FDA panel outlines expectations for nitrosamine testing, AI limits and comparator strategies
June 11, 2026 | Human Foods Program, Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA), Department of Health and Human Services (HHS), Executive, Federal
This article was created by AI summarizing key points discussed. AI makes mistakes, so for full details and context, please refer to the video of the full meeting. Please report any errors so we can fix them. Report an error »
FDA scientists used a Session 4 Q&A to clarify agency expectations around nitrosamine impurities, acceptable intake (AI) limits and strategies generics can use when reference listed drugs are unavailable.
On testing and confirmatory evidence, Matthew Vera, supervisory chemist, said when a risk assessment suggests a nitrosamine "in theory" could form but appears difficult in practice, applicants should pursue confirmatory testing and attempt to prepare a reference standard. "So you don't need to prove the absence without a standard," Vera said, adding that inability to make a standard plus literature and experimental evidence can justify a conclusion in the risk assessment.
Panelists also explained why FDA has requested additional data beyond the enhanced Ames assay for some submissions. Shin Fu, a pharmacologist on the panel, said when guidance was published in 2023 the enhanced Ames data were limited and regulators lacked information on how the assay performed for some nitrosamine sources. For that reason FDA requested in vitro mammalian cell mutation assays and metabolism studies "to give us a little bit more confidence about the results," and the agency is actively analyzing submissions to understand discordant findings.
On acceptable intake and specifications, Joanne Chia said AI recommendations are reported in nanograms per day and that, "for purposes of establishing controls, we do recommend that you use the MDD of the API." Chia also said posted interim AI limits are temporary and "should not be proposed as specification limits" because they do not represent final FDA recommended acceptable intake; instead, posted interim limits can represent situations where FDA does not intend to object to distribution.
When a reference listed drug and reference standard are off the market because of nitrosamine issues, Rong Wang said generic applicants "may use another approved product on the market that is confirmed nitrosamine‑free in the BE study." If no suitable approved comparator exists, applicants may consider alternative reference standards (for example, a different dosage form with an established BE relationship) but should consult FDA early to confirm acceptability.
Panelists also addressed harmonization across regulators. Shin Fu said many methodologies have been harmonized, citing the CPC approach and ongoing work on the ICH M7 nitrosamine addendum, but added that regulators do not share confidential submission data and FDA cannot uncritically accept another regulator's conclusions without reviewing the underlying data: "Although there is communication between regulators, regulators don't share the data."
Why it matters: Nitrosamine impurities have prompted product recalls and development delays; clarification of testing expectations, acceptable intake reporting and comparator strategies affects how generics are developed and when they can be distributed.
The session concluded with no policy changes announced; panelists repeatedly encouraged applicants to provide robust, product‑specific scientific justification and to engage FDA early when using alternative comparators or proposing nonstandard approaches.
On testing and confirmatory evidence, Matthew Vera, supervisory chemist, said when a risk assessment suggests a nitrosamine "in theory" could form but appears difficult in practice, applicants should pursue confirmatory testing and attempt to prepare a reference standard. "So you don't need to prove the absence without a standard," Vera said, adding that inability to make a standard plus literature and experimental evidence can justify a conclusion in the risk assessment.
Panelists also explained why FDA has requested additional data beyond the enhanced Ames assay for some submissions. Shin Fu, a pharmacologist on the panel, said when guidance was published in 2023 the enhanced Ames data were limited and regulators lacked information on how the assay performed for some nitrosamine sources. For that reason FDA requested in vitro mammalian cell mutation assays and metabolism studies "to give us a little bit more confidence about the results," and the agency is actively analyzing submissions to understand discordant findings.
On acceptable intake and specifications, Joanne Chia said AI recommendations are reported in nanograms per day and that, "for purposes of establishing controls, we do recommend that you use the MDD of the API." Chia also said posted interim AI limits are temporary and "should not be proposed as specification limits" because they do not represent final FDA recommended acceptable intake; instead, posted interim limits can represent situations where FDA does not intend to object to distribution.
When a reference listed drug and reference standard are off the market because of nitrosamine issues, Rong Wang said generic applicants "may use another approved product on the market that is confirmed nitrosamine‑free in the BE study." If no suitable approved comparator exists, applicants may consider alternative reference standards (for example, a different dosage form with an established BE relationship) but should consult FDA early to confirm acceptability.
Panelists also addressed harmonization across regulators. Shin Fu said many methodologies have been harmonized, citing the CPC approach and ongoing work on the ICH M7 nitrosamine addendum, but added that regulators do not share confidential submission data and FDA cannot uncritically accept another regulator's conclusions without reviewing the underlying data: "Although there is communication between regulators, regulators don't share the data."
Why it matters: Nitrosamine impurities have prompted product recalls and development delays; clarification of testing expectations, acceptable intake reporting and comparator strategies affects how generics are developed and when they can be distributed.
The session concluded with no policy changes announced; panelists repeatedly encouraged applicants to provide robust, product‑specific scientific justification and to engage FDA early when using alternative comparators or proposing nonstandard approaches.
View the Full Meeting & All Its Details
This article offers just a summary. Unlock complete video, transcripts, and insights as a Founder Member.
✓
Watch full, unedited meeting videos
✓
Search every word spoken in unlimited transcripts
✓
AI summaries & real-time alerts (all government levels)
✓
Permanent access to expanding government content
30-day money-back guarantee
