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FDA declines to extend nitrosamine risk assessment deadline

Posted 26 July 2021 | By Joanne S. Eglovitch 

FDA declines to extend nitrosamine risk assessment deadline

The US Food and Drug Administration (FDA) rejected pleas from the pharmaceutical industry to extend the deadline for conducting nitrosamine risk assessments to 1 September, standing firm on the 31 March deadline.
Industry representatives also told FDA to align its guidance with the International Council on Harmonization’s M7 guidance on impurity testing, saying that divergent expectations have “created many challaneges for the pharmaceutical industry and increased the potenial for disruptions to global supply chains that could ultimately lead to drug shortages." 
These complaints were laid out in recently published minutes from the 4 May FDA-industry virtual meeting, where the industry laid out its complaints on implementing the agency’s nitrosamine guidance. The meeting was held at the request of the Association for Accessible Medicines (AAM), the Pharmaceutical Research and Manufacturers of America (PhRMA) and the Consumer Healthcare Products Association (CHPA).
FDA issued guidance on nitrosamine testing for drugs in September 2020 (RELATED: N-Nitrosamine impurities: FDA issues detection, prevention guidance, Regulatory Focus 1 September 2020) The guidance called on manufacturers  to assess the nitrosamine impurity risks associated with all chemically synthesized active pharmaceutical ingredients and all approved or marketed drug products that contain those active pharmaceutical ingredients (APIs) or other sources of nitrosamines by 1 March 2021. The deadline was extended to 31 March over industry complaints that it could not met the deadline.
The nitrosamine that has been most commonly found at elevated levels in pharmaceutical products is N-nitrosodimethylamine (NDMA), which was first found in valsartan, an angiotensin II receptor blocker, in mid-2018.
Time consuming risk assessments
The industry groups complained that FDA did not allow enough time for conducting these assessments, which they called “time-consuming” and “resource-intensive” and requested that the deadline be extended to 1 September.
They also asserted that conducting these risk assessments has prompted manufacturers to “shift valuable resources from other critical activities, including the development and manufacture of COVID-19-related therapeutics and innovative, new products for non-COVID-related serious conditions with unmet medical need, as well as the manufacture of affordable generics which account for nearly 90% of prescriptions filled in the U.S.”
Yet FDA stood firm on its current deadline. “We have not planned for additional extensions at the current time.”
Industry also complained that the “magnitude” of the risk assessments and subsequent confirmatory testing may have an impact of the global supply chain and may prompt drug shortages.
FDA only conceded that that it was “willing to work with facilities that detect excessive nitrosamine contamination to prevent or mitigate a shortage.”
FDA said that in the past it has been flexible and has allowed manufacturers who found higher than acceptable intake levels to “continue to distribute batches to alleviate a shortage, and we will continue to evaluate each product and contamination on a case-by-case basis with a goal of balancing risk to exposure with the benefits from continued use of the drug.”
Needs alignment with ICH M7
Industry groups also complained that FDA’s approach for setting NDMA threshold is not aligned with the ICH M7 guidance. As a result, the acceptable impurity limits are “inconsistent among regions.”
FDA specifies in the guidance that the acceptable limit for all nitrosamine impurities not exceed 96 nanograms daily, and also requires a risk assessment to ensure that drugs do not exceed this threshold. The M7 guidance sets less stringent limits. 
The industry has in the past complained that the FDA’s guidance on nitrosamines sets an overly conservative threshold for acceptable levels of nitrosamines in products. (RELATED: FDA’s OGD hears ways to accelerate complex generic development, Regulatory Focus, 24 June 2021).
The ICH M7 guidance, finalized in June 2017, features sections on considerations for marketed products, drug substance and drug product impurity assessments, hazard assessments elements, risk characterization, control, and documentation. The guidance also includes three appendices or scenarios for the application of MCH M7 and provides case examples to illustrate potential control approaches. (RELATED: FDA Finalizes ICH M7 Guidance on Mutagenic Carcinogens, Regulatory Focus, 13 March 2018)
The industry would also like to see more clarity around the acceptability of M7 control options.
Industry queried FDA as to whether it would accept the International Pharmaceutical Excipients Council (IPEC) Questionnaire for Excipient Nitrosamine Risk Evaluation for conducting nitrosamine risk assessments. FDA said that it has not yet evaluated the IPEC tool, recommending that firms compare any prepared questionnaire or other risk assessment tool with the recommendations in the nitrosamine guidance.
FDA/industry meeting minutes discussing FDA’s guidance on nitrosamines


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Tags: FDA, nitrosamines

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