FDA Update: Revised Implementation Timelines For Nitrosamine Impurities (June 23, 2025)

On June 23, 2025, the FDA updated its guidance on nitrosamine impurities in drugs. This mainly affects the “Recommended Implementation Timelines” (Table 4) on the CDER Nitrosamine Impurity Acceptable Intake Limits webpage.

The update gives extra time for drug companies to check, control, and reduce nitrosamine impurities in their products because this process can be complex and take a lot of resources.

Key Change: New Timelines

Earlier, the FDA asked companies to complete confirmatory testing and submit required CMC changes by August 1, 2025.

Now, if companies can’t finish everything by this date, they should submit a Progress Update by August 1, 2025 instead.

• This update is called “NDSRI Update”.
• It should go in the Annual Report, section eCTD 1.13.14.
• If the Annual Report is already submitted, submit a revision.
• Next Annual Report deadlines stay the same.

What the Progress Update Should Include

The FDA expects companies to provide:

• Whether nitrosamines form during forced degradation tests
• Which nitrosamines were detected
• Validated test methods for nitrosamines
• Batch and test details (which lots tested, test dates)
• Confirmatory test results (ng/day or ppm)
• Root cause analysis, if available
• Mitigation strategies being used
• Estimated timeline for full implementation

If some details aren’t available, explain why with scientific justification.

For products not requiring Annual Reports, companies should still keep documentation ready for inspection.

Extra Notes for Some Applicants

• Companies using interim acceptable intake limits (Table 3) should also submit a Progress Update by August 1, 2025.
• This helps the FDA decide if the interim limits timeline should change.

Updated Implementation Table (Simplified)

What the FDA Guidance Now Covers

The June 2025 update also revised:

• Acceptable Intake (AI) Limits for some nitrosamines based on:
  • Carcinogenic Potency Categorization Approach (CPCA)
  • Compound-specific or surrogate data
• Interim AI Limits
• Analytical methods for confirmatory testing
• Safety testing methods
• Other scientific and technical points

The FDA recognizes that not all companies can finish mitigation by the original deadline.

What This Means for Companies

• The August 1, 2025 deadline is now about testing and progress updates, not full completion.
• Companies must document the current stage and actions taken.
• FDA will review updates and adjust timelines as needed.
• Be transparent in Annual Reports to show regulatory responsibility and avoid compliance issues.

Next Steps for Companies

Before July 31, 2025:

1. Prepare a summary of nitrosamine assessments and mitigation plans.
2. Ensure analytical methods are validated (or explain limitations).
3. Submit the NDSRI Update via the Annual Report or a revised submission.
4. Keep documentation ready for non-application products.
5. Include updates on interim AI limits, if applicable.

Final Thoughts

This FDA update shows a balanced approach:

• Protect patients
• Give companies realistic timelines

The NDSRI Update acts as a bridge between testing and full implementation.

Companies should act quickly and transparently to ensure compliance and build trust with the FDA. More guidance from the FDA is expected after reviewing the August 2025 submissions.