Genotoxic Impurities

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Today we are going to discuss on the Genotoxic Impurities and its assessments.

The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue.

The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.

In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.

A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals.

From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose. Higher limits may be justified under certain conditions such as short-term exposure periods.

For determination of acceptable levels of exposure to genotoxic carcinogens considerations of possible mechanisms of action and of the dose-response relationship are important components. Based on the above considerations genotoxic impurities may be distinguished into the following two classes:

  • Genotoxic compounds with sufficient (experimental) evidence for a threshold-related mechanism

This approach calculates a “Permitted Daily Exposure” (PDE), which is derived from the NOEL, or the lowest- observed effect level (LOEL) in the most relevant (animal) study using “uncertainty factors” (UF).

  • Genotoxic  compounds  without  sufficient   (experimental)  evidence  for   a   threshold-related mechanism

The assessment of acceptability of genotoxic impurities for which no threshold mechanisms are identified   should   include   both   pharmaceutical   and   toxicological   evaluations.   In   general, pharmaceutical measurements should be  guided by  a  policy of  controlling levels to  “as  low as reasonably practicable” (ALARP principle), where avoiding is not possible.  Levels considered being consistent with the ALARP principle following pharmaceutical assessment should be assessed for acceptability from a toxicological point of view.

A TTC value higher than 1.5 µg/day may be acceptable under certain conditions, e.g. short-term exposure, for treatment of a life-threatening condition, when life expectancy is less than 5 years, or where the impurity is a known substance and human exposure will be much greater from other sources (e.g. food). Genotoxic impurities that are also significant metabolites may be assessed based on the acceptability of the metabolites.

The concentration limits in ppm of genotoxic impurity in drug substance derived from the TTC can be calculated based on the expected daily dose to the patient using equation (1).

(1) Concentration limit (ppm) = TTC [µg/day]/dose (g/day]

The TTC concept should not be applied to carcinogens where adequate toxicity data (long-term studies) are available and allow for a compound-specific risk assessment.


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