An improved analytical method for quantitation of nitrosamine impurities in ophthalmic solutions using liquid chromatography with tandem mass spectrometry

Abstract

Nitrosamines are known to be a group of probable human carcinogens that are generally formed by the reaction of secondary and tertiary amines, amides, carbamates, or derivatives of urea with nitrite or other nitrogenous agents. Nitrites are common nitrosating impurities that have been reported in many excipients at part per million levels. Guidelines from FDA and EMA have identified potential nitrosamine impurities that could theoretically be present in drug products. As part of the guidelines, it's crucial to have an established method to screen drug substances and products. Furthermore, drug products containing buffers/salts and polymeric excipients were challenging to test as current literature methods would not retain early-eluting nitrosamine impurities long enough to bypass the salts/excipients from the mass spectrometer ion source using a converter switch.An improved analytical method, aligned with the FDA and EMA guidance, using HPLC/MS/MS, was developed by our lab to address the above unmet need. The method demonstrates an excellent sensitivity and linearity range (0.2–200 ng/mL). It was also shown that the method tolerates much higher organic solvents percentage as diluent. Interested readers can use the method as a starting point for further optimization for analyzing their specific drug substances and drug products.