WHO Essential Drugs Strategy

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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
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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?

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WHO/HTP/EDM/QSM
Pre-qualification

• 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

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Joint project with other UN organizations
Prequalification of HIV/AIDS Drugs - UN joint
activity

• Partners
• UNAIDS
• UNICEF
• UNFPA
• WHO
• With the support of World Bank
• All organizations are also members of the
  International Pharmaceutical Co-ordination Group
  (IPC)m
• WHO role
• Technical assistance based on WHO norms and
  standards, plus ICH and other standards, where
  applicable

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Procurement, Quality and Sourcing Project
The prequalification part of the project has two
major activities countries are providing
expertise

• 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

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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
  bodies
• Widely discussed in many fora
• FIP Congress, Nice 2002
• Supported by ICDRA in 2002 and 2004, representing
  more than 100 national drug regulatory
  authorities
• Transparent (all information available on the web
  site http//www.who.int/medicines/)
• Open to both innovators and multisource/generic
  manufacturers
• No cost for applicants during pilot phase

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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
  organizations.

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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
  profiles".

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Procurement, Quality and Sourcing Project
Prequalification generics or not?

• FDA requirements for generic drugs
  (www.fda.gov/cder/ogd)
• 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.

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WHO/HTP/EDM/QSM
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
  ingredient(s)
• 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)
  http//www.ifpma.org/ich5q.htmlstability

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WHO/HTP/EDM/QSM
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
  packaging
• 4.8 Stability testing

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WHO/HTP/EDM/QSM
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

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WHO/HTP/EDM/QSM
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

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WHO/HTP/EDM/QSM
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

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WHO/HTP/EDM/QSM
General procedure Prequalification

• 6. Site inspection
• WHO GMP
• 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
  submitted?

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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
  market

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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
• CHIRALITY / ENANTIOMERIC PURITY
• 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)

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Problems encountered
Access to HIV/AIDS Drugs and Diagnostics of
Assured Quality Quality problems (III)

• CHIRALITY / ENANTIOMERIC PURITY Lamivudine
  example (1)
• No information on the stereochemical
  configuration
• 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
  biobatch
• ...

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Problems encountered
Access to HIV/AIDS Drugs and Diagnostics of
Assured Quality Quality problems (IV)

• BIOEQUIVALENCE
• 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?)

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Summary of Identified Deficiencies in all Files
Requiring BE Studies(interim review, 64 files in
total)

• Major deficiencies
• No bioequivalence study performed and no adequate
  justification for not performing a study (32
  files)
• 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
  file)

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Summary of Identified Deficiencies in all Files
Requiring BE Studies(interim review, 64 files in
total)

• Minor deficiencies
• No information on batch size of test product
• Certificate of Analysis of test batch not
  submitted
• In-vitro dissolution profiles not submitted
• for test product
• for reference product
• for different strengths of the same product

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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
  published SERIOUS QUALITY PROBLEMS
• Malaria
• 27 Product dossiers, mainly artemesinin and
  combination products
• List of product(s) published in August 2003
• HOW TO ASSESS?
• Some neither originators nor generics

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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
  finalization

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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
  combination
• no additional clinical studies required

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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!

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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.