Drug regulation and quality assurance WHO normative functions

Drug regulation and quality assurance: WHO normative functions in the field of pharmaceuticals Technical Briefing Seminar 20 September 2005 Sabine Kopp, Ph. D presented by Marie Rabouhans Quality Assurance and Safety: Medicines Department of Medicines Policy and Standards TBS 2005

Main points addressed n n TBS 2005 2 WHO role and function WHO standard setting process WHO international guidelines, standards and norms in the area of quality assurance WHO's operational strategies

WHO does the work? n 192 Member States Two governing bodies: n WHO Secretariat: n TBS 2005 3 - World Health Assembly - Executive Board - 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)

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 Period of maximum 4 years Possibility to renew n n TBS 2005 4

What is the WHO Expert Committee? n n n Official Advisory Body to Director-General of WHO Governed though rules and procedures (Ref. WHO Manual) 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… TBS 2005 5

Outcome of the WHO Expert Committee? n Report of the WHO Expert Committee: - n 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 constitutes TBS 2005 6 WHO technical guidance

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 WHO Expert Committee on Drug Dependence WHO Expert Committee on Biological Standardization n n TBS 2005 7 Joint FAO/WHO Expert Committee on Food Additives ….

How does the WHO consultation process work? n n n n TBS 2005 8 Step 1. Preliminary consultation and drafting Step 2. Draft guidelines Step 3. Circulation for comments Step 4. Revision process. . (back to step 2 and 3 as often as needed) WHO Expert Committee (EC) meeting ä if guideline adopted, published in EC report as Annex -> WHO Governing bodies -> Recommendation to Member States for implementation

WHO Partners n n n n TBS 2005 9 National and regional authorities International organizations (UNAIDS, UNFPA, UNICEF, World Bank, WIPO, WTO, WCO, etc) International professional and other associations, NGOs (including consumer associations, MSF, industry: IFPMA-IGPAWSMI, FIP, WMA, etc) WHO Expert Panels (official nomination process) Specialists from all areas, regulatory, university, industry……… WHO Collaborating Centres (official nomination process) Pharmacopoeia Commissions and Secretariats, national institutions and institutes. . Regional and inter-regional groups (ICH…)

Quality Assurance in WHO Historical overview ® 1874 1902 1906 ® 1925 ® ® ® TBS 2005 10 Discussion on Unification of terminology and composition of drugs First Conference organized by Belgian Government Agreement on Unification of the Formulae of Potent Drugs ratified by 19 states Brussels agreement (signed 1929) League of Nations: “international pharmacopoeia”

Quality Assurance in WHO Historical overview - 2 ® ® 1947 Interim Commission of WHO takes up health related work of League of Nations ® TBS 2005 11 1937 First meeting (experts from B, DK, F, NL, CH, UK, USA) League of Nations 1948 First World Health Assembly established Expert Committee on Unification of Pharmacopoeia

Challenges: past and present… n TBS 2005 12 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

Challenges: past and present… n TBS 2005 13 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

Global challenges … n National vs international requirements Number of requirements n Application and interpretation of requirements n Import vs export control on national level Quality assurance systems applied Knowledge of product by parties involved in manufacture n n Cross-border promotion and sale n Free trade zones TBS 2005 14

Global challenges… n Number of national and international inspections by same party Number of inspections in same site by different parties Applicability of new technologies in different settings Contracts, agreements, eg Mutual Recognition Agreements Risks of mistakes, accidents, human errors etc n Counterfeit drugs n …. . . n n TBS 2005 15

Experience with WHO pre-qualification project n Major problems with quality of medicines used in HIV/AIDS, TB Malaria treatment, experience in past years of project: ä n TBS 2005 16 > 70% of manufacturing sites did not pass in first inspection and > 80% of more than 400 dossiers evaluated do not meet requirements Can lead to: treatment failure; development of resistance; avoidable deaths + wasted resources

WHO’s global guidelines and strategies n n n TBS 2005 17 Requirements for drug registration and model legislation Networking among and with regulatory authorities International alerts Counterfeit network Global norms and standards and nomenclature (INN) …. .

INNs TBS 2005 18

WHO’s global quality assurance guidelines Cover: n Production n Quality Control n Quality related regulatory guidelines Inspection Distribution from manufacture to delivery to patient n n n TBS 2005 19

International Pharmacopoeia ® ® implementation: “ready for use” by Member States ® TBS 2005 20 current: Third edition Scope since 1975: ® Model List of Essential Drugs and ® Drugs recommended by WHO Specific disease programmes, e. g. Malaria, TB, HIV/AIDS

WHO’s strategy for quality control ® Step-wise approach: l l l TBS 2005 21 - Basic tests (identification) - Screening tests (TLC) - International Pharmacopoeia + International chemical reference materials: ICRS and - IR reference spectra -

Links to other partners and programmes ® Establishment of specifications for antiretrovirals, HIV medicines l l l TBS 2005 22 - Collaboration with other pharmacopoeias, including PDG, Ph. Eur. USP, JP, IP, Ch. Ph - Collaboration with manufacturers - Collaboration with suppliers (also agencies) for HIV drugs

WHO’s global guidelines - quality control - ä ä TBS 2005 23 International specifications (Int. Ph. , screening tests. . ) WHO Model Certificate of Analysis (COA) for use in trade and procurement Considerations for requesting analysis of drug samples Quality control laboratories v Good practices for national control labs v List of equipment v External qc assessment scheme for labs

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 ® ® ® TBS 2005 24

WHO’s global guidelines - distribution v WHO Certification Scheme for Products Moving in International Commerce v SMACS new scheme for pharmaceutical starting materials: - model certificate, when inspected by national authority v - WHO model for self-assessment for manufacture of pharmaceutical starting materials n Good Distribution and Trading Practices for pharmaceutical starting materials (GTDP) Good Distribution Practices (GDP) (for products in prep. ) n Good Storage Practices (GSP) n TBS 2005 25

WHO’s global guidelines - production n Good Manufacturing Practices (GMP) …. . 1. Main principles for pharmaceutical products n 2. … for starting materials, including n ä ä n 3. … for specific pharmaceutical products: ä ä ä TBS 2005 26 active pharmaceutical ingredients pharmaceutical excipients Sterile pharmaceutical products Biological products Investigational pharmaceutical products for clinical trials in humans Herbal medicines Radiopharmaceuticals

WHO’s global guidelines - inspection n Inspection of…. . n pharmaceutical manufacturers ä drug distribution channels (products) Guidelines for pre-approval inspection Quality systems requirements for national GMP inspectorates ä n n n TBS 2005 27 Model GMP certificate Model report for inspections

WHO’s global guidelines and strategies risk analysis n TBS 2005 28 Application of risk analysis to production of pharmaceuticals, adopted in 2001

WHO stability guidelines n Title: “guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms” n n -> stability testing of final drug products -> well established (e. g. generics) -> in conventional dosage forms (e. g. tablets) n --> close collaboration with n ICH group Q 1, ASEAN and other regional harmonization groups TBS 2005 29

WHO’s guidance on interchangeability of medicines n WHO guideline on registration requirements to established interchangeability for multisource pharmaceutical products (1996 under revision) n Guidance on selection of comparator products for equivalence assessment of interchangeable generic products (under revision) TBS 2005 30

WHO’s operational strategies n n TBS 2005 31 Assist Member States to strengthen or establish national drug regulation (upon request) Study alternative ways of improving control and safe trade of starting materials and products Promote cooperation and harmonization among countries (e. g. ICDRA) Collaborate with regional and inter-regional regulatory harmonization efforts (in all 6 WHO regions)

WHO’s operational strategies -2 v v v TBS 2005 32 Work with interested parties and countries to combat counterfeit and substandard drugs (International Convention? ) 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 Gobal Fund)

WHO efforts aim to improve access to quality medicines n n TBS 2005 33 Provide standards and norms in area of quality assurance of medicines Pre-qualification project for UN procurement Provide assistance in regulatory area Promote logical order of actions: ä Priority setting (ABC first … ) ä Capacity building ä Collaboration and co-operation

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