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

2. 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

3. WHO does the work? 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 (World Health Day)

4. 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

5. 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:
Voting members ("Expert") selected from WHO Panel of Experts
Technical advisers
Observers: - international organizations, NGOs, professional associations…

6. 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

7. 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 ….

8. 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

9. 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…)

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

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. 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

13. 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

14. 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

15. 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
…...

16. Experience with WHO pre-qualification project
Major problems with quality of medicines used in HIV/AIDS, TB Malaria treatment, experience in past years of project:
> 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

17. 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) …..

18. INNs

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

20. 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

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

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

23. WHO’s global guidelines - 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 equipment
External qc assessment scheme for labs

24. 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

25. 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 in prep.)
Good Storage Practices (GSP)

26. 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

27. 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

28. WHO’s global guidelines and strategies - risk analysis
Application of risk analysis to production of pharmaceuticals, adopted in 2001

29. 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)
--> close collaboration with
ICH group Q1, ASEAN and other regional harmonization groups

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

31. 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)

32. WHO’s operational strategies -2-
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)

33. WHO efforts  aim to improve access to quality medicines
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:
Priority setting (ABC first … )
Capacity building
Collaboration and co-operation