The FDA quietly posted an update to the CDER Nitrosamine Impurity Acceptable Intake Limits webpage yesterday.  The latest update is unusual in that it is not an update to any of the posted AI limits, but rather the text added below Table 4 noting that the FDA is allowing additional time for submission of required changes and is requesting a progress report.

As recently as this year’s Generic Drugs Forum, held April 9-10, 2025, it was confirmed that the FDA was holding fast to the August 1, 2025 compliance date (as we previously blogged about here).  However, questions have been raised about industry’s ability to meet the August 1, 2025 date as early as publication of Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs): Guidance for Industry, which first publicized it in 2023.  Whatever precipitated the FDA’s change of heart, it is good to see that the Agency has found a way to request information from application holders to better understand their challenges and expected timelines and to offer a chance to potentially collaborate in the extension.

In the June 23rd update, the FDA requests that applicants provide a progress update and include it in their next annual report (AR), if it is due by August 1st, or provide a one-time revision to the AR if it has already been submitted for this yearly cycle.  The information is to be placed in the in the Log of Outstanding Regulatory Business section (1.13.14 ) of the AR and titled “NDSRI Update.”  The update is requested to include the following information, or justification for not providing the following:

  • 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; and
  • estimate of the timeframe when mitigation will be completed.

For non-application products that are not subject to AR submission requirements, the FDA notes that the update should be prepared and retained so that it is available upon request.  Applicants that are using the interim AI limits described in Table 3 are also requested to provide a progress update by August 1, 2025.  These updates are to support the FDA’s intention to update the duration listed in the table (Table 3) in a future website update.

Hopefully the future website update will also include a revision to Table 4 to allow companies more time to address their outstanding challenges and bring their products into compliance.

In the meantime, if you have questions on nitrosamine impurities, preparing the newly requested NDSRI update, or need further assistance with nitrosamine impurity issues, please email us at LCS@LachmanConsultants.com for a consultation.