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Mirabilis: Prediction and assessment of purge factors for potentially mutagenic impurities in a chemical process

pdf fileBurns MJ; Hill (Murphy) NS; James LJR; Stalford SA; Ott MA; Sanchez-Ruiz A; Patel ML;

The presence of potentially mutagenic impurities (PMIs) is heavily regulated in the manufacture of drug substances.

  • Highly reactive functional groups such as aromatic amines, primary alkyl bromides and epoxides are commonly assumed to be PMIs, but are common to many synthetic approaches due to this reactivity and the high utility this creates.1
  • The ICH M7 guideline defines the measures and controls that must be observed for DNA-reactive impurities in pharmaceutical agents. Control option 4 in the guideline indicates that the use of scientific principles and prior knowledge of chemical reactivity may be used as a suitable control in conjunction with some form of quantitative assessment in lieu of analytical testing.2
  • In practice, PMIs encountered during synthesis may require no analytical testing to determine their presence in the final product, if it is demonstrated that the process involved can reasonably be expected to purge the PMI through chemical and/or physical means. The same reactivity that necessitates their inclusion in a synthetic route may also excuse them from analytical testing.
  • Purge factors were introduced by Teasdale et al.3,4 as a measure of the carryover of a PMI based on key physicochemical properties including reactivity, solubility, volatility and physical processes (e.g. chromatography). A multiplication of the purge factors for each step would yield a total purge factor for the given PMI across the whole process.3,4
  • Mirabilis is web-based software designed to standardise the application of these purge factors across industry and facilitate submission to regulators.
    Crucially, Mirabilis takes a conservative approach and will deliberately under-predict the true purge factor to act as a fail-safe.

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