Prompted by recent recalls, regulators scramble to address novel nitrosamines

Regulatory NewsRegulatory News | 31 October 2022 |  By 

Updated 3 November 2022*

The discovery of novel nitrosamine impurities in pharmaceuticals, coming after the valsartan/nitrosamine crisis of 2018, has caught global regulators and industry by surprise as more products than anticipated are affected by these impurities.
The situation raises new questions about how to set daily acceptable intake limits for pharmaceutical products when toxicological data on these impurities is scarce.
These novel nitrosamines, also called nitrosamine drug substance-related impurities (NDSRIs), were not previously identified 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).
The 2020 guidance set daily acceptable limits for N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and four other nitrosamines, but does not address the novel nitrosamines recently detected.
Hundreds of products affected
Nitrosamine impurities have been a source of concern to regulators worldwide since they were detected in valsartan medicines in 2018. Though nitrosamines occur naturally in very small quantities, they are a potential carcinogen.
Martin Ehlert, vice-president of research and development for Apotex, told Regulatory Focus that since 2018, new novel nitrosamines have been detected in pharmaceuticals, affecting hundreds of products, and catching regulators and industry off guard.
When the 2020 guidance was issued, the initial perception among experts was that “the problem would be contained and would impact only a small fraction of drug products approved in the US, maybe 10 or 20 or 30.”
Ehlert said there is now greater appreciation among regulators that “essentially any drug that has an active ingredient that is a vulnerable amine is most likely going to form a corresponding nitrosamine.”
He added that about 20% of all small-molecule drugs consist of vulnerable amines, making them susceptible to nitrosamine formation. These drugs include beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and selective serotonin reuptake inhibitors (SSRIs), with beta blockers being of particular concern. “If a patient needs them, there are no good substitutes, so this is why it has become such an issue for industry, branded and generic alike.”
Ehlert said, “It is my belief that the FDA and all the other international regulators who had serious concerns on this didn’t realize how broad the problem would become and how quickly it would become a broad problem.”
Novel nitrosamines were detected this year in Merck’s diabetes drug Januvia, where traces of Nitroso STG-19 19 (NTTP) were found. FDA did not withdraw Januvia due to fears of a shortage. Conversely, when elements of N-nitroso-varenicline were found in Pfizer’s smoking cessation drug Chantix in 2021, that drug was recalled.
Industry is grappling with how to set daily acceptable limits for these novel nitrosamines, as the toxicological data is not yet available. This “is what industry is struggling with and the most important issue of today,” Ehlert said.
To avoid product contamination, manufacturers have the option of reformulating products or deviating from old formulations, which “is an enormous problem” affecting both brand name and generic companies, he added.
Regulators meeting with industry
Ehlert said there are ongoing interactions between regulators and industry to address how these impurities should be controlled. While the EU and Canada have attempted to address this issue by setting default limits for novel nitrosamines, FDA has not yet moved to revise its 2020 guidance.
The European Medicines Agency (EMA) and Health Canada set a default daily acceptable limit of 18 nanograms per day for these novel nitrosamines for which there is no known toxicological data, as part of a “precautionary” measure. According to Ehlert, the Canadian Generic Pharmaceutical Association (CGPA) just concluded a bilateral meeting with Health Canada where the nitrosamine issue “was one of the biggest topics” discussed.
The  Association for Accessible Medicines (AAM) presented their perspectives on addressing novel impurities to FDA on 31 October.
Pandora’s box
FDA, said Ehlert, in response, has not yet taken action to address to broader list of impurities than those specified in 2020 guidance. FDA “realized they opened up the lid to Pandora’s box and they’re trying to figure out what to do now.”
FDA explained to Focus some of the actions they are taking to address novel nitrosamines. In March 2021, FDA sponsored a scientific workshop to address gaps in knowledge on novel nitrosamines and the research needed to address nitrosamine impurities.
In November 2021, FDA also published an update on NDSRI risk mitigation strategies (RELATED: FDA suggests alternative approaches for nitrosamine risk assessments, Regulatory Focus, 23 November 2021).
Officials also said the 2020 guidance “may be updated to provide clarity on specific topics, as appropriate” when asked whether the nitrosamine guidance would be updated to address novel nitrosamines.

* A previous version of this story mischaracterized the meeting betwen FDA and AAM.


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