1. Drug regulation and quality assurance: WHO normative functions in the field of pharmaceuticals Technical Briefing Seminar 19 September 2006 Sabine Kopp, PhD Quality Assurance and Safety: Medicines Department of Medicines Policy and Standards TBS 2005

2. TBS 2006 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. TBS 2006 3 WHO does the work? 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. TBS 2006 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. TBS 2006 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 Voting members ("Expert") selected from WHO Panel of Experts ä Technical advisers ä Observers: - international organizations, - NGOs, - professional associations…

6. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 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. TBS 2006 16 WHOs 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. TBS 2006 17 INNs

18. TBS 2006 18 WHOs 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. TBS 2006 19 The International Pharmacopoeia current: Third edition - > 4 th edition in preparation 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

20. TBS 2006 20 WHOs strategy for quality control Step-wise approach: - Basic tests (identification) - Screening tests (TLC) - The International Pharmacopoeia - International chemical reference standards (ICRS) - IR reference spectra

21. TBS 2006 21 Links to other partners and programmes Establishment of specifications for antiretrovirals, HIV/AIDS medicines - Collaboration with other pharmacopoeias, including PDG, Ph.Eur., USP, JP, IP, ChPh - Collaboration with manufacturers - Collaboration with suppliers (also agencies) for HIV drugs

22. TBS 2006 22 WHOs 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. TBS 2006 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. TBS 2006 24 WHOs 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)

25. TBS 2006 25 WHOs 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

26. TBS 2006 26 WHOs global guidelines -production (2) n New additional GMP texts (adopted in 2004+2005): 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)

27. TBS 2006 27 WHOs 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

28. TBS 2006 28 WHOs global guidelines and strategies - risk analysis n Application of risk analysis to production of pharmaceuticals ( adopted in 2001)

29. TBS 2006 29 WHO stability guidelines n Title: guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms 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

30. TBS 2006 30 WHOs 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

31. TBS 2006 31 Related WHOs 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....

32. TBS 2006 32 WHOs 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)

33. TBS 2006 33 WHOs 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)

34. TBS 2006 34 aim to improve access to quality medicines n Provide standards and norms in area of quality assurance of medicines n Pre-qualification project 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

35. TBS 2006 35 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!

36. 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