1. 1 WH O Technical Briefing | September 2010 Safe quality medicines

2. Medicines quality assurance: WHO normative functions in the field of pharmaceuticals Sabine Kopp, PhD Quality Assurance and Safety: Medicines Department of Medicines Policy and Standards

3. 3 WH O Technical Briefing | September 2010 Main points addressed n WHO standard setting process n WHO international guidelines, standards and norms in the area of quality assurance n What's new ?

4. 4 WH O Technical Briefing | September 2010 WHO does the work? n 193 Member States n Two governing bodies: - World Health Assembly - Executive Board n WHO Secretariat: - Headquarters - six Regional Offices and Country offices - WHO Expert Panels and Expert Committees (e.g... on the International Pharmacopoeia and Pharmaceutical Preparations) Constitution 1946, in force since 7 April 1948 (World Health Day)

5. 5 WH O Technical Briefing | September 2010 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

6. 6 WH O Technical Briefing | September 2010 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…

7. 7 WH O Technical Briefing | September 2010 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

8. 8 WH O Technical Briefing | September 2010 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 ….

9. 9 WH O Technical Briefing | September 2010 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) n Expert Committee (e.g. revision of general methods included in The International Pharmacopoeia)

10. 10 W HO Technical Briefing | September 2010 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

11. 11 W HO Technical Briefing | September 2010 WHO Partners n National and regional authorities n International organizations (UNAIDS, UNFPA, UNICEF, World Bank, WIPO, WTO, WCO, etc) n International professional and other associations, NGOs (including consumer associations, MSF, industry: IFPMA-IGPA- WSMI, FIP, WMA, etc) n WHO Expert Panels (official nomination process) n Specialists from all areas, regulatory, university, industry……… n WHO Collaborating Centres (official nomination process) n Pharmacopoeia Commissions and Secretariats, national institutions and institutes.. n Regional and inter-regional groups (ICH…)

12. 12 W HO Technical Briefing | September 2010 Why need for stringent standards for medicines? "… drugs are a public good and not simply just another commodity: first for their high social value, and then because consumers and prescribers are unable to assess their quality, safety and efficacy" (Dr Gro Harlem Brundtland, former Director General of the World Health Organization) n  medicines belong to one of the most regulated group of products

13. 13 W HO Technical Briefing | September 2010 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”

14. 14 W HO Technical Briefing | September 2010 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

15. 15 W HO Technical Briefing | September 2010 Quality of medicines remains a problem in many countries

16. 16 W HO Technical Briefing | September 2010 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

17. 17 W HO Technical Briefing | September 2010 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

18. 18 W HO Technical Briefing | September 2010 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 - Internet n Free trade zones

19. 19 W HO Technical Briefing | September 2010 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, eg Mutual Recognition Agreements n Risks of mistakes, accidents, human errors etc n Counterfeit drugs n …...

20. 20 W HO Technical Briefing | September 2010 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 international standards and nomenclature

21. 21 W HO Technical Briefing | September 2010 INNs

22. 22 W HO Technical Briefing | September 2010 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

23. 23 W HO Technical Briefing | September 2010 Adopted WHO guidance texts and guidelines in medicines quality assurance (without PhInt) Maintain to keep up to date: ä Total of : ä 56 CURRENT official WHO guidance texts and guidelines to date, including 7 (4 updates, 3 new, adopted 2009)

24. 24 W HO Technical Briefing | September 2010 Quality Control http://www.who.int/medicines/areas/quality_safety/quality_assurance/control/ 12 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

25. 25 W HO Technical Briefing | September 2010 WHO’s global guidelines - quality control - ä International specifications (Ph. Int., screening tests..) ä WHO Model Certificate of Analysis (COA) ä Considerations for requesting analysis of samples ä Quality control laboratories:  Good practices for national control labs  List of equipment  External qc assessment scheme for labs

26. 26 W HO Technical Briefing | September 2010 International Pharmacopoeia Ph.Int.  current: 4 th edition! Supplement 1, no 2 in prep.  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

27. 27 W HO Technical Briefing | September 2010

28. 28 W HO Technical Briefing | September 2010 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: 1 April 2010 ä -Water content by Karl-Fischer: 1 September 2010 ä -Dissolution test: 1 February 2011 ä -Related substances by HPLC: 15 July 2011 ä -Related substances by TLC: 15 January 2012 ä -Assay by HPLC: 15 June 2012 ä -Dissolution test: 15 October 2012

29. 29 W HO Technical Briefing | September 2010 Distribution http://www.who.int/medicines/areas/quality_safety/quality_ass urance/distribution More than 9 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

30. 30 W HO Technical Briefing | September 2010 Production - http://www.who.int/medicines/areas/quality_safety/quality_assurance/pro duction/ http://www.who.int/medicines/areas/quality_safety/quality_assurance/pro duction/ 18 guidance documents and guidelines, including: - Good Manufacturing Practices (GMP) …..Consisting of 12 major "guideline" texts (regularly updated, new texts added as needs are identified) - ….. Training materials (slides, video, GMP text) - Risk analysis (HACCP)

31. 31 W HO Technical Briefing | September 2010 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

32. 32 W HO Technical Briefing | September 2010 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

33. 33 W HO Technical Briefing | September 2010 Inspection http://www.who.int/medicines/areas/quality_safety/quality_assurance/in spections/en/index.html 6 guidance documents and guidelines

34. 34 W HO Technical Briefing | September 2010 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

35. 35 W HO Technical Briefing | September 2010 Quality related regulatory standards http://www.who.int/medicines/areas/quality_safety/quality_assurance/re gulatory_standards/ 17 guidance documents and guidelines, including : - Stability testing requirements - Interchangeability of generic medicines - Fixed-dose combination - All prequalification procedures

36. 36 W HO Technical Briefing | September 2010 WHO’s guidance on interchangeability of medicines n WHO guideline on registration requirements to established interchangeability for multisource pharmaceutical products (revised in 2006) n Guidance on selection of comparator products for equivalence assessment of interchangeable generic products (under revision)

37. 37 W HO Technical Briefing | September 2010 WHO’s guidance on interchangeability of medicines (2) n Proposal to waive in vivo bioequivalence requirements for the WHO model List of Essential Medicines (immediate release, solid dosage forms) n Guidelines for organizations performing in vivo bioequivalence studies

38. 38 W HO Technical Briefing | September 2010 Related WHO’s guidances … n All guidelines for Prequalification of medicines, laboratories ….. n Model Quality Assurance System for Assessment of Procurement Agencies n Guideline for sampling of pharmaceuticals n Guidelines for registration of fixed-dose combination medicinal products n....

39. 39 W HO Technical Briefing | September 2010 New WHO guidelines adopted during 45 th Expert Committee held 18-22 October 2010 n Good Pharmacy Practice (joint FIP/WHO, revised) n Guidance for Pharmaceutical Microbiology laboratories (new) n Procedure for prequalification of laboratories (revised) n Preparing a Laboratory Information File (update) n GMP: main principles (revised) n GMP for blood establishments (jointly with ECBS) n GMP for HVAC (revised)

40. 40 W HO Technical Briefing | September 2010 New WHO guidelines adopted during 45 th Expert Committee held 18-22 October 2010 (2) n GMP for sterile pharmaceutical products (revised) n Guiding principles on transfer of technology (new) n Guidelines for preparing a Site Master File (new) n Model guidance for the storage and transport of time- and temperature sensitive pharmaceutical products (new, jointly with ECBS) n Guidance on submission of documentation for prequalification of innovator FPPs approved by stringent regulatory authorities (new)

41. 41 W HO Technical Briefing | September 2010 New WHO guidelines adopted during 45 th Expert Committee held 18-22 October 2010 (3) n Procedure for prequalification of medicines (revised) n Guideline for submission of documentation for a multisource (generic) finished product (new) n Special guidance for artemisinin as a starting materials for production of antimalarials (subject to confirmation of impurity profile, new) n Definition of substandard medicines (new) n Procedure for adoption of ICRS (revised)

42. 42 W HO Technical Briefing | September 2010 New Specifications adopted during 45 th Expert Committee held 18-22 October 2010 (3) 27 new specifications and general texts, including : n Antiretrovirals n Anti-TB medicines n Antimalarials n Anti-infectives n Paediatrics

43. 43 W HO Technical Briefing | September 2010 What is in the QA pipeline? Guidelines/guidance : ä Paediatrics development (new) ä Development of generics (new) ä Risk analysis (update) ä Guideline on submission of documentation for a multisource (generic) product – quality part (new)

44. 44 W HO Technical Briefing | September 2010 What is in the QA pipeline? - 2 - Guidelines/guidance: ä Update of Comparator List ä Update of stability requirements in Member States ä Advice to NMRAs on Diethylene glycol intoxication ä Tools and framework for monitoring of market situation

45. 45 W HO Technical Briefing | September 2010 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

46. 46 W HO Technical Briefing | September 2010 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

47. 47 W HO Technical Briefing | September 2010 As health professionals, in public and private sector, as an international community...we have a lot left to do …all of us, together, things that do matter, in right time and in right order!

48. 48 W HO Technical Briefing | September 2010 WHO Medicines Quality Assurance website: http://www.who.int/medicines/areas/quality_safety/quality_assurance