Safe quality
medicines
1 WHO Technical Briefing | 17 November 2009
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 international guidelines,
standards and norms in the
area of medicines quality
assurance
WHO's anti-counterfeiting
activities and IMPACT
3 WHO Technical Briefing | 17 November 2009
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
4 WHO Technical Briefing | 17 November 2009
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…)
5 WHO Technical Briefing | 17 November 2009
WHO’s medicines quality assurance
guidelines
Cover:
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Production
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Quality Control
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Quality related regulatory guidelines
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Inspection
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Distribution
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 from manufacture to delivery to patient
6 WHO Technical Briefing | 17 November 2009
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 laboratory equipment
 External qc assessment scheme for labs
7 WHO Technical Briefing | 17 November 2009
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
8 WHO Technical Briefing | 17 November 2009
9 WHO Technical Briefing | 17 November 2009
WHO’s strategy for quality control
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Step-wise approach:
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- Basic tests (identification)
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- Screening tests (TLC)
- The International Pharmacopoeia
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+ International chemical reference standards (ICRS)
+ IR reference spectra  1. Suppl.
10 WHO Technical Briefing | 17 November 2009
External Quality Assessment Scheme for National
Drug Quality Control Laboratories
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Phase 4 (06/2007 - 05/2009)
- 50 laboratories participate
- Studies:
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Titration
Water content by Karl-Fisher
Dissolution test
Determination of glucose by polarimetry
HPLC assay
11 WHO Technical Briefing | 17 November 2009
WHO’s global guidelines - distribution
WHO
Certification Scheme for Pharmaceutical
Products Moving in International Commerce
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SMACS new scheme for pharmaceutical starting
materials:
 - Model certificate, when inspected by national authority
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- Model for self-assessment for manufacture of pharmaceutical
starting materials
12 WHO Technical Briefing | 17 November 2009
WHO’s global guidelines – distribution (2)
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Good Distribution and Trading Practices for
pharmaceutical starting materials (GTDP)
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Good Distribution Practices (GDP) (for
products) (newly revised)
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Good Storage Practices (GSP)
13 WHO Technical Briefing | 17 November 2009
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 (newly revised)
Pharmaceutical excipients
14 WHO Technical Briefing | 17 November 2009
WHO’s global guidelines - production (2)
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3. … for specific pharmaceutical products:
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Sterile pharmaceutical products (revised)
Biological products (rev in progress)
Investigational pharmaceutical products for clinical
trials in humans
Herbal medicines Herbal medicines (revised)
Radiopharmaceuticals
15 WHO Technical Briefing | 17 November 2009
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
16 WHO Technical Briefing | 17 November 2009
WHO’s global guidelines and strategies risk analysis
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Application of risk analysis to production of
pharmaceuticals (adopted in 2001)
17 WHO Technical Briefing | 17 November 2009
WHO stability guidelines
newly revised !
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Scope now covers:
active pharmaceutical ingredients + finished
pharmaceutical products
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Marketed + new
++ List of WHO Member States' required long-term
stability conditions as per info received from
countries, "real" conditions required by national
authorities
--> close collaboration with ICH group Q1, ASEAN, GCC and other
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regional harmonization groups
18 WHO Technical Briefing | 17 November 2009
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)
19 WHO Technical Briefing | 17 November 2009
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
20 WHO Technical Briefing | 17 November 2009
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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21 WHO Technical Briefing | 17 November 2009
44th WHO Expert Committee on Specifications for
Pharmaceutical Preparations
Texts for inclusion in The International Pharmacopoeia
 Medicines for HIV and related conditions:
 — lopinavir
 — tenofovir disoproxil fumarate
 — efavirenz (revised text)
 — indinavir capsules
 — saquinavir tablets
 — tenofovir tablets
 — lopinavir and ritonavir tablets
22 WHO Technical Briefing | 17 November 2009
44th WHO Expert Committee on Specifications for
Pharmaceutical Preparations
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Antimalarial medicines
— artesunate
— amodiaquine tablets
— artesunate tablets
— quinine bisulfate tablets
— quinine sulfate tablets (revised text)
Antituberculosis drugs
— amikacin (revised text)
— amikacin sulfate (revised text)
— kanamycin monosulfate
— kanamycin acid sulfate
— amikacin injection
23 WHO Technical Briefing | 17 November 2009
44th WHO Expert Committee on Specifications for
Pharmaceutical Preparations
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Other medicines
— oxytocin
— mebendazole (revised text)
— oseltamivir phosphate (revised text)
— oxytocin injection
Radiopharmaceuticals
final texts for the 18 individual and
2 general monographs
24 WHO Technical Briefing | 17 November 2009
Global quality assurance guidelines adopted in 44th
Expert Committee
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Update of good distribution practices for pharmaceutical products
(based on recommendation from IMPACT working group)
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Update of good practices for quality control laboratories
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Guideline for the preparation of a contract research organization
master file (CROMF)
Guideline on requalification of prequalification dossiers
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Updates and revisions of GMP texts, e.g.
 for actives pharmaceutical ingredients
 for sterile pharmaceutical products
 for products containing hazardous materials
25 WHO Technical Briefing | 17 November 2009
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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26 WHO Technical Briefing | 17 November 2009
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
27 WHO Technical Briefing | 17 November 2009
Problem: Counterfeiting medicines is a major
public health concern
28 WHO Technical Briefing | 17 November 2009
What is the problem?
 Counterfeiting medicines is a lucrative "business" and
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seems emerging, affecting both developing and
developed countries
The real magnitude of the problem is unknown:
 Existing data not comprehensive
 All parties concerned reluctant to make data AVAILABLE
or REPORT
29 WHO Technical Briefing | 17 November 2009
Is there a health risk ?
Under treatment or non-treatment
 Public health risk: ineffective medicines
 Intoxication: harmful ingredients
 No quality assurance
 Adverse reactions not monitored: an effective product
recall not possible
 Erosion of public confidence in medical care and health
systems
 Waste of money
 ….
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30 WHO Technical Briefing | 17 November 2009
WHO’s work in combating counterfeit
medicines: Three strategies
1.
Providing tools, international norms, standards and guidelines to
assist that drugs circulating in national and international
commerce are safe, efficacious and of good quality
2.
Providing support to Member States to build national regulatory
capacity
3.
Developing global activities to combat counterfeit medicines
31 WHO Technical Briefing | 17 November 2009
32 WHO Technical Briefing | 17 November 2009
IMPACT's conceptual framework
1.
2.
IMPACT: a voluntary coalition of partners with purpose of
coordinating international activities aimed at combating
counterfeit medical products
IMPACT partners reflect fact that combating counterfeiting
of medical products cannot be successfully achieved by
health sector alone but requires coordinated effort and
effective collaboration among health sector, enforcement,
border control, justice (all at different administrative
levels), as well as health professionals, manufacturers,
importers, distributors, media, patients/consumers
33 WHO Technical Briefing | 17 November 2009
IMPACT's conceptual framework
3.
IMPACT led by WHO to keep focus on public health
implications of counterfeiting rather than on IPR-related
aspects
4.
IMPACT output include recommendations, policy advice,
and reference and training materials that reflect
consensus reached among IMPACT partners
34 WHO Technical Briefing | 17 November 2009
Who is/should be in IMPACT ?
All 193 WHO Member States and major international partners, such as:
European Commission
35 WHO Technical Briefing | 17 November 2009
How does IMPACT work?
 Secretariat: WHO
 5 working groups, focusing on areas where weaknesses
were identified and action is required at national and
international level:
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legislative and regulatory infrastructure
regulatory implementation
enforcement
technology
communication
36 WHO Technical Briefing | 17 November 2009
Issues arising during past 12 months
 Concerns that fight against counterfeit medicines may have
negative impact on generics
 Use of counterfeit argument for limiting free trade / competition
/ parallel trade
 Use of term "counterfeit medicinal product" in patent disputes
 Concerns from some parties that technical measures would be
too costly, e.g. for OTC and Generics
37 WHO Technical Briefing | 17 November 2009
Future … until WHA 2010 + …
 New programme in EMP – ACM
 Continuation of WHO involvement in IMPACT as Chair and
Secretariat
 Fund-raising and staffing for ACM and IMPACT related activities
 Communication with WHO Member States to prepare the WHA
2010
38 WHO Technical Briefing | 17 November 2009
Conclusions
 Fighting counterfeit medicines
 Working together with all parties concerned, nationally
and internationally, is the key!
39 WHO Technical Briefing | 17 November 2009
WHO Medicines Quality Assurance and
IMPACT websites:
http://www.who.int/impact
http://www.who.int/medicines/areas/quality_safety/quality_assurance
40 WHO Technical Briefing | 17 November 2009