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WHO Essential Drugs Strategy


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Title: WHO Essential Drugs Strategy

Prequalification of drugs for priority diseases
EDM Technical Briefing March 2004
Dr Lembit Rägo Coordinator Quality Assurance and
Safety Medicines Essential Drugs and Medicines
Policy Health Technology and Pharmaceuticals
Cluster World Health Organization
HIV/AIDS Crisis. Demand for affordable
antiretrovirals is increasing. Numerous generic
manufacturers offering products. Challenges for
UN family and procurement agencies/organizations
  • Which way to go to get the best
  • possible protection of public health
  • with the resources available?

  • What is the problem?
  • Sub-standard drugs purchased
  • weak or absent quality assurance systems
  • Lot of money invested in procurement
  • no harmonized quality assurance system available
    for procurement organizations/initiatives
  • Duplication of work
  • lack of harmonized standards (GMP inspections)
  • Risk Sourcing sub-standard drugs, waste of money
    and, health risks to patientshe from

Joint project with other UN organizations
Prequalification of HIV/AIDS Drugs - UN joint
  • Partners
  • WHO
  • With the support of World Bank
  • All organizations are also members of the
    International Pharmaceutical Co-ordination Group
  • WHO role
  • Technical assistance based on WHO norms and
    standards, plus ICH and other standards, where

Procurement, Quality and Sourcing Project
The prequalification part of the project has two
major activities countries are providing
  • I. Assessment of products dossiers i.e. quality
    specifications, pharmaceutical development,
    bioequivalence etc. teams of professionals from
    national drug regulatory authorities Brazil,
    Canada, Denmark, Estonia, Finland, France,
    Germany, Hungary, Indonesia, Malaysia,
    Philippines, Spain, South-Africa, Sweden,
    Switzerland, Tanzania, Zimbabwe ...
  • II. Manufacturing site inspections teamwork of
    inspectors WHO representative (qualified GMP
    inspector), inspector from well-established
    inspectorate (Pharmaceutical Inspection
    Convention Scheme countries) and national
    inspector(s) Canada, France, Italy, Switzerland,
    The Netherlands
  • Quality control analysis - upon need but not
    always necessarily before prequalification and
    supply, increasingly as part of follow-up

Procurement, Quality and Sourcing Project
Prequalification basic principles
  • Voluntary for participating manufacturers
  • Legitimate - General procedure and standards
    approved through WHO Expert Committee system
    involving all WHO Member States and WHO Governing
  • Widely discussed in many fora
  • FIP Congress, Nice 2002
  • Supported by ICDRA in 2002 and 2004, representing
    more than 100 national drug regulatory
  • Transparent (all information available on the web
    site http//www.who.int/medicines/)
  • Open to both innovators and multisource/generic
  • No cost for applicants during pilot phase

(No Transcript)
Some relevant ICDRA 2004 recommendatins
  • WHO is urged to create - as a matter of urgency -
    model guidelines for regulatory approval of
    prescription only fixed dose combination drugs
    with special emphasis on drugs for communicable
    diseases with high public health impact.
  • Regulators have a role and responsibility to
    facilitate access to drugs of public health
    importance including proposing changes in the
    respective regulations in order to facilitate
    access without compromising on quality, safety
    and efficacy.
  • WHO should continue pre-qualification of drugs
    for priority disease programmes, particularly
    HIV, malaria and TB.
  • Countries should adopt the WHO Guidelines on
    Developing Measures for Combating Counterfeit
    Drugs, raise public and political awareness of
    the problem, increase national, international
    cooperation and data exchange between all
    stakeholders, including drug regulatory
    authorities , interested nongovernmental
    organizations , law enforcement agencies,
    industries, and relevant international

Procurement, Quality and Sourcing Project
Prequalification misunderstandings and critics
  • Too high standards increasing prices
  • Too high and unnecessary standards for
    developing countries
  • Too bureaucratic and slow, not proactive and
    not able to provide products
  • Too low standards
  • . " This leaves the impression with readers that
    the ARVs approved by WHO are in fact generic
    products that are interchangeable with their
    innovator cousins. From available documents,
    however, we conclude that they are copy products
    with unknown quality, safety and efficacy

Procurement, Quality and Sourcing Project
Prequalification generics or not?
  • FDA requirements for generic drugs
  • Thus, a generic drugs must
  • 1. contain the same active ingredients as the
    innovator drugs as the innovator drug
  • 2. be identical in strength, dosage form, and
    route of administration
  • 3. have the same use indications
  • 4. be bio-equivalent
  • 5. meet the same batch requirements for identity
    , strength, purity and quality
  • 6. be manufactured under the same strict
    standards of GMP required for innovator products.

General procedure Prequalification
  • What will be required for generic drugs (1) ?
  • 1. Details of the product
  • 2. Regulatory situation in other countries
  • 3. Active pharmaceutical ingredient(s) (API)
  • 3.1 Properties of the active pharmaceutical
  • 3.2 Sites of manufacture of API(s)
  • 3.3 Route(s) of synthesis
  • 3.4 Specifications
  • API described in a pharmacopoeia
  • API not described in a pharmacopoeia
  • 3.5 Stability testing
  • WHO Expert Committee on Specifications for
    Pharmaceutical Preparations, Thirty-fourth
    report. Geneva, World Health Organization, 1996
    65-79(WHO TRS, No 863, as amended in 2002)

General procedure Prequalification
  • What will be required (2)?
  • 4. Finished product
  • 4.1. Formulation
  • 4.2. Sites of manufacture
  • 4.4. Manufacturing procedure
  • 4.5 Specifications for excipients
  • 4.6 Specifications for the finished product
  • 4.7 Container/closure system(s) and other
  • 4.8 Stability testing

General procedure Prequalification
  • What will be required (3)?
  • 4.9 Container labelling
  • 4.10 Product information
  • 4.11 Patient information and package inserts
  • 4.12 Justification for any differences to the
    product in the country or countries issuing
    the submitted WHO-type certificate(s)
  • 4.13 Interchangeability (bioequivalence studies)
  • 4.14 Summary of pharmacology, toxicology and
    efficacy of the product

General procedure Prequalification
  • Steps of the Procedure
  • 1. Invitation for EOI
  • Wide publication
  • Open, transparent
  • Specify products required
  • 2. Guidelines for product dossier compilation and
    requirements available
  • Multi-source products
  • Innovator products

General procedure Prequalification
  • 3. Receiving of dossiers
  • 4. Screening of dossiers
  • Screen for completeness
  • Inform supplier
  • Listed for a possible site inspection
  • 5. Dossier evaluation
  • Team of experts (quality, pharmaceutical
    development, bio-equivalence etc)
  • From national regulatory authorities
  • Standard Including, but not limited to WHO
    Manual and guidelines " Marketing Authorization
    of Pharmaceutical Products with special Reference
    to Multisource (Generic) Products a Manual for a
    Drug Regulatory Authority, WHO/DMP/RGS/98.5)
  • Outcome of the evaluation communicated to supplier

General procedure Prequalification
  • 6. Site inspection
  • Inspection team
  • Appointed inspector
  • Experience, qualification, preferably from DRA
  • Local, national inspectorate
  • WHO representative
  • 7. Report and outcome
  • Reports on dossier evaluation and site inspection
  • Communicated to supplier/manufacturer
  • Compliance? Additional information to be

Pilot project
Access to HIV/AIDS Drugs and Diagnostics of
Acceptable Quality Quality Problems (I)
  • Assessment from ABC to XYZ
  • API source, impurities, lack of stability data
    lack or defective bioequivalence data
  • Manufacturing site inspections
  • Manufacturers not ready, often non-compliance
    with WHO cGCP
  • Upgrading of facilities to comply with WHO cGMP
  • DRAs issued CPP yet non-compliance
  • Inspections reveal non-compliance, e.g.
    antibiotics (penicillin), hormones and other
    products manufactured in the same site
  • No validation
  • Time needed to respond to report
  • double standards local vs. international

Problems encountered
Access to HIV/AIDS Drugs and Diagnostics of
Assured Quality Quality problems (II)
  • Specific problems Unacceptable chiral activity,
    stereo-isomerism of active pharmaceutical
    ingredient (API) - potentially inactive API
  • Stavudine
  • Lamivudine
  • Indinavir (1/ 32 possible stereoisomers)
  • Saquinavir mesylate (1/64 possible)
  • Ritonavir
  • Only one enantiomer registered and claimed in the
    innovators dossier
  • EMEA/CPMP/375/96 EPAR (-) Lamivudine selected
    because less cytotoxic than () Lamivudine and
    the racemate (5050 mixture)

Problems encountered
Access to HIV/AIDS Drugs and Diagnostics of
Assured Quality Quality problems (III)
    example (1)
  • No information on the stereochemical
  • No information on how the synthesis can lead to
    the correct enantiomer ? evidence of structure /
    right enantiomer?
  • No validation on manufacturing process of the
    API only 2 batches with batch size unknown ?
    batch-to-batch consistency not demonstrated/ is
    the same enantiomer obtained each time? Is it
    contaminated with the same amount of the
    undesirable stereoisomer each time?
  • Absence of control of the undesirable enantiomer
    in the finished pharmaceutical product including
  • ...

Problems encountered
Access to HIV/AIDS Drugs and Diagnostics of
Assured Quality Quality problems (IV)
  • Lamivudine examples
  • 1 file for oral solution ? no BE study required
  • 6 files for tablets from 4 manufacturers
  • 2 manufacturers no BE study
  • 2 manufacturers BE study included for at least
    one formulation strength
  • Major deficiencies identified in BE studies from
    both manufacturers (assay validation, relevant
    test product?)

Summary of Identified Deficiencies in all Files
Requiring BE Studies(interim review, 64 files in
  • Major deficiencies
  • No bioequivalence study performed and no adequate
    justification for not performing a study (32
  • Inadequate validation data of bioanalytical
    method (14 files)
  • No verification that test product used in
    bioequivalence study is identical to product
    intended for marketing (13 files)
  • 90 Confidence Intervals for pharmacokinetic
    parameters not presented (9 files)
  • Non-assessable Comparative Efficacy Study(1

Summary of Identified Deficiencies in all Files
Requiring BE Studies(interim review, 64 files in
  • Minor deficiencies
  • No information on batch size of test product
  • Certificate of Analysis of test batch not
  • In-vitro dissolution profiles not submitted
  • for test product
  • for reference product
  • for different strengths of the same product

Pilot project
Access to HIV/AIDS Drugs and Diagnostics of
Acceptable Quality
  • Expanded
  • Tuberculosis products First line as well as
    second line treatment
  • 119 Product dossiers
  • Several inspections in various countries
  • List of products and manufacturers not yet
  • Malaria
  • 27 Product dossiers, mainly artemesinin and
    combination products
  • List of product(s) published in August 2003
  • Some neither originators nor generics

Pilot project
Expansion to cover other important areas?
  • Prequalification of QC laboratories
  • Standards and procedure ready
  • Two laboratories assessed, one approved
  • Prequalification of procurement agencies
  • Standards and procedure ready
  • Model Quality Assurance System created, under

Pre-qualification of a triple FDC from generic
manufacturers has caused a lot of "emotions"
  • lamivudine stavudine nevirapine
  • Issues
  • No originator FDC
  • Regulatory principles the same as applied by FDA
    and EMEA to Trizivir from GSK (
    lamivudinezidovudineabacavir) i.e.
  • based on bioequivalnce studies against loose
  • no additional clinical studies required

Procurement, Quality and Sourcing Project
Prequalification project
  • Current status
  • Good news
  • Relatively large number of ARV products and
    suppliers indicated
  • Many potential suppliers appreciating feedback
    and willing to improve
  • Unique knowledge obtained about generic ARVs and
    other products, including TB products
  • Quality generic products do exist
  • Bad news
  • Only limited number of products have met the
    required standards
  • Takes time to get into compliance
  • Data to be generated, tests carried out
  • GMP upgrade needed
  • Bad quality generics may undermine the public
    confidence in generics
  • Quality Assurance at a price!


http//mednet3.who.int/prequal/default.shtml Quali
ty can not be assessed, tested or inspected into
the product. It has to be built into it.
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