FDA deadline update
Consider me surprised. I figured if a delay was coming, it would have already happened. How are we understanding this? Only delays in mitigation and control are allowed or any delay, with justification?
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For those applicants unable to submit the necessary changes within this timeline, provide a progress update as described below by August 1, 2025.
The progress update should include the following information:
- 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
Note: If you cannot provide responses to the information requested above, submit justification.
I think delays are allowed with justification. I am interested that FDA intends to update the duration of the interim limits in Table 3.
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That’s how I’m understanding this, too
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Welcome the flexibility … I hope I am capturing all the changes here:
What actually changed?
| Item | Original expectation | After FDA’s 23 June 2025 communication |
|---|---|---|
| Confirmatory testing & risk evaluation | Complete testing for at-risk products and decide on mitigation by 1 Aug 2025 | No change – FDA “reiterates” this date. |
| Submission of CMC changes (specs, reformulation, etc.) | Same 1 Aug 2025 target implied in 2024 guidance | FDA now concedes many strategies will take longer; if you cannot file by 1 Aug 2025 you must instead file a progress update (see below). |
| Progress update requirement | Not previously required | Required by 1 Aug 2025 in lieu of completed supplements; content detailed below. |
| Future timeline for full implementation | Not provided | FDA will issue a “revised targeted timeline” after reviewing the August progress updates. |
Minimum content of the “NDSRI Update” (to be placed in eCTD section 1.13.14)
- Forced-degradation outcome – do targeted studies show the API can form an NDSRI?
- Which NDSRI(s) were detected (name/identifier).
- Validated analytical method used (or method in validation).
- Batches & dating – list lots tested and the time gap between manufacture and analysis.
- Quantitative results (ng day-1 or ppm).
- Root cause (if known).
- Mitigation actions already taken (e.g., lower nitrite spec, reformulation).
- Estimated completion date for full mitigation.
- Justification if any element above cannot yet be provided. [fda.gov]
Practical next steps for companies
- Gap check this week
- Verify whether complete CMC supplements can still be filed by 1 Aug. If not, switch resources to compiling the progress update.
- Lock the analytical package
- Even partial method validation data are acceptable so long as limitations are transparent in the Update.
- Document decision logic
- Capture why a specification change, reformulation, or alternate supplier path was chosen; you will need this in the eventual supplement.
- Coordinate cross-functionally
- Regulatory Affairs should draft the eCTD Update; QC/Analytical provides data; Manufacturing/CMC confirms mitigation timeline; Quality Assurance signs off.
- Forecast supply risk
- If mitigation timelines threaten supply continuity, begin communication with FDA’s drug-shortage staff early (the Update should flag this).
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Well said. This was what I was thinking, too
Interestingly, the footnote related to this item in the update refers to guidance that talks about forced degradation performed on the drug product instead of API, it is unclear if nitrosatability studies directly on API are acceptable? Possibly they do not only want to see the answer to this question, but also how it translates to a DP matrix.
“For example, in instances where formation of nitrosamine impurities may occur through nitrosation of the API or API fragments, such as the NDSRIs that are identified by FDA in the nitrosamine guidance web page, a manufacturer or applicant may demonstrate in the risk assessment that subjecting the drug to nitrosating conditions (i.e., targeted forced degradation) will not form nitrosamine impurities in the drug product.”
See ** → section V.A of: Nitrosamine final guidance = quote above.
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More than ever, the work from Ashworth et al. is so relevant.
Conditions Proposed as standard for nitrosation exploration
Condition 1
Charge the potentially vulnerable amine as a free base or salt and acetic acid to a reaction vessel. The volume of acetic acid should be around 30% of the total final reaction volume. To the reaction vessel, charge an aqueous solution of sodium nitrite (1.5 equiv). The target reaction concentration is 0.1 M with respect to the input amine. The reaction mixture should be held at a temperature of 20–25 °C with a minimized and static headspace to avoid NOx depletion and sampled after 1, 4, and 24 h for analysis. The reaction mixture may be a slurry; care should be taken to ensure that the reaction mixture is sufficiently agitated. To avoid side reactions, no additional cosolvents should be used. The large excess of acetic acid used will ensure no significant impact on reaction pH from the charge of the amine, amine salt, or nitrite.
Example: N-Methylaniline (107 mg, 1 mmol, 1 equiv) was weighed into a 20 mL vial equipped with a stir bar. Acetic acid (3 mL) was added to the reaction vial. An aqueous solution of sodium nitrite (103 mg, 1.5 mmol, 1.5 equiv in 7 mL of water) was added to the reaction vessel, resulting in a reaction concentration of 0.1 M. The reaction mixture was held under agitation at 20–25 °C with a static headspace and was sampled after 1, 4, and 24 h for analysis.
Condition 2
Charge the potentially vulnerable amine as a free base or salt to a reaction vessel. Add water followed by dilute aqueous hydrochloric acid to obtain a pH between 3 and 4. If the substrate is the salt of a strong acid, addition of hydrochloric acid may not be required to obtain the desired pH. If the addition of hydrochloric acid is not required, charge 1 equiv of sodium chloride to the reaction vessel instead to ensure presence of chloride ions. To the reaction vessel, charge an aqueous solution of sodium nitrite (1.5 equiv) and adjust the pH to 3–4 with dilute HCl if required. The target reaction concentration is 0.1 M with respect to the input amine. The reaction mixture should be held at a temperature of 20–25 °C with a minimized and static headspace to avoid NOx depletion and sampled after 1, 4, and 24 h for analysis. At each sampling point, the pH should be checked and adjusted with dilute HCl if necessary to maintain the desired range of pH 3–4. The reaction mixture may be a slurry; care should be taken to ensure that the reaction mixture is sufficiently agitated. To avoid side reactions, no additional cosolvents should be used.
Example: N-Methylaniline (107 mg, 1 mmol, 1 equiv) was weighed into a 20 mL vial equipped with a stir bar. Water (5 mL) was added, and the pH was checked. In the case of pH > 4, the solution pH was carefully adjusted to pH 3–4 using 1 M aqueous HCl. An aqueous solution of NaNO2 (103 mg, 1.5 mmol, 1.5 equiv in 4 mL of water) was then added. The target reaction concentration was 0.1 M. The reaction mixture was held under agitation at 20–25 °C with a static headspace and was sampled after 1, 4, and 24 h for analysis.
Condition 3
Charge the potentially vulnerable amine as a free base to the reaction vessel and add an organic aprotic solvent that solubilizes the amine (for example, acetonitrile, THF, or DCM). To the reaction vessel add tert-butyl nitrite (1.5 equiv). The target reaction concentration is 0.1 M. The reaction mixture should be held at a temperature of 20–25 °C with a minimized and static headspace to avoid NOx depletion and sampled after 1, 4, and 24 h for analysis.
These reactions can usefully be performed with deuterated solvent in an NMR tube with a Young’s tap closure to enable real-time monitoring of the reaction by NMR if desired. Use of the amine free base allows the exploration of neutral nitrosation conditions in organic media.
Example: N-Methylaniline (107 mg, 1 mmol, 1 equiv) was weighed into a 20 mL vial equipped with a stir bar. DCM (10 mL) was added. tert-Butyl nitrite (155 mg, 1.5 mmol, 1.5 equiv) was charged. The reaction mixture was held under agitation at 20–25 °C with a static headspace and was sampled after 1, 4, and 24 h for analysis.
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We’ve had really good luck with the t-butyl nitrite. Highly recommend the paper below.
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Has been translated to the EFPIA/IQ NAP recommendations, question is though if we now really have to extrapolate such (and other stress testing protocols proposed) to the drug product or if this really an exemplary suggestion in the FDA guidance.
Let’s not forgot the incident with Vonoprazan on 2023…
I think FDA has realized that nitrosamines are not a life cycle issue. It should have been addressed during approval of the drugs. Also, by stressing certain limits in marketed products they are showing their jugular. None of us know what levels of nitrosamines were present pre-2018 in these thousands of products. So, they are basically giving a break to the marketed products. However, they are going to be very strict with products which are still in the process of being approved.
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NDSRIs standards are not commercially available; therefore, the Applicant has to commence the trials to synthesize the impurities (if possible) and characterize them as a reference standard. As per health authorities’ guidance, in some cases, if, despite extensive efforts, it becomes apparent that the relevant nitrosamine impurity cannot be synthesized, then this could be an indication that the nitrosamine either does not exist or that there is no risk of it being formed. Therefore, I think additional forced degradation is not required to ascertain whether NDSRIs can form.
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I would agree. When done properly, this work could support the claim that the NDSRI does not form.
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