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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
2QCL Training Seminar, Tanzania | 5-7 December 2007
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
3QCL Training Seminar, Tanzania | 5-7 December 2007
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)
4QCL Training Seminar, Tanzania | 5-7 December 2007
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
5QCL Training Seminar, Tanzania | 5-7 December 2007
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…
6QCL Training Seminar, Tanzania | 5-7 December 2007
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
7QCL Training Seminar, Tanzania | 5-7 December 2007
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 ….
8QCL Training Seminar, Tanzania | 5-7 December 2007
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
9QCL Training Seminar, Tanzania | 5-7 December 2007
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…)
10QCL Training Seminar, Tanzania | 5-7 December 2007
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
11QCL Training Seminar, Tanzania | 5-7 December 2007
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”
12QCL Training Seminar, Tanzania | 5-7 December 2007
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
13QCL Training Seminar, Tanzania | 5-7 December 2007
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
14QCL Training Seminar, Tanzania | 5-7 December 2007
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
15QCL Training Seminar, Tanzania | 5-7 December 2007
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
16QCL Training Seminar, Tanzania | 5-7 December 2007
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 …...
17QCL Training Seminar, Tanzania | 5-7 December 2007
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
18QCL Training Seminar, Tanzania | 5-7 December 2007
INNs
19QCL Training Seminar, Tanzania | 5-7 December 2007
WHO’s medicines quality assurance guidelines
Cover:
Production Quality Control Quality related regulatory guidelines Inspection Distribution from manufacture to delivery to patient
20QCL Training Seminar, Tanzania | 5-7 December 2007
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 labsList of equipmentExternal qc assessment scheme for labs
21QCL Training Seminar, Tanzania | 5-7 December 2007
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
22QCL Training Seminar, Tanzania | 5-7 December 2007
23QCL Training Seminar, Tanzania | 5-7 December 2007
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
24QCL Training Seminar, Tanzania | 5-7 December 2007
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
25QCL Training Seminar, Tanzania | 5-7 December 2007
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
26QCL Training Seminar, Tanzania | 5-7 December 2007
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
27QCL Training Seminar, Tanzania | 5-7 December 2007
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
28QCL Training Seminar, Tanzania | 5-7 December 2007
WHO’s global guidelines – distribution (2)
Good Distribution and Trading Practices for pharmaceutical starting materials (GTDP)
Good Distribution Practices (GDP) (for products)
Good Storage Practices (GSP)
29QCL Training Seminar, Tanzania | 5-7 December 2007
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
30QCL Training Seminar, Tanzania | 5-7 December 2007
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)
31QCL Training Seminar, Tanzania | 5-7 December 2007
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
32QCL Training Seminar, Tanzania | 5-7 December 2007
WHO’s global guidelines and strategies - risk analysis
Application of risk analysis to production of pharmaceuticals (adopted in 2001)
33QCL Training Seminar, Tanzania | 5-7 December 2007
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
34QCL Training Seminar, Tanzania | 5-7 December 2007
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
35QCL Training Seminar, Tanzania | 5-7 December 2007
WHO Stability guidelines second draft 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
36QCL Training Seminar, Tanzania | 5-7 December 2007
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)
37QCL Training Seminar, Tanzania | 5-7 December 2007
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
38QCL Training Seminar, Tanzania | 5-7 December 2007
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....
39QCL Training Seminar, Tanzania | 5-7 December 2007
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
40QCL Training Seminar, Tanzania | 5-7 December 2007
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
41QCL Training Seminar, Tanzania | 5-7 December 2007
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)
42QCL Training Seminar, Tanzania | 5-7 December 2007
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)
43QCL Training Seminar, Tanzania | 5-7 December 2007
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!
44QCL Training Seminar, Tanzania | 5-7 December 2007
WHO Medicines Quality Assurance website:
http://www.who.int/medicines/areas/quality_safety/quality_assurance