Genotoxic impurities are compounds that have the potential to cause detrimental effect on cells by destroying or altering chromosomes, causing cell mutations. These mutations can sometimes be serious thereby causing malignancies that can be multi-stepped in their condition causing severe damage to the health of the consumer. These malignancies can be involved in tumor genesis or aneuploidy in germ cells which may give rise to inherited diseases such as cancer.

To limit potential carcinogenic risk, the International Council on Harmonization has harmonized guidelines for impurities. These guidelines provide guidance for the identification, categorization, qualification, and control of these mutagenic impurities.


Sources for such kind of genotoxic materials can be of any kind, with a majority of them coming through the synthetic route for preparation of the final product. Some possible sources are listed below:

  1. Starting materials of the compounds/natural sources of the compounds
  2. Reagents involved in the reactions
  3. Intermediates of the reaction
  4. Solvents used during the preparation of the products
  5. Unwanted side-reactions of the API (active pharmaceutical ingredient) with containers or excipients et cetera
  6. Synthetic process by-products that get carried into the main product
  7. Decomposition products of the active ingredient or excipients
  8. Reactions of the excipients and the container


Genotoxic impurities are present at very low levels, and hence the quantification of these impurities is only possible using the highly sensitive, ‘gold standard’ LC-MS-MS methods.

Importance of Analysis

Genotoxic impurities need to be analyzed at every step to ensure no carry-over into the human system due to their inherent carcinogenic potential. It is now mandatory to submit data to regulatory authorities for statutory approvals.