Critical Analysis of Drug Product Recalls due to Nitrosamine Impurities

Abstract

A product recall is the outcome of a careful pharmacovigilance; and it is an integral part of drug regulation. Among various reasons for product recall, the detection of unacceptable levels of carcinogenic impurities is one of the most serious concerns. The genotoxic and carcinogenic potential of N-nitrosamines raises a serious safety concern, and in September 2020, the FDA issued guidance for the pharmaceutical industry regarding the control of nitrosamines in drug products. The FDA database shows that >1400 product lots have been recalled from the market due to the presence of carcinogenic N-nitrosamine impurities at levels beyond the acceptable intake limit of 26.5 ng/day. The drugs that were present in recalled products include valsartan, irbesartan, losartan, metformin, ranitidine, and nizatidine. This perspective provides a critical account of these product recalls with an emphasis on the source and mechanism for the formation of N-nitrosamines in these products.

Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications

“…Cancer classifications of some nitrosamines found in pharmaceutical drugs and structurally related Nnitrosomethylalkylamines (NMAs). Multiple causes can lead to nitrosamine contamination of drugs [14][15][16][17][18]. Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions.…”

“…While there no carcinogenicity data are available for N-nitroso-varenicline, N-nitroso compounds as a group have been identified as a "cohort of concern" in internationally harmonized guidance on impurities in pharmaceuticals, based on their mutagenic properties and carcinogenic potencies [13]. Multiple causes can lead to nitrosamine contamination of drugs [14][15][16][17][18]. Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions.…”

“…Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions. Additional sources of Multiple causes can lead to nitrosamine contamination of drugs [14][15][16][17][18]. Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions.…”

“…These conditions have resulted in unacceptable levels of NDMA in the drug ranitidine and have led to the market withdrawal of all prescription and OTC ranitidine-containing products in the US [20]. While some aspects of this problem, such as source of contamination and mechanisms of formation as well as some risk estimates have been discussed elsewhere [16][17][18]21], we calculated cancer risk estimates using chemical-specific cancer potencies developed by different agencies [8,9,22,23]. We further illustrate the significant carcinogenic potential of additional N-nitrosomethyl-n-alkylamines (NMAs) besides NDMA; these NMAs are closely related to several other contaminants identified to-date and if present in medications, would raise additional concerns.…”

“…Multiple causes can lead to nitrosamine contamination of drugs [ 14 , 15 , 16 , 17 , 18 ]. Nitrosamines can form from precursors under certain conditions during the manufacturing process, e.g., the simultaneous presence of a secondary, tertiary or/and quaternary amine and nitrite under acidic reaction conditions.…”