1. 1 WH O Technical Briefing | September 2011 Safe quality medicines

2. Medicines quality assurance: WHO Expert Committee on Specifications for Pharmaceutical Preparations Sabine Kopp, PhD Quality Assurance and Safety: Medicines Department of Essential Medicines and Pharmaceutical Policies

3. 3 WH O Technical Briefing | September 2011 Main points addressed n Who is WHO? n How does WHO set standards? n Which WHO guidelines, standards and norms exist in the area of quality assurance? n What's new ?

4. 4 WH O Technical Briefing | September 2011 Who is WHO? Governing bodies n World Health Assembly (WHA) Delegations from 193 Member States Meeting yearly in May n Executive Board (EB) Representatives from 34 Member States + Meeting biannually in January and May

5. 5 WH O Technical Briefing | September 2011 Impressions from World Health Assembly n - SSFFC

6. 6 WH O Technical Briefing | September 2011 Impressions from World Health Assembly Floor of the Assembly Dr Margaret Chan, WHO Director-General Mr Bill Gates, Co-chair of the Bill & Melinda Gates Foundation Her Excellency Sheikh Hasina, Prime Minister of Bangladesh Dr Christos Patsalides, President of the Sixty-fourth World Health Assembly and Minister of Health of Cyprus, and Dr Maria Teresa Valenzuela (Chile), Chair of Committee B.

7. 7 WH O Technical Briefing | September 2011 WHO is WHO ? Secretariat and experts n WHO Secretariat: - Headquarters - six Regional Offices and 149 Country offices n Experts: - WHO Expert Panels and Expert Committees - WHO Collaborating Centres - + partners n Constitution signed 1946, in force since 7 April 1948 (World Health Day)

8. 8 WH O Technical Briefing | September 2011 WHO Partners With Regulatory Bodies… n National/Regional regulatory authorities n Regional/Interregional regulatory groups (ASEAN, GCC, ICH, PANDRH...) Within WHO… n WHO disease programmes (Stop TB, Roll-Back Malaria, HIV/AIDS, Tropical Neglected Diseases, programmes on Children, Women's Health… ) n Prequalification Programme – A United Nations Programme managed by WHO

9. 9 WH O Technical Briefing | September 2011 WHO Partners (2) With Organizations and Associations… n International organizations (UNAIDS, UNICEF, IAEA, Global Fund, World Bank…) n International professional and other associations, NGOs (incl. industry, consumer associations: IFPMA, IGPA, WSMI, IPEC, FIP, WMA, MSF…) With Standard-setting Bodies, such as … n Pharmacopoeia Commissions and Secretariats (e.g. British Brazilian, Chinese, European, Indian, Korean, Japanese, USP,.. )

10. 10 W HO Technical Briefing | September 2011 WHO Partners (3) With "recognized" Experts… n WHO Expert Panel on The International Pharmacopoeia and Pharmaceutical Preparations (official nomination process) n Specialists from all areas for specific projects (regulatory, university, industry…) With "recognized" Laboratories… n National/Regional Quality control laboratories n WHO Collaborating Centres (official nomination process)

11. 11 W HO Technical Briefing | September 2011 How to become a "WHO Expert"? n Official nomination process n Upon proposal to WHO in consultation with: l Member State/national government (citizenship)+ l WHO Regional Office (in accordance with Member State) + l WHO Headquarters n Period of maximum 4 years n Possibility to renew

12. 12 W HO Technical Briefing | September 2011 What is the WHO Expert Committee? n Official Advisory Body to Director-General of WHO n Governed though rules and procedures (Ref. WHO Manual) n Participation in Expert Committee (EC) meetings: ä Members ("Expert") selected from WHO Panel of Experts ä Technical advisers ä Observers: - international organizations, - NGOs, - professional associations…

13. 13 W HO Technical Briefing | September 2011 Outcome of the WHO Expert Committee? n Report of the WHO Expert Committee: - Summarizes discussion - Gives recommendations to WHO + Member States - Includes newly adopted guidelines; - Is presented to WHO Governing Bodies for final comments, endorsement and implementation by Member States n  constitutes WHO technical guidance

14. 14 W HO Technical Briefing | September 2011 WHO Expert Committees rules and procedures  WHO Basic Documents n Constitution of WHO ä Expert Committees: chapter V, article 18; chapter VIII, articles 38-40 ä For normative function - pharmaceuticals: Chapter 2, article 2 (u): " to develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products;" n Regulations for Expert Advisory Panels and Committees, including, Annex – Rules of Procedure for Expert Committees

15. 15 W HO Technical Briefing | September 2011 Examples of WHO Expert Committees ? n WHO Expert Committee on Specifications for Pharmaceutical Preparations n WHO Expert Committee on the Selection and Use of Essential Medicines n WHO Expert Committee on Drug Dependence n WHO Expert Committee on Biological Standardization n Joint FAO/WHO Expert Committee on Food Additives n ….

16. 16 W HO Technical Briefing | September 2011 When does the WHO Expert Committee start development of a guideline/guidance? n Based on recommendations by : n World Health Assembly resolutions (e.g. WHA 20.34, GMP - Good manufacturing practices) n Executive Board resolutions (e.g. EB37.R9 delegating certain functions of INN Programme to DG based on advice from Experts) n International Conference of Drug Regulatory Authorities (e.g. 10 th +11 th ICDRA – FDC guidelines + Certification Scheme for pharmaceutical starting materials moving into international commerce) n Other WHO programmes and clusters (e.g. necessity for quality control specifications for specific medicines of major public health interest and feedback from Prequlifcation programme) n Expert Committee (e.g. revision of general methods included in The International Pharmacopoeia)

17. 17 W HO Technical Briefing | September 2011 How does the WHO consultation process work? n Step 1. Preliminary consultation and drafting n Step 2. Draft guidelines n Step 3. Circulation for comments n Step 4. Revision process n.......... (back to step 2 and 3 as often as needed) n  WHO Expert Committee (EC) meeting ä  if guideline adopted, published in EC report as Annex n -> WHO Governing bodies n -> Recommendation to Member States for implementation

18. 18 W HO Technical Briefing | September 2011 WHO Governing bodies …

19. 19 W HO Technical Briefing | September 2011 Medicines Quality Assurance in WHO 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 W HO Technical Briefing | September 2011 Medicines Quality Assurance in WHO 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 W HO Technical Briefing | September 2011 Medicines Quality Assurance in WHO Historical overview (3)  1st "WHO Expert Committee on Specifications for Pharmaceutical Preparations" ( ECSPP) meeting held 13-17 October 1947  Report of 1st ECSPP meeting published in:  Official Records of WHO, No 8, page 54ff, 1947

22. 22 W HO Technical Briefing | September 2011 Quality of medicines remains a problem

23. 23 W HO Technical Briefing | September 2011 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

24. 24 W HO Technical Briefing | September 2011 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

25. 25 W HO Technical Briefing | September 2011 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 Global tools to help ensure that patients receive quality safe quality medicines n Global norms and international standards and nomenclature

26. 26 W HO Technical Briefing | September 2011 INNs

27. 27 W HO Technical Briefing | September 2011 WHO’s medicines quality assurance guidelines Cover: n Development n Production n Quality Control n Quality related regulatory guidelines n Inspection n Distribution n  from manufacture (and before) to delivery to patient

28. 28 W HO Technical Briefing | September 2011 Adopted WHO guidance texts and guidelines in medicines quality assurance (without PhInt) Maintain to keep up to date: ä More than 60 CURRENT official WHO guidance texts and guidelines to date, including 15 (8 updates + 7 new adopted 2010)

29. 29 W HO Technical Briefing | September 2011 Quality Control http://www.who.int/medicines/areas/quality_safety/quality_assurance/contr ol/ More than 10 guidance documents and guidelines, including - Good laboratory practices + training materials - Guidelines for establishment of chemical reference standards - Model certificate of analysis - International Pharmacopoeia + Basic tests

30. 30 W HO Technical Briefing | September 2011 International Pharmacopoeia Ph.Int.  current: 4 th edition! Supplement 1 +2  implementation: “ready for use” by Member States  Scope since 1975:  Model List of Essential Medicines and  Drugs recommended by WHO Specific disease programmes, e.g. Malaria, TB, HIV/AIDS, medicines for children

31. 31 W HO Technical Briefing | September 2011 External Quality Assessment Scheme for National Drug Quality Control Laboratories n Phase 5 (01/2010 - 12/2012) - 60 laboratories participate - Studies: ä - Assay by titration ä -Water content by Karl-Fischer ä -Dissolution test ä -Related substances by HPLC ä -Related substances by TLC ä -Assay by HPLC ä -Dissolution test

32. 32 W HO Technical Briefing | September 2011 Distribution http://www.who.int/medicines/areas/quality_safety/quality_ass urance/distribution Some 10 guidance documents and guidelines, e.g.: - Certification schemes (CPP and SMACS) - Quality system for Procurement - Good distribution practices for starting materials and finished products - Good storage practices

33. 33 W HO Technical Briefing | September 2011 Production - http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/ http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/ Some 20 guidance documents and guidelines, including: - Good Manufacturing Practices (GMP) …..Consisting of more than 10 major "guideline" texts (regularly updated, new texts added as needs are identified) - ….. Training materials (slides, video, GMP text) - Risk analysis (HACCP) – moving to "quality risk management"

34. 34 W HO Technical Briefing | September 2011 WHO’s global guidelines -production n Good Manufacturing Practices (GMP) ….. n 1. Main principles for pharmaceutical products ä Requirement for the sampling of starting materials (amendment) ä Water for pharmaceutical use ä Heating, ventilation and air-conditioning (HVAC) systems ä Validation n 2. … for starting materials, including ä Active pharmaceutical ingredients ä Pharmaceutical excipients

35. 35 W HO Technical Briefing | September 2011 WHO’s global guidelines -production (2) n 3. … for specific pharmaceutical products: ä Sterile pharmaceutical products ä Biological products (rev in progress) ä Investigational pharmaceutical products for clinical trials in humans ä Herbal medicines ä Radiopharmaceuticals ä Blood establishments

36. 36 W HO Technical Briefing | September 2011 WHO’s global guidelines - 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 http://www.who.int/medicines/areas/quality_safety/qual ity_assurance/inspections/en/index.html

37. 37 W HO Technical Briefing | September 2011 Quality related regulatory standards http://www.who.int/medicines/areas/quality_safety/quality_assurance/re gulatory_standards/ Some 20 guidance documents and guidelines, including : - Stability testing requirements - Interchangeability of generic medicines - Fixed-dose combination - All prequalification procedures

38. 38 W HO Technical Briefing | September 2011 46 th WHO Expert Committee on Specifications for Pharmaceutical Preparations – outcome - 1- 1. Adopted texts: The International Pharmacopoeia - Medicines for HIV and related conditions: - Ritonavir tablets -Antimalarial medicines ä Artesunate ä Artenimol -Antituberculosis medicines ä Rifampicin - Anti-infectives: - Pyrantel chewable tablets

39. 39 W HO Technical Briefing | September 2011 46 th WHO Expert Committee on Specifications for Pharmaceutical Preparations – outcome -2- - Antituberculosis drugs (ctd) n Ofloxacin tablets n Levofloxacin n Levofloxacin tablets - For anti-infectives: n Amoxicillin oral suspension n Levamisole tablets n Metronidazole oral suspension n Sulfamethoxazole and trimethoprim tablets

40. 40 W HO Technical Briefing | September 2011 46 th WHO Expert Committee on Specifications for Pharmaceutical Preparations – outcome -3- - For other medicines n Medroxyprogesterone injection n Paediatric retinol oral solution For harmonized general texts (based on PDG texts) n Test for sulfated ash n Test for bacterial endotoxins n Test for sterility n Tablet friability n Disintegration test for tablets and capsules

41. 41 W HO Technical Briefing | September 2011 46 th WHO Expert Committee on Specifications for Pharmaceutical Preparations – outcome -4- n Bulk density and tapped density of powders n Test for extractable volume for parenteral preparations n Microbiological examination of non-sterile products: microbial enumeration tests n Microbiological examination of non-sterile products: tests for specified microorganisms n Microbial quality of pharmaceutical preparations n Test for particulate contamination

42. 42 W HO Technical Briefing | September 2011 46 th WHO Expert Committee on Specifications for Pharmaceutical Preparations – outcome -5- n General policy topics and general revision issues for: ä Uniformity of content for single-dose preparations n Supplementary information section for the Ph.Int. n The Committee adopted the following new ICRS: ä Lumefantrine for system suitability

43. 43 W HO Technical Briefing | September 2011 46 th WHO Expert Committee on Specifications for Pharmaceutical Preparations – outcome -6- 2. Adopted global quality assurance guidelines: ä WHO good manufacturing practices: water for pharmaceutical use ä Pharmaceutical development of multisource (generic) pharmaceutical products ä Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification Programme: quality part

44. 44 W HO Technical Briefing | September 2011 46 th WHO Expert Committee on Specifications for Pharmaceutical Preparations – outcome -7- ä Monograph development for The International Pharmacopoeia ä Development of paediatric medicines: points to consider in formulation ä Quality requirements of artemisinin as a starting material in the production of antimalarial active pharmaceutical ingredients

45. 45 W HO Technical Briefing | September 2011 In the pipeline - quality assurance for medicines.. n Ph.Int.: Harmonization with PDG general texts – for those evaluated by ICH Q4B, continue n External Quality Assessment Scheme for National Drug Quality Control Laboratories, 5 th series, 3 rd test in process, 4 th in preparation n Guidance on selection of comparator products for equivalence assessment of interchangeable generic products (revision)

46. 46 W HO Technical Briefing | September 2011 In the pipeline.. n Risk analysis based on HACCP towards Quality Risk Management n Guideline on submission of documentation for a multisource (generic) product – quality part – general guidance n Tools and framework for monitoring of market situation n International meeting(s) for world pharmacopoeiae

47. 47 W HO Technical Briefing | September 2011 Advantages of WHO's Expert Committee standard-setting process n 1. Guidelines and specifications validated internationally, through an independent scientific process, adoption by members of WHO Expert Advisory Panels n 2. Collaboration with standard-setting organizations and parties, including regional and national pharmacopoeias n 3. Networking and close collaboration with WHO Member States, Drug Regulatory Authorities, national medicines quality control laboratories

48. 48 W HO Technical Briefing | September 2011 Advantages of WHO's Expert Committee standard-setting process (2) n 4. Links with other WHO activities n 5. Reality check: Input from manufacturers (including international associations of research, generic and self-medication associations) around the world n 6. Consideration of costs, e.g. keeping need for reference standards at a minimum n 7. Service FREE FOR USE by all Member States

49. 49 W HO Technical Briefing | September 2011 WHO Medicines Quality Assurance website: http://www.who.int/medicines/areas/quality_safety/quality_assurance http://www.who.int/medicines/areas/quality_safety/quality_assurance

50. 50 W HO Technical Briefing | September 2011 Safe quality medicines