FDA extends deadline for nitrosamine testing submissions
The US Food and Drug Administration (FDA) has announced that it will give drugmakers more time to conduct testing for nitrosamine drug substance-related impurities (NDSRIs) in approved pharmaceuticals if they cannot meet the 1 August 2025, deadline. Manufacturers will need to submit progress reports during this extended period.This announcement was published on the FDA's web page regarding the recommended acceptable intake limits for nitrosamine impurities, specifically in the section about implementation timelines.
FDA said that established August deadline is posing challenges for manufacturers.
“While FDA reiterates that applicants should conclude confirmatory testing for products with a risk of nitrosamine drug substance-related impurity (NDSRI) formation and submit necessary changes by August 1, 2025, FDA is allowing additional time for submission of required changes. Many applicants have submitted NDSRI mitigation proposals, but FDA acknowledges that timeframes for full implementation of NDSRI control or mitigation strategies may vary depending upon the specific strategy, for example adding a specification or reformulation. Therefore, FDA acknowledges that the original August 1, 2025 timeline is not achievable for all approved applications for at-risk products.”
Manufacturers unable to submit the necessary testing within this timeline must instead provide the progress update in annual reports for new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs).
The progress update should include the following information:
- Address whether nitrosamine drug substances and related impurities (NDSRIs) can form under targeted forced degradation studies;
- Identify any NDSRIs detected;
- Describe the nitrosamine test method used;
- Describe the product batches that were analyzed;
- Provide confirmatory test results for any NDSRIs found in the product;
- Identify the root cause of the impurity;
- Describe attempts made to mitigate the identified NDSRIs; and
- Provide an estimated timeframe for when the mitigation will be completed.
Several FDA guidelines describe two types of nitrosamines, small molecule nitrosamines and NDSRIs, and cover acceptable intake limits.
One is the final guidance issued in August 2023, titled Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) commonly referred to as the RAIL guidance. This guidance provides recommendations for acceptable intake limits of NDSRIs based on predicted carcinogenic potency categorization.
The other is its final guidance Control of Nitrosamine Impurities in Human Drugs, issued in September 2024. This guidance outlines two categories of nitrosamines: small-molecule nitrosamines and NDSRIs. (RELATED: FDA revises final guidance on nitrosamine impurities, Regulatory Focus 4 September 2024)
Nitrosamine impurities have raised concerns among regulators globally since their identification in valsartan medicines in 2018. Although nitrosamines naturally occur in very small amounts, they are considered potential carcinogens.
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