1. 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

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? 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 (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:
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. 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

11. Medicines 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”

12. 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

13. 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

14. 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

15. 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

16. 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
…...

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 international standards and nomenclature

18. INNs

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

20. 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

21. 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:

23. 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

24. 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/ /2009)
Series of 5 tests
50 participating laboratories, including WHO Collaborating Centres
In all 6 WHO regions

25. Participation in External Quality Assurance Scheme -> link with PQ Programme
Phase 3 (07/ /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/ /2009)
15 QC laboratories involved in prequalification procedure invited

26. 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

27. 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)

28. 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

29. 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)

30. 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

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

32. 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

33. 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

34. 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

35. 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)

36. 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

37. 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
....

38. 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

39. 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

40. 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)

41. 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)

42. …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!

43. WHO Medicines Quality Assurance website: