FDA Relents on Thresholds for Mutagenic Impurities in Drug Products with Less-Than-Lifetime Exposures

  • April 15, 2013

By Carrie Rabe

In an effort to limit patient exposure to drug impurities with the potential to cause cancer, the FDA has (with some exceptions) required Sponsors to reduce levels of mutagenic impurities to a level considered to have negligible cancer risk. For years, this level has been uniformly set at a daily intake of 1.5 µg/day regardless of whether a drug is used rarely or daily over most of a patient’s lifetime. Considerable time and effort on the part of Sponsors has been expended testing trace amounts of impurities for mutagenicity and, if found to have mutagenic potential, reducing levels present in drug products so that intake of the impurity would not exceed 1.5 μg/day. On April 12th, the FDA posted on its guidance website, the draft ICH M7 guidance entitled, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. The draft multidisciplinary guidance addresses several facets of the assessment of risk from potentially mutagenic impurities, but is most notable for the extension to marketed drug products of the staged Threshold of Toxicological Concern (staged TTC) concept already applied to drugs in development (see the 2008 draft guidance on Genotoxic and Carcinogenic Impurities in Drug Substance and Products: Recommended Approaches). In this latest draft guidance, the acceptable daily intake for mutagenic impurities in marketed drug products is increased from the uniform rate of 1.5 µg/day to values that take both the total cumulative dose of the impurity and the duration of exposure into consideration. The acceptable intake of mutagenic impurities described in this new draft guidance increases in a stepwise fashion with larger safety factors applied for the shorter duration exposures:


The Weinberg Group has extensive experience with the toxicology issues in drug development and can assist in applying these and other changes described in the guidance.

Carrie Rabe, Ph.D. is a Senior Consultant at The Weinberg Group, the world’s leading food and drug consulting firm. If you have any questions or thoughts on this blog post or others, please contact us.