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

Main points addressed 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? 193 Member States Two governing bodies: - World Health Assembly - Executive Board 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)

How to become a "WHO Expert"? Official nomination process Upon proposal to WHO in consultation with: Member State/national government (citizenship)+ WHO Regional Office (in accordance with Member State) + WHO Headquarters Period of maximum 4 years Possibility to renew

What is the WHO Expert Committee? Official Advisory Body to Director-General of WHO Governed though rules and procedures (Ref. WHO Manual) Participation in Expert Committee (EC) meetings: Members ("Expert") selected from WHO Panel of Experts Technical advisers Observers: - international organizations, - NGOs, - professional associations…

Outcome of the WHO Expert Committee? 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  constitutes WHO technical guidance

Examples of WHO Expert Committees ? WHO Expert Committee on Specifications for Pharmaceutical Preparations WHO Expert Committee on the Selection and Use of Essential Medicines WHO Expert Committee on Drug Dependence WHO Expert Committee on Biological Standardization Joint FAO/WHO Expert Committee on Food Additives ….

How does the WHO consultation process work? 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  if guideline adopted, published in EC report as Annex -> WHO Governing bodies -> Recommendation to Member States for implementation

WHO Partners 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-IGPA- WSMI, 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…)

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)  medicines belong to one of the most regulated group of products

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

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

Challenges: past and present… Manufacture direct from API -> finished product Manufacture of API in sites close to or same as product Experience and long-standing knowledge of production, product and manufacture of parties involved Few intermediates in sales chain Usually stable trade and sales connections

Challenges: past and present… Rationalization of drug production Contracting-out of many steps in manufacture Many intermediates in trade and sales chain Trade, shipping, long distances involved Increase of risks… Increase of requirements and documentation Increase of national control mechanisms

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

Global challenges… 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 Counterfeit drugs …...

WHO’s global guidelines and strategies Requirements for drug registration and model legislation Networking among and with regulatory authorities International alerts Counterfeit network Global norms and international standards and nomenclature

INNs

WHO’s medicines quality assurance guidelines Cover: Production Quality Control Quality related regulatory guidelines Inspection Distribution  from manufacture to delivery to patient

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

The International Pharmacopoeia (Ph.Int.) current: 4th edition! Supplement 1 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 and HIV/AIDS, and paediatrics Now: as - Publication, - CD-ROM and - online: http://www.who.int/phint

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

Capacity building Phase 4 (06/2007 - 01/2009) Series of 5 tests WHO External Quality Assessment Scheme for National Drug Quality Control Laboratories Capacity building Phase 4 (06/2007 - 01/2009) Series of 5 tests 50 participating laboratories, including WHO Collaborating Centres In all 6 WHO regions

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

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

WHO’s global guidelines – distribution (2) Good Distribution and Trading Practices for pharmaceutical starting materials (GTDP) Good Distribution Practices (GDP) (for products) – under revision through IMPACT's input Good Storage Practices (GSP)

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

WHO’s global guidelines - production (2) Newly revised and additional GMP texts: 1. Main principles for pharmaceutical products +++ requirement for the sampling of starting materials (amendment) water for pharmaceutical use heating, ventilation and air-conditioning (HVAC) systems Validation 3. … for specific pharmaceutical products: Herbal medicines (revised)

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

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

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

WHO Stability guidelines - newly adopted What's new? Scope covers: active pharmaceutical ingredients + pharmaceutical products Marketed + new Transition period recommended for already marketed actives and products Additional advice given, e.g. model reports currently used in WHO Prequalification Programme

WHO Stability guidelines - newly adopted What's new? (2) Cross-reference to other guidelines, e.g. ICH text on photostability 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

WHO’s guidance on interchangeability of medicines WHO guideline on registration requirements to established interchangeability for multisource pharmaceutical products (newly revised 2006) Guidance on selection of comparator products for equivalence assessment of interchangeable generic products (under revision)

WHO’s guidance on interchangeability of medicines (2) Proposal to waive in vivo bioequivalence requirements for the WHO model List of Essential Medicines (immediate release, solid dosage forms) Guidelines for organizations performing in vivo bioequivalence studies

Related WHO’s guidances … All guidelines for Prequalification of medicines, laboratories ….. Model Quality Assurance System for Assessment of Procurement Agencies Guideline for sampling of pharmaceuticals Guidelines for registration of fixed-dose combination medicinal products ....

Advantages of WHO's Expert Committee standard-setting process 1. Guidelines and specifications validated internationally, through an independent scientific process, adoption by members of WHO Expert Advisory Panels 2. Collaboration with standard-setting organizations and parties, including regional and national pharmacopoeias 3. Networking and close collaboration with WHO Member States, Drug Regulatory Authorities, national medicines quality control laboratories

Advantages of WHO's Expert Committee standard-setting process (2) 4. Links with other WHO activities 5. Reality check: Input from manufacturers (including international associations of research, generic and self-medication associations) around the world 6. Consideration of costs, e.g. keeping need for reference standards at a minimum 7. Service FREE FOR USE by all Member States

WHO’s operational strategies 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- 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)

…all of us, together, things that do matter, 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!

WHO Medicines Quality Assurance website: http://www.who.int/medicines/areas/quality_safety/quality_assurance