration with manufacturers - link with project on pre-qualification of suppliers for HIV drugs

25. 25 WHO - EDM SK 2003 Type of monographs  Drug substances  Excipients  Finished dosage forms  General methods and requirements:  oral sold dosage forms  dissolution testing …

26. 26 WHO - EDM SK 2003 INNs

27. 27 WHO - EDM SK 2003 WHO’s global guidelines and strategies - distribution  WHO Certification Scheme for Products Moving in International Commerce  new scheme for pharmaceutical starting materials:  - WHO model GMP certificate, when inspected  - WHO model for self-assessment for manufacture of pharmaceutical starting materials n Good Distribution and Trading Practices for pharmaceutical starting materials n Good Storage Practices n Good Distribution Practices (in preparation)

28. 28 WHO - EDM SK 2003 WHO’s global guidelines and strategies - production n Good Manufacturing Practices ….. n 1. Main principles for pharmaceutical products n 2. … for starting materials, including ä active pharmaceutical ingredients ä pharmaceutical excipients n 3. … for specific pharmaceutical products: ä Sterile pharmaceutical products ä Biological products ä Investigational pharmaceutical products for clinical trials in humans ä Herbal medicines ä Radiopharmaceuticals

29. 29 WHO - EDM SK 2003 WHO’s global guidelines and strategies - inspection n Inspection of….. ä pharmaceutical manufacturers ä drug distribution channels (products) n Guidelines for pre-approval inspection n Quality systems requirements for national GMP inspectorates n Model GMP certificate n Model report for inspections

30. 30 WHO - EDM SK 2003 WHO’s global guidelines and strategies - risk analysis n Application of risk analysis to production of pharmaceuticals, adopted in 2001

31. 31 WHO - EDM SK 2003 WHO stability guidelines n Title: “guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” n n -> stability testing of final drug products n -> well established (e.g. generics) n -> in conventional dosage forms (e.g. tablets)

32. 32 WHO - EDM SK 2003 Developments in 2001 n 2001: new alternative being discussed to modify both ICH and WHO guidelines n for zone IV to: --> 30°C and 65% RH (then: 70%) n Consultative procedure: mailing of request to experts and discussion during informal consultation n Discussion and adoption during WHO Expert Committee on Specifications for Pharmaceutical Preparations held 22-26 October 2001 in Geneva

33. 33 WHO - EDM SK 2003 Long-term storage conditions modified n Zone I21°C45% RH n Zone II25°C60% RH n Zone III30°C35% RH n Zone IV30°C65 %RH l when special transportation and storage conditions were identified as being outside these criteria, additional study data supporting these conditions may need to be made available.

34. 34 WHO - EDM SK 2003 Developments in 2002 -…. n February 2002: ICH Data package for registration in climatic zones II and IV --> signed off by all 6 ICH partners as step 2 document n Consultative process in all three ICH regions by regulatory agencies n Comments and new drafts circulated in ICH Working Group n Discussed at ICH meeting February 2003 n now ICH document step 4

35. 35 WHO - EDM SK 2003 Access to HIV/AIDS Drugs and Diagnostics of Assured Quality - pilot procurement project n Partners: ä WHO ä UNICEF ä UNAIDS ä UNFPA ä The World Bank (support) ä --> now expanded to anti-TB and antimalarial medicines

36. 36 WHO - EDM SK 2003 Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality n Problems and deficiencies identified: ä General Problems identified with ARVs l Several substances and products not in pharmacopoeia l unacceptable chiral activity, stereo-isomerism l unacceptable impurities l lack of reference standards l no analytical methods and method validation l Regulatory authorities not following WHO recommendations for registration of products l Regulatory approval not based on thorough evaluation

37. 37 WHO - EDM SK 2003 Pilot Procurement, Quality and Sourcing Project Access to HIV/AIDS Drugs and Diagnostics of Assured Quality n GMP deficiencies: ä Hormones, cytotoxics and ARVs in same area ä Qualification and validation lacking (premises, systems, equipment, processes) ä Cleaning validation ä No verification of air classification of areas for sterile product manufacturing ä Sampling and testing of APIs ä Loss in traceability of materials used in production

38. 38 WHO - EDM SK 2003 WHO’s operational strategies n Assist countries to strengthen or establish national drug regulation n Study alternative ways of improving control and safe trade of starting materials and products n Promote the use of WHO norms and standards n Promote cooperation and harmonization among countries

39. 39 WHO - EDM SK 2003 WHO’s operational strategies -2-  Work with interested parties and countries to combat counterfeit and substandard drugs  Establishing national and regional quality control laboratories  Training of drug regulatory staff  Development of “how to” manuals and tools

40. 40 WHO - EDM SK 2003 Summary n WHO assists Member States in health related matters n WHO has inter alia a constitutional mandate to develop, establish and promote international standards n WHO issued a number of guidelines and norms in the area of quality assurance n Continuous dialogue and collaboration with with WHO Member States, regional and international harmonization efforts in drug regulation

41. 41 WHO - EDM SK 2003 http://www.who.int/medicines/ Further questions ??????

42. http://who.int/medicines