Nitrosamine, the Industry’s Silent Growing Concern

2021’s health priorities and concerns go far beyond COVID-19. Health agencies and organizations such as the FDA, EMA and even WHO, have recently released communicates warning of the possible contamination from N-Nitrosodimethylamine (NDMA), commonly known as nitrosamine, on drugs. Concerns regarding nitrosamine contamination began rising last year, after the FDA urgently requested the immediate withdrawal of ranitidine OTC drugs from the market.

The reason behind this urgency were the results of the FDA’s “investigation of a contaminant known as NDMA in ranitidine medications.” The agency determined that NMDA impurities in some ranitidine products would increase over time and, when stored above room temperature, may expose consumers to unacceptable levels of this impurity.

NDMA and N-nitrosodiethylamine (NDEA) belong to the so-called “cohort of concern,” which is a group of highly potent mutagenic carcinogens that have been classified by the WHO's International Agency for Research on Cancer as probable human carcinogens. Low levels of NDMA are commonly present in some food and beverages of regular human diets but at these low levels, there is little cancer risk. While the FDA’s initial findings of NDMA in ranitidine showed low levels of impurity, the agency later found that older ranitidine products developed a higher concentration and so did products stored at higher temperatures. The regular consumption and open availability of this drug in the market made the FDA ask for their withdrawal.

 How does nitrosamine appear on medicines?

According to WHO, the formation of nitrosamines is generally only possible when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites under acid conditions.

Its Impact on the Pharmaceutical Industry

In order to respond to the FDA immediate withdrawal request, which came along with EMA’s urgent withdrawal request, stakeholders such as active pharmaceutical ingredients (APIs), excipients, primary packaging and drug product manufacturers. According to Capgemini Engineering, on-time compliance with the EMA and FDA requires companies to quickly hire skilled staff to cope with the volume of work needed to perform the risk assessments.

Nitrosamine’s Status in Mexico

Américo García, Director General of Mexico and Latin America at Apotex, shared in an interview that nitrosamines are threatening the growth of the pharmaceutical market. “The withdrawal of ranitidine has been disruptive for many pharma companies, as nitrosamine are commonly present in drugs. While nitrosamine is more common in food and beverages, the public is more aware of their presence in medicines.” García explained that in the long-term and if found in another drug, it can become a larger concern for the industry.

COFEPRIS addressed this subject back in 2019, when the commission stated that “for now, COFEPRIS does not have sufficient evidence to suggest the suspension of ranitidine treatments. At this time the risk of stopping it is greater than that of the probable exposure to NDMA.”