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Genotoxic Impurities of Pharmaceuticals

All impurities in medicinal products that exceed the quantity thresholds according to the guideline Q3A of the ICH must be identified by appropriate studies [Guidance for Industry - Q3A Impurities in New Drug Substances, June 2008]. This also applies to degradation products of the impurities that are found in stability tests in this concentration range.
The following studies are recommended for the identification of impurities:

Genotoxicity Studies

  • Ames Test [OECD 471]
  • In vitro Metaphase Chromosome Aberration Assay [OECD 473]
  • mini-Ames (Ames MPF Test)

DNA reactive impurities can be potentially carcinogenic even at low concentrations (below the identification threshold) and must be tested in accordance with the M7guideline of the ICH (M7 Guideline - Assessment and Control of DNA reactive (mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk).

These mutagens are usually determined in a bacterial reverse mutation test, such as the Ames test - (OECD 471). If it is not possible to isolate or synthesise the impurities, or the amount of sample is limited, the guideline recommends a miniaturised test method, such as the Ames - MPF test. If the result of the bacterial mutagenicity test is negative, no further genotoxic testing is necessary. In case of a positive result a further assessment of the impurities would be required.


Genotoxicity Testing for Pharmaceuticals intended for Human Use in the Preclinical Phase

The development and testing of pharmaceuticals goes through many different phases. The investigation of the active compounds for genotoxicity is a legal requirement for product safety and of great importance and for approval of the authorities.

2011 the ICH (International Conference on Harmonization) developed a guideline which describes the testing of new drugs on genotoxicity and interpretation of data. This should be implemented in a next step in the EU, Japan and the United States (Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use S2 (R1), 2011)

The guideline recommends the following procedure for the testing of the active ingredient:

  • Assessment of mutagenicity
    Ames Test [OECD 471] or Ames MPF Test
  • Assessment of genotoxicity in mammalian cells in vitro
    in vitro Metaphase Chromosome Aberration Assay [OECD 473]
    in vitro Micronucleus Test [OECD 487]
    in vitro Mouse Lymphoma Cell Gene Mutation Assay (MLA)[OECD 490]
    Hypoxanthine-guanine phosphoribosyl transferase Test: HPRT Test [OECD 476]

In case the results of the in vitro studies are positive two further in vivo studies are required!

  • Assessment of genotoxicity in mammalian cells in vivo
    in vivo Micronucleus Test
    in vivo Chromosomal Aberration Test
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