The industry as a whole rejoiced on Friday with the publication of the new NDSRI guidance from the FDA, previously discussed here.  Now that we all have had more time to carefully read and absorb the details posted by the FDA in the guidance and on the corresponding webpage, many will discover that there are still a few discrepancies from other health authorities as well as a new call to action for manufacturers and application holders in the U.S. 

The new NDSRI guidance builds on the general Control of Nitrosamine Impurities in Human Drugs (Rev. 1, February 2021), also referred to as the Nitrosamines Guidance, accessible here.  The new guidance is specifically focused on NDSRIs or nitrosamine impurities that have a significant structural similarity to the drug substance in a drug product.  These larger molecules have long been argued to have a different, and often lower, carcinogenic potential due to their larger and more complex structure.  The new NDSRI guidance acknowledges these concerns and references the work of the FDA and other health authorities to develop an approach for evaluating the predicted carcinogenic potency based on structural features.  This approach, the Carcinogenic Potency Categorization Approach (CPCA), was first published in July in EMA/409815/2020 Rev. 16 as part of the response to Q&A 10, which also extracted the list of acceptable intake (AI) limits and published them in an annex to the document.  July also saw the publication of an updated version of Health Canada’s Guidance on nitrosamine impurities that adopted the CPCA and an expanded list of AI limits, also provided in an appendix.  Now in early August, the FDA has provided its own version as part of a new guidance and a dedicated webpage focused on NDSRIs.  The lists of AIs provided by each health authority have some subtle differences and the FDA chose to keep the 26.5 ng/day lower limit, rather than the 18 ng/day used in Europe and Canada, but there is a much bigger difference that followers of the nitrosamines saga should have noted. 

I like that the FDA chose to focus a new and separate guidance on NDSRIs rather than incorporating these impurities into the existing guidance as other health authorities have done.  These impurities generally do not pose the same risk as the simple nitrosamines listed in the original Nitrosamines Guidance and, as the science has evolved, it is refreshing to see that the FDA’s approach to these impurities has also evolved, and the Agency now asks the same of drug product manufacturers.  It may have gone unnoticed in the first reading of the guidance, but by providing an NDSRIspecific guidance, the FDA has also provided a new timeline for assessment and control of these nitrosamine impurities separate from the previous timeline.  Section V of the NDSRI guidance notes that the previous timelines in the Nitrosamines Guidance do not apply to NDSRIs, and a new timeline is outlined for assessment, confirmation, and submission of changes to address NDSRIs.  The FDA is asking firms to do quick assessments of risk for NDSRI formation through review of their original risk assessments to ensure that NDSRIs were considered, or to reevaluate the risk of NDSRI formation by November 1, 2023.  If a risk of NDSRI formation is identified, then manufacturers and applicants are directed to move into confirmatory testing as soon as possible, with submission of any required changes to their drug product applications by August 1, 2025.  This extension is more than the six months originally proposed in the nonrulemaking docket that the FDA opened in early May, and is in line with the comments received that answered this question, which is evidence that the FDA was listening. 

It seems unlikely that we will see complete agreement across the major regulatory agencies globally on a topic as complex as nitrosamine impurities, but the extended timelines and other updates in the new guidance are confirmation that the FDA has adapted with the updated scientific information that has continued to be produced on this subject, and is taking rational steps for the assessment and control of NDSRIs. 

There isn’t a lot of time to ensure that your risk assessment for nitrosamine impurity formation is in alignment with both FDA guidances, but it is good to see that the FDA has provided an updated timeline to ensure that risk of NDSRIs is appropriately assessed.  By publishing a new standalone NDSRI guidance, the FDA has provided a clear, structure-based framework for setting AI limits for performing confirmatory testing, and the Agency has provided additional time for manufacturers and applicants to update their applications for control of NDSRIs.  If you have any questions about risk assessment for NDSRI formation in your firm’s products, please reach out to Lachman at