Transcript 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.

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




2
WHO role and function
WHO standard setting
process
WHO international guidelines,
standards and norms in the
area of quality assurance
WHO's operational strategies
WHO does the work?

193 Member States
Two governing bodies:

WHO Secretariat:

3
- World Health Assembly
- Executive Board
- 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)
How to become a "WHO Expert"?
4

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
What is the WHO Expert Committee?



5
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…
Outcome of the WHO Expert Committee?

Report of the WHO Expert Committee:
-

6
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
Examples of WHO Expert Committees ?
7

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

….
How does the WHO consultation process
work?




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



8
Step 1. Preliminary consultation and drafting
Step 2. Draft guidelines
Step 3. Circulation for comments
WHO Partners








9
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…)
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)

10
 medicines belong to one of the most
regulated group of products
Medicines Quality Assurance in WHO
Historical overview


1874
1902
1906

1925


11
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”
Medicines Quality Assurance in WHO
Historical overview (2)
12

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
Challenges: past and present…

13
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
Challenges: past and present…

14
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
Global challenges …








15
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
Global challenges…




Contracts, agreements, eg Mutual Recognition Agreements
Risks of mistakes, accidents, human errors etc
Counterfeit drugs

…...


16
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
WHO’s global guidelines and strategies





17
Requirements for drug registration and model
legislation
Networking among and with regulatory authorities
International alerts
Counterfeit network
Global norms and international standards and
nomenclature
INNs
18
WHO’s medicines quality assurance
guidelines
Cover:
19

Production

Quality Control

Quality related regulatory guidelines

Inspection

Distribution

 from manufacture to delivery to patient
WHO’s global guidelines - quality control -




20
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
The International Pharmacopoeia
(Ph.Int.)




21
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:
http://www.who.int/phint
22
WHO’s strategy for quality control

Step-wise approach:

- Basic tests (identification)

- Screening tests (TLC)
- The International Pharmacopoeia



23
+ International chemical reference standards (ICRS)
+ IR reference spectra
WHO External Quality Assessment Scheme for
National Drug Quality Control Laboratories

Capacity building

Phase 4 (06/2007 - 01/2009)
Series of 5 tests
50 participating laboratories, including WHO
Collaborating Centres
In all 6 WHO regions



24
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)

25
15 QC laboratories involved in prequalification procedure invited
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

26
- Model for self-assessment for manufacture of pharmaceutical
starting materials
WHO’s global guidelines – distribution (2)
27

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)
WHO’s global guidelines - production



Good Manufacturing Practices (GMP) …..
1. Main principles for pharmaceutical products
2. … for starting materials, including



3. … for specific pharmaceutical products:





28
active pharmaceutical ingredients
pharmaceutical excipients
Sterile pharmaceutical products
Biological products
Investigational pharmaceutical products for clinical trials in humans
Herbal medicines
Radiopharmaceuticals
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)
29
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


30

Model GMP certificate

Model report for inspections
WHO’s global guidelines and strategies -
risk analysis

31
Application of risk analysis to production of
pharmaceuticals (adopted in 2001)
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
32
WHO Stability guidelines - newly adopted
What's new?

Scope covers:
active pharmaceutical ingredients +
pharmaceutical products
33

Marketed + new

Transition period recommended for already
marketed actives and products

Additional advice given, e.g. model reports
currently used in WHO Prequalification Programme
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
34
WHO’s guidance on interchangeability of
medicines
35

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)
WHO’s guidance on interchangeability of
medicines (2)
36

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
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
....

37
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

38
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


39
7. Service FREE FOR USE by all Member States
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)


40
Collaborate with regional and inter-regional regulatory
harmonization efforts (in all 6 WHO regions)
WHO’s operational strategies -2-
41

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)
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!
42
WHO Medicines Quality Assurance website:
http://www.who.int/medicines/areas/quality_safety/quality_
assurance
43
44