An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals

Abstract

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed.

Keywords: AI, acceptable intake; APIs, active pharmaceutical ingredients; ARBs, angiotensin II receptor blockers; AZBC, 4′-(azidomethyl)-[1.1′-biphenyl]-2-carbonitile; AZBT, 5-(4′-(azidomethyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole; AZTT, 5-(4′-((5-(azidomethyl)-2-butyl-4-chloro-1H-imidazol-1-yl) methyl)-[1,1′-biphenyl]-2-yl)-1H-tetrazole; CDER, center for drug evaluation and research; CPNP, 1-cyclopentyl-4-nitrosopiperazine; Control limits; DBA, N,N-dibutylamine; DEA, N,N-diethylamine; DIPEA, N,N-diisopropylethylamine; DMA, dimethylamine; DMF, N,N-dimethyl formamide; DPA, N,N-dipropylamine; EMA, European Medicines Agency; EPA, Environmental Protection Agency; FDA, Food and Drug Administration; HSA, Health Sciences Authority; IARC, International Agency for Research on Cancer; ICH, International Council for Harmonisation; LD50, median lethal dose; MBA, N-methylamino-N-butyric acid; MDD, maximum daily dose; MNP, 1-methyl-4-nitrosopiperazine; NAP, nitrosation assay procedure; NDBA, N-nitrosodibutylamine; NDEA, N-nitrosodiethylamine; NDIPA, N-nitrosodiisopropylamine; NDMA, N-nitrosodimethylamine; NDSRIs, Nitrosamine drug substance-related impurities; NEIPA, N-nitroso ethylisopropylamine; NMBA, N-nitroso-N-methyl-4-aminobutyric acid; NMP, N-methyl pyrrolidinone; NOCs, N-nitroso compounds; Nitrosamines; Nitrosation; PPRs, proportionate reporting ratios; Ranitidine; SARs, structure–activity relationships; Sartans; TD50, median toxic dose; TEA, triethylamine; TMA, trimethylamine; TTC, threshold of toxicological concern; USFDA, United States Food Drug and Administration; USP, United States Pharmacopoeia; WHO, World Health Organization.