TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD MANUFACTURING PRACTICE AND BIOEQUIVALENCE WITH A FOCUS ON ARTEMISININS

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TRAINING WORKSHOP ON PHARMACEUTICAL QUALITY, GOOD
MANUFACTURING PRACTICE AND BIOEQUIVALENCE WITH A
FOCUS ON ARTEMISININS

• Introduction
• Efficacy and Safety Issues

Hans Kemmler Consultant to WHO White Sands,
23.Aug. 2006
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The Prequalification Project

• The Prequalification project, set up in 2001, is
  a service provided by the WHO to facilitate
  access to medicines that meet unified standards
  of quality, safety and efficacy for HIV/AIDS,
  malaria and tuberculosis.

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Overview

• Defining efficacy and safety of a medicine
  (finished pharmaceutical product FPP)
• Dossier requirements
• Use of guidelines

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Defining Efficacy and Safety
The Clinical Quality of a Medicine
Efficacy and safety of the active ingredient
Information on the appropriate and safe use
Galenical formulation
All aspects are assessed during prequalification
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Efficacy and Safety of the Active Ingredient

• Investigated and documented in preclinical and
  clinical trials of possibly different
  galenic formulations

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Galenic Formulation

• Has an influence on e.g.
• Bioavailability
• Best active ingredient will be of no use if
  contained in a stainless steel capsule
• (local) tolerability

Because different formulations can have different
bioavailability or tolerability, the information
about which formulation has been used in which
trial(s) is essential for the assessment of the
FPP.
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Information on the Appropriate and Safe Use

• Best active ingredient in best galenical
  formulation will be of no use if used for wrong
  condition, e.g. antimalarial used to treat
  headache
• It will be even dangerous if safety relevant
  information is not complete

Information in SPC and PIL must be justified by
and referenced in the documented evidence.
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Dossier requirements

• Manufacturers interested in participating in the
  prequalification project have to submit a product
  dossier for assessment
• The product dossiers have to contain the required
  data and information as stipulated in the
  Prequalification Project Guidelines (Presentation
  Dr. Sterzik)
• Guidelines available http//mednet3.who.int/prequ
  al/ (all on CD-ROM 1)

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Prequalification Requirements for Finished
Pharmaceutical Products (FPPs)

• Website WHO (http//mednet3.who.int/prequal/defau
  lt.htm)
• Manufacturers are requested to submit a covering
  letter, sample and product dossier (generics --
  innovator) including a completed checklist.
• Generics If innovators exist and are approved
  Bioequivalence study, assessed with WHO Technical
  Report 937 WHO EXPERT COMMITTEE ON
  SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS
  TRS 937
• Innovator What data and information needs to be
  submitted in a dossier for an innovator product?

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Artemisinin - Innovators?

• What data and information needs to be submitted
  in a dossier for an innovator product?
• For innovator products, registered/licensed in
  the USA, EU or Japan Submit the following
  information
• A WHO-type Certificate of a Pharmaceutical
  Product issued by one of the regulatory authority
  of ICH regions (or other stringent regulatory
  authorities), together with the summary of
  product characteristics (SmPC)
• Assessment report(s) issued by the respective
  regulatory authority
• ........
• Does not apply to most of FPP for which
  Expression of Interest was invited

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Dossier requirements

• Particulars for artemisinin containing FPP
• Note to applicants expressing interest for
  supplying artemisinin-containing drug products
• Because all products on current Expression of
  Interest list are combinations, the consideration
  of the combinations guideline is of utmost
  importance
• Guideline for registration of fixed-dose
  combination medicinal products
• (WHO Technical Report Series No. 929, 2005)

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Focus of Todays Lectures

• Artemisinins based generics
• Orally applied products on the EoI-List All are
  combinations
• Artesunate amodiaquine
• Artemether/lumefantrine
• Artesunate mefloquine
• Artesunate sulphadoxine/pyrimethamine

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Wanted for BE-Studies

• A generic FPP
• An acceptable comparator
• BUT Choice of comparator is not trivial
• On WHO-Prequalification Project Website follow
  Selection of comparator product Note to
  Applicants on the Choice of Comparator Products
  for the Prequalification Project (on CD-ROM 1)
• One big problem still to be solved Only one of
  the combinations is already approved in ICH
  region and prequalified Not a topic today

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Use of Guidelines

• Guidelines are guidances, no law
• But
• It should be apparent that the relevant
  guidelines are known
• deviations from guidelines should be based on
  scientific justification
• Guidelines make life easier
• especially for applicants

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Use of Guidelines

• No presentation, no training course can help to
  avoid the thorough study of guidelines
• To find all relevant guidelines is - to some
  degree - an art
• WHO website provides an excellent starting point

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Where to Find Guidelines

• In previous and following presentations some
  references to guidelines are given
• in distributed material (CD-ROMs) many more are
  included or referenced
• see in particular the presentations of the
  previous workshop (Kiev, 2005, on CD-ROM 1) for
  many additional references in particular relevant
  for bioequivalence studies

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Other Useful Documents

• On the accompanying CD-ROM 2 will be a complete
  and detailed Table of Contents (TOC) for a
  bioequivalence study report
• In my opinion, a very valuable help for
  scientists intending to conduct such a study
• also useful for other study reports to give an
  idea about the detailedness of a Full Study
  Report

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Other Useful Documents

• Also on CD-ROM 1 Annex 7 (a template)
  Presentation of bioequivalence trial
  information
• Together with the TOC, these documents should, if
  properly populated, help to avoid gt90 of
  currently encountered deficits in submitted
  bioequivalence trials

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Other Useful Documents

• WHO Guidelines for registration of fixed-dose
  combination medicinal products !!! (see CD-ROM 1)
• Sample analysis for a comparative bioavailability
  study (see CD-ROM 2, and general hint If
  questions about BE-studies arise, the website of
  the Canadian health authority should be one of
  the first places to look at)

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Difficulties in understanding

• Delays in prequalification by lack of mutual
  understanding
• Not only language problems, but
• same words have different meanings for people
  with different previous experience e.g.A full
  study report is obviously something different
  for an European assessor and for an employee of a
  Chinese company. This doesnt mean that one is
  right and the other not!!!

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Difficulties in understanding

• Talking and asking helps a lot, therefore one of
  our intentions for this workshop
• Less presentations about something which is
  better read anyway
• More time for discussion

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Finally The bare necessities

• Apart from the intrinsic efficacy/safety of the
  active ingredient, the bioavailability is THE
  clinical quality mark of a FPP, therefore
• Without pharmacokinetic characterisation in
  humans,
• either through Phase I Studies for innovators or
  through bioequivalence studies for multi-source
  products
• no Finished Pharmaceutical Product will pass the
  prequalification.

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Thank you For inviting usFor listeningFor many
questions