FDA sets acceptable intake limits for nitrosamines in drugs

The US Food and Drug Administration (FDA) on Friday issued a final guidance that outlines a framework for predicting the mutagenic and carcinogenic risk of nitrosamine drug substance-related impurities (NDSRIs) and sets recommended acceptable intake (AI) limits for these compounds that are identified in drug products and active pharmaceutical ingredients (APIs).

FDA calls on manufacturers of approved products to evaluate these NDSRI risks within three months of final guidance’s publication, and recommends these assessments be completed by 1 November 2023. The guidance further specifies that by 1 August 2025, manufacturers and applicants should ensure that any NDSRIs in their drug products meet the FDA-recommended AI limit and its carcinogenic potency category.

Regulators around the globe have raised concerns about the presence of nitrosamine impurities in pharmaceuticals following the discovery of novel nitrosamine impurities in valsartan and other angiotensin II receptor blocker (ARB) drugs in 2018. A more recent case involved novel nitrosamines detected in Merck’s diabetes drug Januvia last year, where traces of Nitroso STG-19 19 (NTTP) were found. (RELATED: Prompted by recent recalls, regulators scramble to address novel nitrosamines, Regulatory Focus 31 October 2022)

These NDSRIs were not previously covered in FDA’s February 2020 guidance on nitrosamine control and testing (RELATED: N-Nitrosamine impurities: FDA issues detection, prevention guidance, Regulatory Focus, 1 September 2020).

FDA subsequently issued a call for stakeholder feedback on testing for these novel nitrosamines in May. (RELATED: FDA wants feedback on testing methods for new nitrosamines, Regulatory Focus 5 May 2023)

Limited data to inform safety assessments

FDA said there is limited compound-specific data that is available to inform safety assessments for NDSRIs. This uncertainty “has led to some applicants conducting unnecessary studies or, in some cases, discontinuing drug products from the market. Because nitrosamine impurities have been identified in many drug products, disruptions in supply and access have increased, sometimes resulting in drug shortages. These challenges can impact patient access to medications, particularly with respect to drug products that are considered medically necessary.”

The guidance outlines a three-step mitigation strategy FDA expects manufacturers and applicants to use to assess the presence of NDSRIs. This strategy mirrors the earlier guidance in 2020 on nitrosamine testing.

The first part is to conduct risk assessments for nitrosamines in their APIs and drug products; the second part is to conduct confirmatory testing if risks are identified; and the last step involves reporting changes implemented to prevent the presence of these impurities in APIs and drug products in approved and pending NDAs and ANDAs.

Guidance sets AI limits

The guidance then introduces a methodology that uses a predicted carcinogenic potency categorization to assign a recommended AI limit to an NDSRI. This approach is based on principles of the International Council on Harmonisation’s (ICH) M7(R2) guideline, which recommends the use of structure-activity relationship (SAR) concepts to classify the mutagenic and carcinogenic risk of impurities to limit their carcinogenic risk.

The FDA states that an AI limit is “a level that approximates an increased cancer risk of one additional case in 100,000 people based on a conservative assumption of daily exposure to the impurity over a lifetime (70 years).”

The guidance’s Table 1 shows the predicted carcinogenic potency categories and associated recommended AI limits; these limits range from 26.5 ng/day to 1500 ng/day. The guidance also includes a flowchart to predict the carcinogenic potency category of an NDSRI and identity an AI limit.

The guidance specifies that any drug product or API exceeding these thresholds should not be released to the market; however, FDA said it may exercise enforcement discretion when warranted to prevent or mitigate a drug shortage.

The agency also announced the launch of a webpage containing current recommended acceptable intake limits of certain NDSRIs that may be at risk of forming in human drugs, and FDA intends to update this information periodically.

Final guidance

FDA sets acceptable intake limits for nitrosamines in drugs

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