Transcript Safe quality medicines 1 WHO Technical Briefing | September 2010 Medicines quality assurance: WHO normative functions in the field of pharmaceuticals Sabine Kopp, PhD Quality Assurance.

Safe quality
medicines
1 WHO Technical Briefing | September 2010
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
Main points addressed
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WHO standard setting process
WHO international guidelines,
standards and norms in the
area of quality assurance
What's new ?
3 WHO Technical Briefing | September 2010
WHO does the work?
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193 Member States
Two governing bodies:
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WHO Secretariat:
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- World Health Assembly
- Executive Board
- Headquarters
- 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)
4 WHO Technical Briefing | September 2010
How to become a "WHO Expert"?
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Official nomination process
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Upon proposal to WHO in consultation with:
 Member State/national government (citizenship)+
 WHO Regional Office (in accordance with
Member State) +
 WHO Headquarters
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Period of maximum 4 years
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Possibility to renew
5 WHO Technical Briefing | September 2010
What is the WHO Expert Committee?
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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 WHO Technical Briefing | September 2010
Outcome of the WHO Expert Committee?
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Report of the WHO Expert Committee:
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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 WHO Technical Briefing | September 2010
Examples of WHO Expert Committees ?
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WHO Expert Committee on Specifications for
Pharmaceutical Preparations
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WHO Expert Committee on the Selection and Use of
Essential Medicines
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WHO Expert Committee on Drug Dependence
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WHO Expert Committee on Biological Standardization
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Joint FAO/WHO Expert Committee on Food Additives
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….
8 WHO Technical Briefing | September 2010
When does the WHO Expert Committee
start development of a guideline/guidance?
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Based on recommendations by :
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World Health Assembly resolutions (e.g. WHA 20.34, GMP Good manufacturing practices)
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Executive Board resolutions (e.g. EB37.R9 delegating certain
functions of INN Programme to DG based on advice from Experts)
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International Conference of Drug Regulatory Authorities
(e.g. 10th +11th ICDRA – FDC guidelines + Certification Scheme for
pharmaceutical starting materials moving into international commerce)
 Other WHO programmes and clusters (e.g. necessity for quality
control specifications for specific medicines of major public health interest)
 Expert Committee (e.g. revision of general methods included in The
International Pharmacopoeia)
9 WHO Technical Briefing | September 2010
How does the WHO consultation process
work?
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Step 1. Preliminary consultation and drafting
Step 2. Draft guidelines
Step 3. Circulation for comments
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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
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-> Recommendation to Member States for implementation
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10 WHO Technical Briefing | September 2010
WHO Partners
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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-IGPAWSMI, 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…)
11 WHO Technical Briefing | September 2010
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)
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 medicines belong to one of the most
regulated group of products
12 WHO Technical Briefing | September 2010
Medicines Quality Assurance in WHO
Historical overview
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1874
1902
1906
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1925
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Discussion on Unification of terminology and composition of drugs
First Conference organized by Belgian Government
Agreement on Unification of the Formulae of Potent Drugs ratified
by 19 states
Brussels agreement (signed 1929)
League of Nations:
“international pharmacopoeia”
13 WHO Technical Briefing | September 2010
Medicines Quality Assurance in WHO
Historical overview (2)
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1937 First meeting (experts from B, DK, F, NL, CH, UK, USA) League of Nations
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1947 Interim Commission of WHO takes up health related work of
League of Nations
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1948 First World Health Assembly established Expert
Committee on Unification of Pharmacopoeia
14 WHO Technical Briefing | September 2010
Quality of medicines remains a problem
in many countries
15 WHO Technical Briefing | September 2010
Challenges: past and present…
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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
16 WHO Technical Briefing | September 2010
Challenges: past and present…
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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
17 WHO Technical Briefing | September 2010
Global challenges …
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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
18 WHO Technical Briefing | September 2010
Global challenges…
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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
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Contracts, agreements, eg Mutual Recognition Agreements
Risks of mistakes, accidents, human errors etc
Counterfeit drugs
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…...
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19 WHO Technical Briefing | September 2010
WHO’s global guidelines and strategies
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Requirements for drug registration and model
legislation
Networking among and with regulatory authorities
International alerts
Counterfeit network
Global norms and international standards and
nomenclature
20 WHO Technical Briefing | September 2010
INNs
21 WHO Technical Briefing | September 2010
WHO’s medicines quality assurance
guidelines
Cover:
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Development
Production
Quality Control
Quality related regulatory guidelines
Inspection
Distribution
 from manufacture (and before) to delivery to
patient
22 WHO Technical Briefing | September 2010
Adopted WHO guidance texts and guidelines
in medicines quality assurance (without PhInt)
Maintain to keep up to date:
 Total of :
 56
CURRENT official WHO guidance texts
and guidelines to date, including 7 (4
updates, 3 new, adopted 2009)
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Quality Control
http://www.who.int/medicines/areas/quality_safety/quality_assurance/control/
12 guidance documents and guidelines, including
- Good laboratory practices + training materials
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Guidelines for establishment of chemical reference standards
Model certificate of analysis
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International Pharmacopoeia + Basic tests
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24 WHO Technical Briefing | September 2010
WHO’s global guidelines - quality control -
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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
25 WHO Technical Briefing | September 2010
International Pharmacopoeia
Ph.Int.
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current: 4th edition! Supplement 1, no 2 in prep.
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,
medicines for children
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27 WHO Technical Briefing | September 2010
External Quality Assessment Scheme for National
Drug Quality Control Laboratories
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Phase 5 (01/2010 - 12/2012)
- 60 laboratories participate
- Studies:
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Assay by titration: 1 April 2010
Water content by Karl-Fischer: 1 September 2010
Dissolution test: 1 February 2011
Related substances by HPLC: 15 July 2011
Related substances by TLC: 15 January 2012
Assay by HPLC: 15 June 2012
Dissolution test: 15 October 2012
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Distribution
http://www.who.int/medicines/areas/quality_safety/quality_ass
urance/distribution
More than 9 guidance documents and guidelines, e.g.:
- Certification schemes (CPP and SMACS)
- Quality system for Procurement
- Good distribution practices for starting materials and finished
products
- Good storage practices
29 WHO Technical Briefing | September 2010
Production
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http://www.who.int/medicines/areas/quality_safety/quality_assurance/pro
duction/
18 guidance documents and guidelines, including:
- Good Manufacturing Practices (GMP)
…..Consisting of 12 major "guideline" texts
(regularly updated, new texts added as needs are
identified)
- ….. Training materials (slides, video, GMP text)
- Risk analysis (HACCP)
30 WHO Technical Briefing | September 2010
WHO’s global guidelines - production
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Good Manufacturing Practices (GMP) …..
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1. Main principles for pharmaceutical products
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Requirement for the sampling of starting materials (amendment)
Water for pharmaceutical use
Heating, ventilation and air-conditioning (HVAC) systems
Validation
2. … for starting materials, including
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Active pharmaceutical ingredients
Pharmaceutical excipients
31 WHO Technical Briefing | September 2010
WHO’s global guidelines - production (2)
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3. … for specific pharmaceutical products:
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Sterile pharmaceutical products
Biological products (rev in progress)
Investigational pharmaceutical products for clinical
trials in humans
Herbal medicines
Radiopharmaceuticals
Blood establishments
32 WHO Technical Briefing | September 2010
Inspection
http://www.who.int/medicines/areas/quality_safety/quality_assurance/in
spections/en/index.html
6
guidance documents and guidelines
33 WHO Technical Briefing | September 2010
WHO’s global guidelines - inspection
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Inspection of…..
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pharmaceutical manufacturers
 drug distribution channels (products)
Guidelines for pre-approval inspection
Quality systems requirements for national GMP
inspectorates
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Model GMP certificate
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Model report for inspections
34 WHO Technical Briefing | September 2010
Quality related regulatory
standards
http://www.who.int/medicines/areas/quality_safety/quality_assurance/re
gulatory_standards/
17 guidance documents and guidelines, including :
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Stability testing requirements
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Interchangeability of generic medicines
Fixed-dose combination
All prequalification procedures
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35 WHO Technical Briefing | September 2010
WHO’s guidance on interchangeability of
medicines
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WHO guideline on registration requirements to
established interchangeability for multisource
pharmaceutical products (revised in 2006)
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Guidance on selection of comparator products for
equivalence assessment of interchangeable
generic products (under revision)
36 WHO Technical Briefing | September 2010
WHO’s guidance on interchangeability of
medicines (2)
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Proposal to waive in vivo bioequivalence
requirements for the WHO model List of Essential
Medicines (immediate release, solid dosage forms)
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Guidelines for organizations performing in vivo
bioequivalence studies
37 WHO Technical Briefing | September 2010
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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38 WHO Technical Briefing | September 2010
New WHO guidelines adopted during 45th Expert
Committee held 18-22 October 2010
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Good Pharmacy Practice (joint FIP/WHO, revised)
Guidance for Pharmaceutical Microbiology
laboratories (new)
Procedure for prequalification of laboratories
(revised)
Preparing a Laboratory Information File (update)
GMP: main principles (revised)
GMP for blood establishments (jointly with ECBS)
GMP for HVAC (revised)
39 WHO Technical Briefing | September 2010
New WHO guidelines adopted during 45th Expert
Committee held 18-22 October 2010 (2)
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GMP for sterile pharmaceutical products (revised)
Guiding principles on transfer of technology (new)
Guidelines for preparing a Site Master File (new)
Model guidance for the storage and transport of
time- and temperature sensitive pharmaceutical
products (new, jointly with ECBS)
Guidance on submission of documentation for
prequalification of innovator FPPs approved by
stringent regulatory authorities (new)
40 WHO Technical Briefing | September 2010
New WHO guidelines adopted during 45th Expert
Committee held 18-22 October 2010 (3)
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Procedure for prequalification of medicines
(revised)
Guideline for submission of documentation for a
multisource (generic) finished product (new)
Special guidance for artemisinin as a starting
materials for production of antimalarials (subject to
confirmation of impurity profile, new)
Definition of substandard medicines (new)
Procedure for adoption of ICRS (revised)
41 WHO Technical Briefing | September 2010
New Specifications adopted during 45th Expert
Committee held 18-22 October 2010 (3)
27 new specifications and general texts,
including :
 Antiretrovirals
 Anti-TB medicines
 Antimalarials
 Anti-infectives
 Paediatrics
42 WHO Technical Briefing | September 2010
What is in the QA pipeline?
Guidelines/guidance :
 Paediatrics development (new)
 Development of generics (new)
 Risk analysis (update)
 Guideline on submission of
documentation for a multisource
(generic) product – quality part (new)
43 WHO Technical Briefing | September 2010
What is in the QA pipeline? - 2 Guidelines/guidance:
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Update of Comparator List
Update of stability requirements in Member States
Advice to NMRAs on Diethylene glycol intoxication
Tools and framework for monitoring of market
situation
44 WHO Technical Briefing | September 2010
Advantages of WHO's Expert Committee
standard-setting process
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1. Guidelines and specifications validated
internationally, through an independent scientific
process, adoption by members of WHO Expert
Advisory Panels
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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
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45 WHO Technical Briefing | September 2010
Advantages of WHO's Expert Committee
standard-setting process (2)
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4. Links with other WHO activities
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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
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7. Service FREE FOR USE by all Member States
46 WHO Technical Briefing | September 2010
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!
47 WHO Technical Briefing | September 2010
WHO Medicines Quality Assurance website:
http://www.who.int/medicines/areas/quality_safety/quality_assurance
48 WHO Technical Briefing | September 2010