WHO Essential Drugs Strategy

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Drug regulation and quality assurance WHO
normative functions in the field of
pharmaceuticals

Sabine Kopp, PhD Quality Assurance and Safety
Medicines Department of Medicines Policy and
Standards
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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

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WHO does the work?

• 193 Member States
• Two governing bodies - World Health
  Assembly
  - Executive Board
• WHO Secretariat - HQ - six
  Regional Offices - WHO Expert Panels
  (e.g... on the International Pharmacopoeia
  and Pharmaceutical Preparations)
  Constitution 1946, in force since 7 April
  1948 (World Health Day)

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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

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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

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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

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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
• .

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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
• -gt WHO Governing bodies
• -gt Recommendation to Member States for
  implementation

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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)

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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 internati
  onal pharmacopoeia

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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

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Challenges past and present

• Past
• Manufacture direct from API -gt 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

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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

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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
• Free trade zones

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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
• ...

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WHOs global guidelines and strategies

• Requirements for drug registration and model
  legislation
• Networking among and with regulatory authorities
• International alerts
• Counterfeit network
• Global norms and standards and nomenclature (INN)
  ..

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INNs
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WHOs global quality assurance guidelines

• Cover
• Production
• Quality Control
• Quality related regulatory guidelines
• Inspection
• Distribution
• ? from manufacture to delivery to patient

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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

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(No Transcript)
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WHOs strategy for quality control

• Step-wise approach
• - Basic tests (identification)
• - Screening tests (TLC)
• - The International Pharmacopoeia
• - International chemical reference standards
  (ICRS)
• - IR reference spectra

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WHOs global guidelines - quality control -

• International specifications (Int.Ph., 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

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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

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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

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Participation in External Quality Assurance
Scheme -gt 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

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WHOs global guidelines - distribution

• WHO Certification Scheme for Products Moving in
  International Commerce
• SMACS new scheme for pharmaceutical starting
  materials - model certificate, when inspected
  by national authority
• - WHO model for self-assessment for manufacture
  of pharmaceutical starting materials
• Good Distribution and Trading Practices for
  pharmaceutical starting materials (GTDP)
• Good Distribution Practices (GDP) (for products)
  
• Good Storage Practices (GSP)

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WHOs 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

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WHOs global guidelines - production (2)

• New 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)

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WHOs 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

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WHOs global guidelines and strategies - risk
analysis

• Application of risk analysis to production of
  pharmaceuticals (adopted in 2001)

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WHO stability guidelines

• Title guidelines for stability testing of
  pharmaceutical products containing well
  established drug substances in conventional
  dosage forms currently under revision !
• -gt stability testing of final drug products
• -gt well established (e.g. generics)
• -gt in conventional dosage forms (e.g. tablets)
  
• --gt close collaboration with
• ICH group Q1, ASEAN and regional harmonization
  groups

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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

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WHO Stability guidelines second draft What's new?
ctd -

• 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
• -gt preference to provide "real" conditions
  required by national authorities

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WHOs 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)
• 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

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Related WHOs 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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WHOs 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)

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WHOs 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)

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WHO efforts

• ? aim to improve access to quality medicines
• Provide standards and norms in area of quality
  assurance of medicines
• Prequalification programme for UN procurement
• Provide assistance in regulatory area
• Promote logical order of actions
• Priority setting (ABC first )
• Capacity building
• Collaboration and co-operation

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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!
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WHO Medicines Quality Assurance
websitehttp//www.who.int/medicines/areas/quali
ty_safety/quality_assurance