Rapid Quantitation of Four Nitrosamine Impurities in Angiotensin Receptor Blocker Drug Substances.

ABSTRACT

Starting in July 2018, the FDA alerted patients and health care professionals to the recall of ARBs such as valsartan by several pharmaceutical companies because of their potential contamination with carcinogenic nitrosamine impurities, including (1) N-nitrosodimethylamine (NDMA), (2) N-nitrosodiethylamine (NDEA), (3) N-nitrosoethylisopropylamine (NEIPA), (4) N-nitrosodiisopropylamine (NDIPA), (5) N-nitrosodibutylamine (NDBA) and (6) N-nitroso-N-methyl-4-aminobutyric acid (NMBA). The FDA initiated a laboratory investigation to develop analytical procedures to test multiple lots of marketed ARB drugs to determine the possible presence of carcinogenic impurities and, if present, quantitate the levels of these impurities. Here the FDA laboratory developed and validated an automated micro-solid phase extraction MS/MS method, where all the analytes are not separated prior to elution to the MS, to simultaneously quantify NEIPA, NDIPA, NDBA and NMBA in ARB drug substances with an instrument sample analysis time of 12 seconds. The method was validated according to the ICH Q2(R1) guideline, and was determined to be specific, accurate, precise and linear over the corresponding nitrosamine analytical ranges. The method has been successfully implemented to quantitate the four nitrosamine impurities in 129 generic losartan, valsartan, olmesartan, irbesartan and telmisartan drug substance samples from 32 lots; and 32 losartan and valsartan drug product samples from 6 lots.