EDQMs Contributions to 3R

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EDQMs Contributions to 3R

• Karl-Heinz Buchheit
• EDQM
• Brussels, 12 October 2006

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EDQM - Council of Europe

• European Convention for the protection of
  vertebrate animals used for experimental and
  other scientific purposes
• Council of Europe, 1986

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EDQMs Contribution to 3R

• European Pharmacopoeia (Ph. Eur.)
• Official Control Authority Batch Release (OCABR)
• Human vaccines plasma derivatives
• Veterinary vaccines
• Biological Standardisation Programme (BSP)

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European Pharmacopoeia

• II. Introduction
• Use of animals. In accordance with the European
  Convention the Commission is committed to the
  reduction of animal usage, wherever possible, in
  pharmacopoeia testing and encourages those
  associated with its work to seek alternative
  procedures. An alternative or modified method is
  adopted by the Commission once it has been
  clearly demonstrated that it offers satisfactory
  control for pharmacopoeial purposes

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European Pharmacopoeia

• 1.1. General Statements
• The tests and assays described are the official
  methods upon which the standards of the
  Pharmacopoeia are based. With the agreement of
  the competent authority, alternative methods of
  analysis may be used for control purposes,
  provided that the methods used enable an
  unequivocal decision to be made as to whether
  compliance with the standards of the monographs
  would be achieved if the official methods were
  used. In the event of doubt or dispute, the
  methods of analysis of the Pharmacopoeia are
  alone authoritative.

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European Pharmacopoeia

• Ph. Eur. cannot be used as excuse not to
  introduce alternative test

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Ph. Eur. - 3R Examples

• Vaccines Test for abnormal toxicity deleted in
  most cases
• Hormones Bioassay replaced by physico-chemical
  method (e.g. somatropin)
• OPV Introduction of MAPREC test and transgenic
  mouse test for neurovirulence

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OCABR (Human)

• Mutual recognition of results throughout EU no
  need for re-testing
• Possibility to move testing upstream in
  production process (e.g. D T vaccines potency
  assay on final bulk)
• Possibility to waive testing of each final lot in
  case of consistent production

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OCABR - Reduced Testing Schemes

• 3 major OCABR OMCLs involved
• 12 different vaccines are concerned (e.g. potency
  assay for rabies vaccine performed in 1/10th of
  every final bulk)
• Most schemes in place since 2001 w/o any problem

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OCABR (Veterinary)

• Mutual recognition of results no re-testing
• In pilot phase
• Reduced to short-listed vaccines (lt10)
• Vast majority undergoes only review of batch
  documentation

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Biological Standardisation Programme

• Establishment of standards for QC of biologicals
• Validation of alternative methods
• Contribution to International Harmonisation by
  common projects with WHO, FDA, Japanese
  Authorities

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BSP - 3R Examples

• HAV in vitro assay instead of in vivo
• IPV rat assay with reduced number of animals
• D T vaccine serological assay instead of
  direct challenge assay
• Somatropin physico-chemical instead of in vivo
  assay
• Erysipelas vaccine serological assay instead of
  challenge assay
• NDV in vitro rather than in vivo assay

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BSP - Ongoing Projects

• Botulinum toxin replacement of LD50 batch
  potency assay
• Tetanus Ig replacement of in vivo challenge test
  by in vitro assay
• Pertussis vaccine (acellular) serological
  potency assay (same animals as for DT vaccine)
• Erythropoetin replacement of in vivo assay