FDA Extends Nitrosamine Timelines

USFDA has allowed drug manufacturers additional time for submission of mitigation actions and required changes for nitrosamine impurities as recommended under RAIL guidance.

In August 2023, FDA issued the RAIL guidance (Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)  with recommended acceptable intake limits for NDSRIs. FDA’s Nitrosamine Guidance introduced and elaborated a three-step mitigation strategy for nitrosamines in drug products

1. Conduct risk assessments for nitrosamines in APIs and drug products;
2. Conduct confirmatory testing if risks are identified; and
3. Report changes implemented to prevent or reduce the presence of nitrosamine impurities in APIs and drug products in approved and pending NDAs and ANDAs.

The RAIL guidance recommended that confirmatory testing for drug products at risk of NDSRI contamination and submission of related changes be completed by August 1, 2025. While the FDA continues to emphasize this target date, it is now allowing additional time for applicants to submit the required changes. The update is published on the FDAs webpage CDER Nitrosamine Impurity Acceptable Intake Limits

Applicants not able to submit the necessary changes by the timeline should provide a progress report by 1 August 2025 which 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),
• A description of attempts to mitigate identified NDSRIs, if mitigation is necessary, and
• An estimate of the timeframe when mitigation will be completed

This information should be included in the Annual Report (AR) where the AR due by August 1, 2025. If the AR for this cycle has already been submitted, applicants should update the Log of Outstanding Regulatory Business section in the AR to include the information on the FDA’s nitrosamine-related recommendations.

Manufacturers of non-application products (e.g., OTCs), who typically do not submit annual reports, are also expected to prepare a progress update and retain documentation for FDA review upon request.

References:

• FDA June 23, 2025 Update on Control of Nitrosamine Impurities in Human Drugs
• FDA Rail (Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) Guidance (August 2023)
• FDA Nitrosamine Guidance: Control of Nitrosamine Impurities in Human Drugs