Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products

This paper outlines strategies in alignment with ICH M7 for systematically assessing the potential risk posed by mutagenic degradants in active pharmaceutical ingredients (API) and formulated products. A mutagen risk assessment (MRA) process that involves degradation should include results from focused drug substance and drug product stress testing experiments (e.g., at elevated temperature, a wide pH range in solution, oxidative, and photolytic stress) as well as accelerated and long-term stability studies in the solid-state. While the MRA may include hypothetical (theoretically predicted) degradation products from computer based and/or knowledge-based approaches, investigations for numerous hypothetical degradation products whose significance have not been verified experimentally should not be initiated based on these results alone. Drug substance and drug product stress (forced degradation) studies should be designed to generate a comprehensive range of potential degradants that encompass all degradation products likely to form under typical ICH storage conditions. As a result of the absence of definitive regulatory guidance covering stress testing (including strategies for impurity identification/elucidation) there are different approaches used within the industry. Three general strategies for triggering structure elucidation of degradants (and hence inclusion in a MRA) are outlined, all of which are consistent with the approaches outlined in ICH Q1A, Q3A/B, and M7. The first approach for triggering structure elucidation is centered around long-term and accelerated stability and ICH Q3A/B thresholds; the second approach focuses on the “major” degradation products and pathways observed during stress testing using an algorithm for defining the threshold for “major” degradation products; the third approach focuses on those degradation products observed during stress testing that meet criteria derived from thresholds that have been scaled from ICH Q3A/B identification thresholds. Regardless of the chosen strategy, it is proposed that only those major degradation products observed at significant levels in stress testing, ICH accelerated, or long-term stability studies be included in the MRA process as this reflects the degradants most likely to be seen in marketed products. Such an approach is consistent with ICH M7. The overall strategy should be based on a risk assessment, where potential degradation products are determined to be either relevant and addressed or irrelevant and excluded from further consideration. The approaches described herein provide an appropriate framework to assess the risk posed by mutagenic impurities (MIs) arising as a result of either drug substance and/or drug product degradation.