WHO and its activities in quality assurance of

medicines

Sabine Kopp, PhD Quality Assurance and Safety: Medicines

Essential Drugs and Medicines PolicyWorld Health Organization

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1. What is WHO? 2. How does WHO work and for

whom? 3. Details on WHO activities in

the areas of quality assurance, including:

- INN - Int. Ph. -GMP -Stability -pre-qualification project...

4. Summary

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1. What is WHO? Some basic facts

192 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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2. How does WHO work and for whom?

WHO’s main functions: inter alia

- To act as the directing and coordinating authority on international health work

- To encourage technical cooperation for health with Member States

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--> WHO responsibilities (inter alia)

To assist governments, upon request, in strengthening health services

To provide information, counsel and assist in the field of health To stimulate eradication of epidemics, endemics and other diseases To promote cooperation among scientific and professional groups

which contribute to the enhancement of health To promote international conventions and agreements in health

matters To promote and conduct research in the field of health To develop, establish and promote international standards for food,

biological and pharmaceutical products ........

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Access gap - financing, delivery and other constraints still limit access to essential drugs

>1/3 of world’s population lacks regular access

320 million in Africa have <50%

Problem worsens with economic pressures

Percentage of populations and number of countries with regular access to essential drugs:

1 = <50% (43)2 = 50-80% (64)3 = 80-95% (30)4 = >95% (41)5 = No data available (1)

Pharmaceutical gaps

Source: WHO/DAP 1998

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What are the priorities for WHO’s medicines strategy?

Access to essential drugs for priority health problems (malaria, TB, childhood, HIV/AIDS) for poor and vulnerable populations

Quality and safety of all medicines creating and maintaining global guidelines and standards supporting effective drug regulation & quality assurance

Rational use of medicines by health professionals by households

National drug policies integrated in national health policies and systems emphasis on implementation and monitoring

WHO medicine strategy

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WHO medicine strategy

What guides and anchors WHO’s work in drugs and medicines policy?

Global norms, standards, guidelines, nomenclature Expert Committees and Expert Panels WHO Collaborating Centres

Essential drugs and national drug policies 1975 resolution introducing essential drugs concept Revised drug strategy (1986) and subsequent WHA resolutions

WHO medicines work today Governing bodies - Assembly, Executive Board, Regional Committees Meeting of Interested Parties - MIP --> changes as from 21 July 2003

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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, MRAs….. Risks of mistakes, accidents, human errors etc Counterfeit drugs …...

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National regulatory and inspection systems

--> approx. 1/3 of WHO Member States have well developed regulatory systems, approx.. 1/3 have none

In developed countries well organized, controlling national market dossiers evaluation and inspections different approaches used, few MRA

In developing countries often difficulties of resources capacity? application of national and international guidelines… --> or non-existent ….

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Experience from WHO's pre-qualification project - example ARVs

Inspections and dossiers evaluation can differ from country to country

Small percentage of products and manufacturers participating in the project comply internationally

Time needed from some manufacturers to get into compliance

data to be generated GMP upgrade

Quality Assurance at a price!

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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 in production, inspection,

quality control, good storage practices and nomenclature (INN) …..

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WHO has a constitutional mandate to

"develop, establish and promote international standards with respect to biological, pharmaceutical and similar products”

(Article 2(u) of WHO's Constitution) --> Good Manufacturing Practices, stability guidelines, …… INN Programme …….

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WHO Procedure for the preparation of guidelines

Preliminary consultation and drafting Draft guidelines Circulation for comments Revision process .......... WHO Expert Committee WHO Governing bodies Recommendation to governments for implementation

--> publication in Technical Reports

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WHO’s global guidelines and strategies - quality control -

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

good practices for national control labs list of equipmentExternal qc assessment scheme for labs

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International PharmacopoeiaHistorical 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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International PharmacopoeiaHistorical 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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International PharmacopoeiaHistorical overview - 3 -

1950 WHA approved publication of Pharmacopoeia Internationalis

1951 named: Expert Committee on International Pharmacopoeia 1959 named: Expert Committee on International Pharmacopoeia

and Pharmaceutical Preparations --> to date

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International Pharmacopoeia

current: Third edition

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

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WHO’s strategy for quality control

Step-wise approach:

- Basic tests (identification) - Screening tests (TLC) - International Pharmacopoeia + International reference materials

(ICRS and IR reference spectra)

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IntPh and links to other WHO activities

Establishment of monographs for antiretrovirals, HIV medicines

- collaboration with other pharmacopoeias, including PDG, Ph.Eur. USP, JP, IP

- collaboration with manufacturers - link with project on pre-qualification of

suppliers for HIV drugs

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Type of monographs

Drug substances

Excipients

Finished dosage forms

General methods and requirements: oral sold dosage forms

dissolution testing…

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INNs

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WHO’s global guidelines and strategies - distribution

WHO Certification Scheme for Products Moving in International Commerce

new scheme for pharmaceutical starting materials: - WHO model GMP certificate, when inspected - WHO model for self-assessment for manufacture of

pharmaceutical starting materials

Good Distribution and Trading Practices for pharmaceutical starting materials

Good Storage Practices Good Distribution Practices (in preparation)

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WHO’s global guidelines and strategies - production

Good Manufacturing Practices ….. 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 and strategies - 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”

-> stability testing of final drug products -> well established (e.g. generics) -> in conventional dosage forms (e.g. tablets)

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Developments in 2001

2001: new alternative being discussed to modify both ICH and WHO guidelines

for zone IV to: --> 30°C and 65% RH (then: 70%)

Consultative procedure: mailing of request to experts and discussion during informal consultation

Discussion and adoption during WHO Expert Committee on Specifications for Pharmaceutical Preparations held 22-26 October 2001 in Geneva

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Long-term storage conditions modified

Zone I 21°C 45% RH Zone II 25°C 60% RH Zone III 30°C 35% RH Zone IV 30°C 65 %RH

when special transportation and storage conditions were identified as being outside these criteria, additional study data supporting these conditions may need to be made available.

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Developments in 2002 -….

February 2002: ICH Data package for registration in climatic zones II and IV --> signed off by all 6 ICH partners as step 2 document

Consultative process in all three ICH regions by regulatory agencies

Comments and new drafts circulated in ICH Working Group Discussed at ICH meeting February 2003 now ICH document step 4

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Access to HIV/AIDS Drugs and Diagnostics of Assured Quality - pilot procurement project

Partners:

WHO UNICEF UNAIDS UNFPA The World Bank (support)

--> now expanded to anti-TB and antimalarial medicines

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Pilot Procurement, Quality and Sourcing Project

Access to HIV/AIDS Drugs and Diagnostics of Assured Quality

Problems and deficiencies identified: General Problems identified with ARVs

Several substances and products not in pharmacopoeia unacceptable chiral activity, stereo-isomerism unacceptable impurities lack of reference standards no analytical methods and method validation Regulatory authorities not following WHO

recommendations for registration of products Regulatory approval not based on thorough evaluation

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Pilot Procurement, Quality and Sourcing Project

Access to HIV/AIDS Drugs and Diagnostics of Assured Quality

GMP deficiencies:

Hormones, cytotoxics and ARVs in same area Qualification and validation lacking (premises, systems,

equipment, processes) Cleaning validation No verification of air classification of areas for sterile product

manufacturing Sampling and testing of APIs Loss in traceability of materials used in production

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WHO’s operational strategies

Assist countries to strengthen or establish national drug regulation

Study alternative ways of improving control and safe trade of starting materials and products

Promote the use of WHO norms and standards Promote cooperation and harmonization among

countries

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WHO’s operational strategies -2-

Work with interested parties and countries to combat counterfeit and substandard drugs

Establishing national and regional quality control laboratories

Training of drug regulatory staff Development of “how to” manuals and tools

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Summary

WHO assists Member States in health related matters

WHO has inter alia a constitutional mandate to develop, establish and promote international standards

WHO issued a number of guidelines and norms in the area of quality assurance

Continuous dialogue and collaboration with with WHO Member States, regional and international harmonization efforts in drug regulation

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http://www.who.int/medicines/

Further questions ??????

http://who.int/medicines