FDA wants feedback on testing methods for new nitrosamines

The US Food and Drug Administration (FDA) is requesting stakeholder input on approaches for identifying and testing novel nitrosamines identified in drug products and active pharmaceutical ingredients (APIs) to help inform safety assessments.

These novel nitrosamines, also called nitrosamine drug substance-related impurities (NDSRIs), were not addressed in FDA’s original nitrosamine guidance published in September 2020 nor the updated guidance issued in February 2021. (RELATED: N-Nitrosamine impurities: FDA issues detection, prevention guidance, Regulatory Focus 1 September 2020)

FDA said in a Federal Register notice this week that “NDSRIs present unique scientific and regulatory challenges for FDA because each NDSRI is unique to the API, and there is limited compound-specific data that is available to inform safety assessments. Additionally, design of validated test methods for identification of NDSRIs and modification of existing test methods for assessment of their mutagenic potential may raise novel scientific considerations.”

The notice is “not intended to communicate FDA's regulatory expectations on these issues but is instead intended to seek input from the public to inform scientific and/or regulatory approaches as appropriate.”

In November 2021, FDA alerted the public to the presence of NDSRIs and said manufacturers could ascertain their presence by using the same three-step process identified in the earlier nitrosamine guidance documents. (RELATED: FDA suggests alternative approaches for nitrosamine risk assessments, Regulatory Focus 23 November 2021)

Last October, an Apotex official told Focus that these impurities are being detected in a higher number of products than anticipated and catching regulators and industry off guard. (RELATED: Prompted by recent recalls, regulators scramble to address novel nitrosamines, Regulatory Focus 31 October 2022).

The notice states that NDSRIs “may have implications for a cohort of pending or approved NDAs and ANDAs.” This poses “unique challenges from a regulatory perspective.” For example, a generic drug applicant typically may qualify the level of an impurity that does not have a limit in an applicable US Pharmacopeia monograph or does not have a recommended acceptable daily intake limit for a reference listed drug.

The agency would like input on several areas, including what additional topics related to nitrosamines should be a priority for the agency and what factors should FDA consider in prioritizing its evaluation of NDSRIs on a compound-specific basis. In addition, the agency wants input on what additional mitigation strategies should be considered for reducing NDSRI formation or eliminating these impurities.

The agency would also like input on the scientific and technical factors it should consider in developing best practices for NDSRI testing, such as whether to use the Ames test or an enhanced Ames test, or to follow up with in vitro mutagenicity and in vivo transgenic tests to support daily acceptance limits or whether additional tests should be considered for assessing mutagenic impurities.

Stakeholders have until 3 July to comment.

Notice

FDA wants feedback on testing methods for new nitrosamines

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