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Acceptability of Low Levels of Genotoxic Impurities in New Drug Substances

Case Reports
  • Bernard Leblanc
  • Claude Charuel
  • Warren Ku
  • Ron Ogilvie
Case Report Series

Abstract

The Safety Working Party (SWP) of the European Committee for Proprietary Medicinal Products (CPMP) published a draft “Position paper on the limits for genotoxic impurities” in December 2002. Genotoxic impurities was a topic selected for the joint Drug Information Association (DIA)/European Medicines Agency (EMEA) meeting that was organised in London on October 27–28, 2003, to facilitate the exchange of opinion and perspective between industry and regulatory scientists. Scientific and regulatory updates were presented and discussed in the light of case studies, which are described in this article. The four cases span a range of different scenarios that can be encountered in development: (i) candidate for life-threatening indication — an alkylating reagent used in synthesis is an impurity in the active substance; (ii) late-stage candidate for non-life-threatening chronic indication — a route change leads to a new intermediate becoming a potential impurity — as it is an isolated intermediate, worker safety data is generated and needs to be risk managed; (iii) late-stage candidate for non-life-threatening chronic indication — a mutagenic and structural-alerting starting material — the commercial route confers excellent purging; and (iv) early-stage candidate for non-life-threatening chronic indication — considers strategic approaches for impurities with structural-alerting functionality under different scenarios (dependent upon toxicological data available, daily dosing regimen, route of delivery etc.).

The outcomes of the discussions of the cases at the DIA/EMEA Workshop are presented in a separate article in this issue of the journal.

Keywords

Drug Substance Ames Test Genotoxicity Test Carcinogenicity Study 50kg Patient 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors would like to thank Dr Peter Kasper and Dr David Kirkland for their invaluable comments and suggestions when reviewing the case studies.

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Bernard Leblanc
    • 1
  • Claude Charuel
    • 1
  • Warren Ku
    • 2
  • Ron Ogilvie
    • 3
  1. 1.Pfizer Global Research and DevelopmentAmboiseFrance
  2. 2.Pfizer Global Research and DevelopmentGrotonUSA
  3. 3.Pfizer Global Research and DevelopmentSandwichUK

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