1. 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

2. 2QC L Training Seminar, Tanzania | 5-7 December 2007 Main points addressed n WHO role and function n WHO standard setting process n WHO international guidelines, standards and norms in the area of quality assurance n WHO's operational strategies

3. 3QC L Training Seminar, Tanzania | 5-7 December 2007 WHO does the work? n 193 Member States n Two governing bodies: - World Health Assembly - Executive Board n WHO Secretariat: - HQ - 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)

4. 4QC L Training Seminar, Tanzania | 5-7 December 2007 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

5. 5QC L Training Seminar, Tanzania | 5-7 December 2007 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…

6. 6QC L Training Seminar, Tanzania | 5-7 December 2007 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

7. 7QC L Training Seminar, Tanzania | 5-7 December 2007 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 ….

8. 8QC L Training Seminar, Tanzania | 5-7 December 2007 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

9. 9QC L Training Seminar, Tanzania | 5-7 December 2007 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…)

10. 10Q CL Training Seminar, Tanzania | 5-7 December 2007 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

11. 11Q CL Training Seminar, Tanzania | 5-7 December 2007 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”

12. 12Q CL Training Seminar, Tanzania | 5-7 December 2007 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

13. 13Q CL Training Seminar, Tanzania | 5-7 December 2007 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

14. 14Q CL Training Seminar, Tanzania | 5-7 December 2007 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

15. 15Q CL Training Seminar, Tanzania | 5-7 December 2007 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

16. 16Q CL Training Seminar, Tanzania | 5-7 December 2007 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 …...

17. 17Q CL Training Seminar, Tanzania | 5-7 December 2007 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

18. 18Q CL Training Seminar, Tanzania | 5-7 December 2007 INNs

19. 19Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s medicines quality assurance guidelines Cover: n Production n Quality Control n Quality related regulatory guidelines n Inspection n Distribution n  from manufacture to delivery to patient

20. 20Q CL Training Seminar, Tanzania | 5-7 December 2007 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

21. 21Q CL Training Seminar, Tanzania | 5-7 December 2007 International Pharmacopoeia  current: 4 th edition! Supplement 1 in preparation  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

22. 22Q CL Training Seminar, Tanzania | 5-7 December 2007

23. 23Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s strategy for quality control  Step-wise approach: - Basic tests (identification) - Screening tests (TLC) - The International Pharmacopoeia + International chemical reference standards (ICRS) + IR reference spectra

24. 24Q CL Training Seminar, Tanzania | 5-7 December 2007 External Quality Assessment Scheme for National Drug Quality Control Laboratories  Capacity building  Third phase  Series of 5 tests  42 participating laboratories, including WHO Collaborating Centres  In all 6 WHO regions

25. 25Q CL Training Seminar, Tanzania | 5-7 December 2007 External Quality Assessment Scheme for National Drug Quality Control Laboratories n Phase 4 (06/2007 - 01/2009) - 50 laboratories invited to participate. - Studies: ä Titration ä Water content by Karl-Fisher ä Dissolution test ä Determination of glucose by polarimetry ä HPLC assay

26. 26Q CL Training Seminar, Tanzania | 5-7 December 2007 Participation in External Quality Assurance Scheme -> link with PQ Programme n Phase 3 (07/2004 - 06/2006) ä 11 of QC laboratories involved in prequalification procedure participated l Algeria, South Africa CENQAM, South Africa RIIP l Ghana, Kenya, Mali, Niger, Senegal, Tanzania, Uganda, Zimbabwe ä 2 other African QC laboratories took part l Morocco, Tunisia n Phase 4 (06/2007 - 01/2009) ä All 15 QC laboratories involved in prequalification procedure invited

27. 27Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s global guidelines - distribution  WHO Certification Scheme for Pharmaceutical Products Moving in International Commerce  SMACS new scheme for pharmaceutical starting materials:  - Model certificate, when inspected by national authority  - Model for self-assessment for manufacture of pharmaceutical starting materials

28. 28Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s global guidelines – distribution (2) n Good Distribution and Trading Practices for pharmaceutical starting materials (GTDP) n Good Distribution Practices (GDP) (for products) n Good Storage Practices (GSP)

29. 29Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s global guidelines -production n Good Manufacturing Practices (GMP) ….. 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

30. 30Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s global guidelines -production (2) n Newly revised and additional GMP texts: 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 3. … for specific pharmaceutical products: +++ ä Herbal medicines (revised)

31. 31Q CL Training Seminar, Tanzania | 5-7 December 2007 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

32. 32Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s global guidelines and strategies - risk analysis n Application of risk analysis to production of pharmaceuticals ( adopted in 2001)

33. 33Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO stability guidelines n Title: “guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” currently under revision ! n -> stability testing of final drug products n -> well established (e.g. generics) n -> in conventional dosage forms (e.g. tablets) n --> close collaboration with ICH group Q1, ASEAN, GCC and other regional harmonization groups

34. 34Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO Stability guidelines second draft What's new? n Scope covers: active pharmaceutical ingredients + pharmaceutical products n Marketed + new n Transition period recommended for already marketed actives and products n Additional advice given, e.g. model reports currently used in WHO Prequalification Programme

35. 35Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO Stability guidelines second draft What's new? (2) n Cross-reference to other guidelines, e.g. ICH text on photostability n List of WHO Member States' required long-term stability conditions as per info received from countries, concept of classification of countries according to climatic zones abandoned -> preference to provide "real" conditions required by national authorities

36. 36Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s guidance on interchangeability of medicines n WHO guideline on registration requirements to established interchangeability for multisource pharmaceutical products (newly revised 2006) n Guidance on selection of comparator products for equivalence assessment of interchangeable generic products (under revision)

37. 37Q CL Training Seminar, Tanzania | 5-7 December 2007 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. 38Q CL Training Seminar, Tanzania | 5-7 December 2007 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. 39Q CL Training Seminar, Tanzania | 5-7 December 2007 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

40. 40Q CL Training Seminar, Tanzania | 5-7 December 2007 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

41. 41Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s operational strategies n Assist Member States to strengthen or establish national drug regulation (upon request) n Study alternative ways of improving control and safe trade of starting materials and products n Promote cooperation and harmonization among countries (e.g. ICDRA) n Collaborate with regional and inter-regional regulatory harmonization efforts (in all 6 WHO regions)

42. 42Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO’s operational strategies -2-  Work with interested parties and countries to combat counterfeit and substandard drugs (IMPACT)  Assistance in establishing and evaluation of national and regional quality control laboratories  Training of drug regulatory staff (e.g. in registration of HIV/AIDS medicines)  Development of “how to” manuals and tools  Responding to national and international requests in area of quality assurance for medicines (e.g. for Global Fund)

43. 43Q CL Training Seminar, Tanzania | 5-7 December 2007 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!

44. 44Q CL Training Seminar, Tanzania | 5-7 December 2007 WHO Medicines Quality Assurance website: http://www.who.int/medicines/areas/quality_safety/quality_ assurance