Transcript Safe quality medicines 1 WHO Technical Briefing | September 2011 Medicines quality assurance: WHO Expert Committee on Specifications for Pharmaceutical Preparations Sabine Kopp, PhD Quality Assurance and.

Safe quality
medicines
1 WHO Technical Briefing | September 2011
Medicines quality assurance:
WHO Expert Committee on
Specifications for Pharmaceutical
Preparations
Sabine Kopp, PhD
Quality Assurance and Safety: Medicines
Department of Essential Medicines and Pharmaceutical Policies
Main points addressed




Who is WHO?
How does WHO set standards?
Which WHO guidelines,
standards and norms exist in
the area of quality assurance?
What's new ?
3 WHO Technical Briefing | September 2011
Who is WHO? Governing bodies

World Health Assembly (WHA)
Delegations from 193 Member States
Meeting yearly in May

Executive Board (EB)
Representatives from 34 Member States +
Meeting biannually in January and May
4 WHO Technical Briefing | September 2011
Impressions from World Health Assembly

- SSFFC
5 WHO Technical Briefing | September 2011
Impressions from World Health Assembly
Floor of the Assembly
Dr Margaret Chan, WHO Director-General
Mr Bill Gates, Co-chair of the Bill & Melinda Gates Foundation
Her Excellency Sheikh Hasina, Prime Minister of Bangladesh
Dr Christos Patsalides, President of the Sixty-fourth World Health Assembly
and Minister of Health of Cyprus, and
Dr Maria Teresa Valenzuela (Chile), Chair of Committee B .
6 WHO Technical Briefing | September 2011
WHO is WHO ? Secretariat and experts



WHO Secretariat:
- Headquarters
- six Regional Offices and 149 Country offices
Experts:
- WHO Expert Panels and Expert Committees
- WHO Collaborating Centres
- + partners
Constitution signed 1946, in force since 7 April 1948
(World Health Day)
7 WHO Technical Briefing | September 2011
WHO Partners
With Regulatory Bodies…


National/Regional regulatory authorities
Regional/Interregional regulatory groups (ASEAN, GCC, ICH,
PANDRH...)
Within WHO…


WHO disease programmes (Stop TB, Roll-Back Malaria,
HIV/AIDS, Tropical Neglected Diseases, programmes on
Children, Women's Health… )
Prequalification Programme – A United Nations Programme
managed by WHO
8 WHO Technical Briefing | September 2011
WHO Partners (2)
With Organizations and Associations…
 International organizations (UNAIDS, UNICEF, IAEA,
Global Fund, World Bank…)
 International professional and other associations, NGOs
(incl. industry, consumer associations: IFPMA, IGPA,
WSMI, IPEC, FIP, WMA, MSF…)
With Standard-setting Bodies, such as …
 Pharmacopoeia Commissions and Secretariats (e.g.
British Brazilian, Chinese, European, Indian, Korean,
Japanese, USP, .. )
9 WHO Technical Briefing | September 2011
WHO Partners (3)
With "recognized" Experts…
 WHO Expert Panel on The International Pharmacopoeia and
Pharmaceutical Preparations (official nomination process)
 Specialists from all areas for specific projects (regulatory,
university, industry…)
With "recognized" Laboratories…
 National/Regional Quality control laboratories
 WHO Collaborating Centres (official nomination process)
10 WHO Technical Briefing | September 2011
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
11 WHO Technical Briefing | September 2011
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…
12 WHO Technical Briefing | September 2011
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
13 WHO Technical Briefing | September 2011
WHO Expert Committees rules and procedures
 WHO Basic Documents

Constitution of WHO



Expert Committees:
chapter V, article 18; chapter VIII, articles 38-40
For normative function - pharmaceuticals:
Chapter 2, article 2 (u): " to develop, establish and promote
international standards with respect to food, biological, pharmaceutical
and similar products;"
Regulations for Expert Advisory Panels and
Committees, including, Annex – Rules of Procedure for Expert
Committees
14 WHO Technical Briefing | September 2011
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

….
15 WHO Technical Briefing | September 2011
When does the WHO Expert Committee
start development of a guideline/guidance?

Based on recommendations by :

World Health Assembly resolutions (e.g. WHA 20.34, GMP - Good
manufacturing practices)

Executive Board resolutions (e.g. EB37.R9 delegating certain functions of
INN Programme to DG based on advice from Experts)

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 and feedback
from Prequlifcation programme)

Expert Committee (e.g. revision of general methods included in The
International Pharmacopoeia)
16 WHO Technical Briefing | September 2011
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



17 WHO Technical Briefing | September 2011
WHO Governing bodies …
18 WHO Technical Briefing | September 2011
Medicines Quality Assurance in WHO
Historical overview


1874
1902
1906

1925


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”
19 WHO Technical Briefing | September 2011
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
20 WHO Technical Briefing | September 2011
Medicines Quality Assurance in WHO
Historical overview (3)

1st "WHO Expert Committee on Specifications
for Pharmaceutical Preparations" ( ECSPP)
meeting held 13-17 October 1947

Report of 1st ECSPP meeting published in:

Official Records of WHO, No 8, page
54ff, 1947
21 WHO Technical Briefing | September 2011
Quality of medicines remains a problem
22 WHO Technical Briefing | September 2011
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
23 WHO Technical Briefing | September 2011
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
24 WHO Technical Briefing | September 2011
WHO’s global guidelines and strategies





Requirements for drug registration and model
legislation
Networking among and with regulatory authorities
International alerts
Global tools to help ensure that patients receive
quality safe quality medicines
Global norms and international standards and
nomenclature
25 WHO Technical Briefing | September 2011
INNs
26 WHO Technical Briefing | September 2011
WHO’s medicines quality assurance
guidelines
Cover:







Development
Production
Quality Control
Quality related regulatory guidelines
Inspection
Distribution
 from manufacture (and before) to delivery to
patient
27 WHO Technical Briefing | September 2011
Adopted WHO guidance texts and guidelines
in medicines quality assurance (without PhInt)
Maintain to keep up to date:
 More
than 60 CURRENT official WHO
guidance texts and guidelines to date,
including 15 (8 updates + 7 new adopted
2010)
28 WHO Technical Briefing | September 2011
Quality Control
http://www.who.int/medicines/areas/quality_safety/quality_assurance/contr
ol/
More than 10 guidance documents and guidelines,
including
- Good laboratory practices + training materials
-
Guidelines for establishment of chemical reference
standards
Model certificate of analysis
-
International Pharmacopoeia + Basic tests
-
29 WHO Technical Briefing | September 2011
International Pharmacopoeia
Ph.Int.



current: 4th edition! Supplement 1 +2
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
30 WHO Technical Briefing | September 2011
External Quality Assessment Scheme for National
Drug Quality Control Laboratories

Phase 5 (01/2010 - 12/2012)
- 60 laboratories participate
- Studies:







-
Assay by titration
Water content by Karl-Fischer
Dissolution test
Related substances by HPLC
Related substances by TLC
Assay by HPLC
Dissolution test
31 WHO Technical Briefing | September 2011
Distribution
http://www.who.int/medicines/areas/quality_safety/quality_ass
urance/distribution
Some 10 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
32 WHO Technical Briefing | September 2011
Production
-
http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/
Some 20 guidance documents and guidelines, including:
- Good Manufacturing Practices (GMP)
-
…..Consisting of more than 10 major "guideline" texts
(regularly updated, new texts added as needs are
identified)
….. Training materials (slides, video, GMP text)
Risk analysis (HACCP) – moving to "quality risk
management"
33 WHO Technical Briefing | September 2011
WHO’s global guidelines - production

Good Manufacturing Practices (GMP) …..

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
2. … for starting materials, including


Active pharmaceutical ingredients
Pharmaceutical excipients
34 WHO Technical Briefing | September 2011
WHO’s global guidelines - production (2)

3. … for specific pharmaceutical products:






Sterile pharmaceutical products
Biological products (rev in progress)
Investigational pharmaceutical products for clinical
trials in humans
Herbal medicines
Radiopharmaceuticals
Blood establishments
35 WHO Technical Briefing | September 2011
WHO’s global guidelines - inspection
http://www.who.int/medicines/areas/quality_safety/qual
ity_assurance/inspections/en/index.html

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
36 WHO Technical Briefing | September 2011
Quality related regulatory
standards
http://www.who.int/medicines/areas/quality_safety/quality_assurance/re
gulatory_standards/
Some 20 guidance documents and guidelines, including :
-
Stability testing requirements
Interchangeability of generic medicines
Fixed-dose combination
All prequalification procedures
37 WHO Technical Briefing | September 2011
46th WHO Expert Committee on Specifications for
Pharmaceutical Preparations – outcome - 1-
1. Adopted texts: The International Pharmacopoeia
-
Medicines for HIV and related conditions:
-
Ritonavir tablets
- Antimalarial medicines


Artesunate
Artenimol
- Antituberculosis medicines

-
Rifampicin
Anti-infectives:
-
Pyrantel chewable tablets
38 WHO Technical Briefing | September 2011
46th WHO Expert Committee on Specifications for
Pharmaceutical Preparations – outcome -2-
- Antituberculosis drugs (ctd)



Ofloxacin tablets
Levofloxacin
Levofloxacin tablets
- For anti-infectives:




Amoxicillin oral suspension
Levamisole tablets
Metronidazole oral suspension
Sulfamethoxazole and trimethoprim tablets
39 WHO Technical Briefing | September 2011
46th WHO Expert Committee on Specifications for
Pharmaceutical Preparations – outcome -3- For other medicines

Medroxyprogesterone injection

Paediatric retinol oral solution
For harmonized general texts (based on PDG texts)

Test for sulfated ash

Test for bacterial endotoxins

Test for sterility

Tablet friability

Disintegration test for tablets and capsules
40 WHO Technical Briefing | September 2011
46th WHO Expert Committee on Specifications for
Pharmaceutical Preparations – outcome -4
Bulk density and tapped density of powders

Test for extractable volume for parenteral preparations

Microbiological examination of non-sterile products: microbial
enumeration tests

Microbiological examination of non-sterile products: tests for
specified microorganisms

Microbial quality of pharmaceutical preparations

Test for particulate contamination
41 WHO Technical Briefing | September 2011
46th WHO Expert Committee on Specifications for
Pharmaceutical Preparations – outcome -5
General policy topics and general revision issues for:

Uniformity of content for single-dose preparations

Supplementary information section for the Ph.Int.

The Committee adopted the following new ICRS:

Lumefantrine for system suitability
42 WHO Technical Briefing | September 2011
46th WHO Expert Committee on Specifications for
Pharmaceutical Preparations – outcome -6-
2. Adopted global quality assurance guidelines:

WHO good manufacturing practices: water for
pharmaceutical use

Pharmaceutical development of multisource (generic)
pharmaceutical products

Guideline on submission of documentation for a
multisource (generic) finished pharmaceutical product for
the WHO Prequalification Programme: quality part
43 WHO Technical Briefing | September 2011
46th WHO Expert Committee on Specifications for
Pharmaceutical Preparations – outcome -7-

Monograph development for The International
Pharmacopoeia

Development of paediatric medicines: points to
consider in formulation

Quality requirements of artemisinin as a starting
material in the production of antimalarial active
pharmaceutical ingredients
44 WHO Technical Briefing | September 2011
In the pipeline - quality assurance for
medicines..



Ph.Int.: Harmonization with PDG general texts – for
those evaluated by ICH Q4B, continue
External Quality Assessment Scheme for National
Drug Quality Control Laboratories, 5th series, 3rd test
in process, 4th in preparation
Guidance on selection of comparator products for
equivalence assessment of interchangeable generic
products (revision)
45 WHO Technical Briefing | September 2011
In the pipeline..




Risk analysis based on HACCP towards Quality Risk
Management
Guideline on submission of documentation for a
multisource (generic) product – quality part – general
guidance
Tools and framework for monitoring of market
situation
International meeting(s) for world pharmacopoeiae
46 WHO Technical Briefing | September 2011
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

47 WHO Technical Briefing | September 2011
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
48 WHO Technical Briefing | September 2011
WHO Medicines Quality Assurance website:
http://www.who.int/medicines/areas/quality_safety/quality_assurance
49 WHO Technical Briefing | September 2011
Safe quality
medicines
50 WHO Technical Briefing | September 2011