The FDA has updated the original nitrosamine impurity guidance after publication last year of Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) (here), also known as the RAIL guidance, caused a few disconnects between the two guidances. Now that we’ve all had more time to carefully read and absorb the updates in the revised, overarching nitrosamine guidance, it seems that the oft-discussed global harmony on this topic is still no closer to reality.
The previous Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry (Revision 1, February 2021) has been significantly rewritten and updated in Revision 2, which can be accessed here. We posted a blog with information from the Federal Register notice on the changes last Wednesday (here). The latest revision does more to incorporate and explain small-molecule impurities and NDSRIs as well as offer more clarity on approaches to risk assessment, testing, specification setting, and handling changes; this updated guidance, the RAIL guidance, and the companion FDA webpage provide more cohesive guidance on nitrosamine impurities from the FDA than ever before.
The revision of the guidance includes a rewrite in order to provide more background on the formation of nitrosamines and potential root causes of formation to assist with assessing the risk posed by APIs and drug products for both small-molecule nitrosamine impurities and NDSRIs. A section on Acceptable Intake (AI) limits and recommendations for control and mitigation strategies incorporates detailed recommendations for API manufacturers separate from drug-product manufacturers as well as how to implement controls using the recommended AIs, including an example control strategy and specification limits for a theoretical product with multiple nitrosamine impurities. The details provided may be helpful to the many applicants who have been struggling with the initial risk assessment process or with how to formulate a control strategy based on their confirmatory testing.
With this added clarity also comes an admission from the FDA that its recommended AIs may differ from those of other regulatory agencies as well as a reminder that products for the U.S. market should reference the AI limits recommended and published by the FDA. This wording was added to the Recommended Safety Testing Methods for Nitrosamine Impurities section of the FDA’s website (here), which was also updated on September 4th. This webpage acknowledges that the FDA understands its position that a negative result in an in vivo mutagenicity study, potentially not supporting an AI limit equal to the qualification thresholds in ICH Q3A (R2) and Q3B (R2), differs from those of other regulatory agencies. Acknowledging differences is half the battle in overcoming them, but the FDA is likely to stick to its current thinking for a while as conducting these tests takes time, so the road to harmonization is likely to be longer. Companies developing new products intended to be offered in multiple markets may need to control nitrosamine impurities to the tightest global AI limit or work with the health authorities in their chosen markets in order to accept a harmonized control strategy and AI limit.
As the science around nitrosamine impurities continues to evolve, recommended AIs will continue to be updated as the FDA receives and reviews new data; discrepancies between the FDA and other health authorities are likely to persist for a while longer as each authority reviews and reacts to data provided to them for review. If you have any questions about risk assessments for nitrosamine impurity formation in your firms’ products or how to handle the changing recommendations, please reach out to Lachman Consultants at LCS@LachmanConsultants.com.
