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

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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

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WHO does the work?

193 Member States Two governing bodies: - World Health Assembly

- Executive Board

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)

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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

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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…

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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

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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 ….

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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

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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…)

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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”

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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

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Challenges: past and present…

Past: 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

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Challenges: past and present…

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

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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 Free trade zones

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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 …...

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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 standards and nomenclature (INN)

…..

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INNs

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WHO’s global quality assurance guidelines

Cover:

Production Quality Control Quality related regulatory guidelines Inspection Distribution from manufacture to delivery to patient

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International Pharmacopoeia

current: 4th 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

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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

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WHO’s global guidelines - quality control -

International specifications (Int.Ph., screening tests..) WHO Model Certificate of Analysis (COA) Considerations for requesting analysis of samples Quality control laboratories:

Good practices for national control labsList of equipmentExternal qc assessment scheme for labs

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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

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External Quality Assessment Scheme for National Drug Quality Control Laboratories

Phase 4 (06/2007 - 01/2009)- 50 laboratories invited to participate.- Studies: Titration Water content by Karl-Fisher Dissolution test Determination of glucose by polarimetry HPLC assay

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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) All 15 QC laboratories involved in prequalification procedure invited

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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

Good Distribution and Trading Practices for pharmaceutical starting materials (GTDP)

Good Distribution Practices (GDP) (for products) Good Storage Practices (GSP)

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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

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WHO’s global guidelines -production (2)

New 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)

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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

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WHO’s global guidelines and strategies - risk analysis

Application of risk analysis to production of pharmaceuticals (adopted in 2001)

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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 and regional harmonization groups

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WHO Stability guidelines second draft 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

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

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

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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)

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

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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....

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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)

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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)

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aim to improve access to quality medicines

Provide standards and norms in area of quality assurance of medicines

Prequalification programme for UN procurement Provide assistance in regulatory area Promote logical order of actions:

Priority setting (ABC first … ) Capacity building Collaboration and co-operation

WHO efforts

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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