FDA Softens August 2025 NDSRI Deadline—Progress Reports Now Accepted

Recently, FDA announced a deadline shift, although the Agency did so quietly.  On June 23, 2025, FDA updated its CDER Nitrosamine Impurity Acceptable Intake Limits webpage to permit manufacturers and sponsors more time to submit required changes for nitrosamine drug substance‑related impurities (NDSRIs) for approved or currently marketed products.  The Agency confirmed that it will now accept progress reports in lieu of full compliance by August 1, 2025, and has explicitly asked sponsors to detail their mitigation efforts in their upcoming annual or amended annual reports.  21 C.F.R. § 314.81(b)(2).

What does this mean?

• Confirmatory testing remains due by August 1, 2025, but FDA has now acknowledged that full implementation of mitigation strategies—such as reformulation or the addition of new specifications—may take longer.
• For firms unable to meet the deadline, progress updates must be submitted by August 1, 2025.
• These updates should be included under a new section titled “NDSRI Update” in the Log of Outstanding Regulatory Business (eCTD 1.13.14) within the annual report—or submitted as an amendment if the company’s annual report for the year has already been filed.

What should be included in the progress report?

FDA has provided a clear checklist for the updates, which must address:

1. Whether NDSRIs can form under forced degradation;
2. The specific NDSRIs detected;
3. Nitrosamine test method(s) with validation information;
4. Product batch(es) analyzed, with dates relative to manufacture;
5. Confirmatory test results (in ng/day or ppm);
6. Root cause of impurity (if known);
7. Mitigation strategies undertaken; and
8. Estimated timeline for completing mitigation.

Per FDA’s update, non-application products without annual report requirements should prepare similar documentation and retain it for FDA inspection requests.

Why FDA changed course

During the April 2025 Generic Drugs Forum (beginning at the 2:38 mark), FDA officials reasserted the August 1 deadline—but also hinted at flexibility in cases of product shortages or technical challenges.  The June 23^rd decision to extend the deadline reflects FDA’s recognition that nitrosamine mitigation strategies vary widely and can demand extensive time and supply‑chain adjustments.  Further, determining the root cause of the nitrosamine source/contamination as well as gathering stability data for reformulation can be difficult and lengthy undertakings.  In addition, the sponsor or manufacturer will need data on nitrosamine buildup over at least part of the dating period to assess whether the levels (ng/day) are problematic.  All of these efforts require much time and many resources.

So, what does this update mean?

• FDA committed to reviewing all progress reports submitted by August 1 and stated that it may issue revised target timelines based on these reports.
• The Agency continued to emphasize that confirmatory nitrosamine testing should be completed even if mitigation lags behind.
• FDA pledged to update its online guidance periodically with new timelines, methods, and scientific insights.

The bigger picture

FDA’s updated approach toes a careful line—enforcing public safety by mandating confirmatory tests and acceptable intake standards, while also avoiding drug shortages by allowing more time for companies to adjust and adapt.  For example, if FDA were to take action now, many generic drugs products could be taken off the market given that the cancer risk is assessed over a 70 year-period.  See FDA, Guidance, Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) at 4 (Aug. 2023); FDA, Guidance, Control of Nitrosamine Impurities in Human Drugs at 12 (Sept. 2024).

Such action would provide little public benefit.  Rather, FDA’s update aligns with the Agency’s ongoing nitrosamine strategy since 2018, which has tackled contaminants in APIs such as ranitidine, metformin, and valsartan.  Coupled with the aforementioned August 2023 NDSRI guidance on acceptable intake limits, testing, and mitigation frameworks and the September 2024 guidance on the control of NDSRIs, this update offers a pragmatic pathway forward for manufacturers.

What should industry do?

• By August 1, 2025:
  • Complete confirmatory testing for at-risk products.
  • Submit the required changes to drug applications via a Prior Approval Supplement or a detailed progress report in your annual report or amended annual report if you have already submitted an annual report for this yearly cycle.
• Continue to move forward on developing and implementing mitigation plans.
• Monitor FDA communications, including the aforementioned webpage, as the Agency may put forth revised timelines and new/revised guidance based on submissions.

Food for thought

FDA’s decision to accept progress reports offers crucial and practical relief for manufacturers and sponsors racing against this looming deadline.  However, this flexibility comes with responsibility:  companies must maintain transparency, complete rigorous testing, and accelerate root cause investigations and mitigation strategies to protect patient health.

We recommend a proactive approach—prioritize preparing now for both documentation and real-world process changes that can help you remain compliant and competitive—and HPM is here to help.