Prompting this renewed concern by the FDA is the realization that not all nitrosamine impurities raise a potential carcinogenic concern.
In a notice published May 4, 2023, in the Federal Register, the Food and Drug Administration has again addressed the presence of nitrosamine impurities in drug products. The FDA is soliciting industry stakeholders, including scientists and others, to weigh in on the identification of nitrosamine drug substance-related impurities (NDSRIs), suggested mitigation strategies for reducing NDSRIs in drug products, best practices for testing for their presence and assessing their mutagenic and carcinogenic potential, and the benefits of and obstacles to collaboration among drug industry members in working cooperatively to establish scientifically sound and safe exposure levels for patients.
For the past five years―beginning in June 2018 with the discovery of a nitrosamine impurity in certain lots of the angiotensin II receptor blocker valsartan―the FDA has sought to understand the sources of such impurities and the mechanisms by which they may form in pharmaceuticals during the manufacturing process or as the drug deteriorates on the shelf. Recalls of such products led to a shortage of essential medicines and a concerted effort by the industry and FDA to address these issues.
Prompting this renewed concern by the FDA is the realization that not all nitrosamine impurities raise a potential carcinogenic concern, and that toxicology assessments are necessary to properly classify them into appropriate risk categories. As the FDA now acknowledges in its published notice, science does not support the mutagenicity of many of these NDSRI compounds, which the FDA noted “are more complex structures than the more commonly identified nitrosamines” in its nitrosamine guidance issued in September 2020 and updated in February 2021.
The presence of a nitrosamine impurity in drug products is determined in specialized bench tests, and its mutagenic or carcinogenic potential is measured in in vitro or in vivo testing and a literature review. Other toxicological assessments may be necessary to classify the impurity, especially in the absence of sufficient toxicity data.
The agency has set a deadline of July 3, 2023, for the receipt of all submissions responsive to its notice, However, the questions it has raised regarding the length of time necessary to conduct accurate nitrosamine mutagenicity testing to establish appropriate average daily nitrosamine intake limits for these drugs suggests that FDA’s timeframe may extend into 2024 and beyond for the development of protocols addressing these infrequently studied molecules.
It will be interesting to see the responses to the FDA’s published notice to determine the range of views on what remains a topic of great concern to the industry, the agency and the general public.
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