On June 23, 2025, the U.S. Food and Drug Administration (FDA or Agency) published an important update regarding nitrosamine impurities. While FDA still encourages companies to complete confirmatory testing for products with a risk of nitrosamine drug substance-related impurity (NDSRI) formation and submit necessary changes to the Agency by August 1, 2025, this update clarifies that the Agency is allowing additional time for companies to submit required changes related to nitrosamine impurities. Instead of submitting changes by August 1, 2025, the update clarifies that companies should submit progress reports on assessing and mitigating the risk of nitrosamine impurities by August 1, 2025.
This important update recognizes that nitrosamine mitigation strategies vary depending on the specific product and strategy, with some products potentially requiring reformulation or addition of a specification. Such changes can have broad implications for supply chains, and the extended deadline to submit and implement changes provides manufacturers additional time to address and address these supply chain challenges.
The update also provides guidance on how to submit progress reports and what to include in such reports. Specifically, applicants should include
- determination of whether NDSRIs can form under targeted forced degradation
- NDSRI(s) detected
- nitrosamine test method with validation
- product batch(es) analyzed and date analyzed relative to date of manufacture
- confirmatory test results for NDSRI(s) in the drug product (in ng/day or ppm)
- root cause (if known)
- description of attempts to mitigate identified NDSRIs, if mitigation is necessary
- estimate of the timeframe when mitigation will be completed
This information should be submitted to FDA as an “NDSRI Update” in the Log of Outstanding Regulatory Business section (eCTD 1.13.14) of the Annual Report (AR).
For an AR that has been submitted for this yearly cycle, FDA instructs applicants to revise the Log of Outstanding Regulatory Business section to include the recommended information on the progress in completing the recommendations from FDA’s nitrosamine guidance.
Manufacturers of nonapplication products, including monograph products, should prepare a progress update and retain the documentation so it is available upon request.
This update reflects FDA’s continued focus on nitrosamine impurities and suggests that manufacturers should continue performing nitrosamine impurity risk assessments and confirmatory testing and developing mitigation plans to address any nitrosamine impurity risks identified. Such nitrosamine impurity risk assessments have been the focus of several recent FDA and other health authority inspections.
The update also acknowledges that the risk assessments and related action plans are time-consuming and likely to affect the pharmaceutical supply chain, potentially causing drug shortages. This underscores the importance of identifying and implementing appropriate interim controls to prevent mitigate nitrosamine impurity risks pending submission and approval of a change plan.
By the end of July 2025, manufacturers should develop a comprehensive summary of activities undertaken to assess products for the risk of nitrosamine impurities and mitigate any risks identified. These summaries are important not just to meet the August 1, 2025 deadline for a progress update to FDA but also to be prepared for any future regulatory inspection.
