1. Drug regulation and 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. 2 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. 3 WHO does the work? n 193 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 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. 5 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. 6 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. 7 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. 8 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. 9 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. 10 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”

11. 11 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

12. 12 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

13. 13 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

14. 14 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

15. 15 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 …...

16. 16 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 and nomenclature (INN) …..

17. 17 INNs

18. 18 WHO’s global 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

19. 19 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

20. 20

21. 21 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

22. 22 WHO’s global guidelines - quality control - ä International specifications (Int.Ph., 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

23. 23 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

24. 24 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

25. 25 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

26. 26 WHO’s global guidelines - distribution  WHO Certification Scheme for Products Moving in International Commerce  SMACS new scheme for pharmaceutical starting materials: - model certificate, when inspected by national authority  - WHO model for self-assessment for manufacture of pharmaceutical starting materials n Good Distribution and Trading Practices for pharmaceutical starting materials (GTDP) n Good Distribution Practices (GDP) (for products) n Good Storage Practices (GSP)

27. 27 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

28. 28 WHO’s global guidelines -production (2) n New 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)

29. 29 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

30. 30 WHO’s global guidelines and strategies - risk analysis n Application of risk analysis to production of pharmaceuticals ( adopted in 2001)

31. 31 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 and regional harmonization groups

32. 32 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

33. 33 WHO Stability guidelines second draft What's new? – ctd - 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

34. 34 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) 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

35. 35 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....

36. 36 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)

37. 37 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)

38. 38  aim to improve access to quality medicines n Provide standards and norms in area of quality assurance of medicines n Prequalification programme for UN procurement n Provide assistance in regulatory area n Promote logical order of actions: ä Priority setting (ABC first … ) ä Capacity building ä Collaboration and co-operation WHO efforts

39. 39 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!

40. 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