Title : Trace level detection of mutagenic N-nitroso nintedanib in pharmaceutical substances and products using a highly sensitive LC-MS/MS method
Abstract:
Nintedanib is a tyrosine kinase inhibitor containing structural features that may facilitate the formation of N-nitroso drug substance-related impurities, raising important concerns regarding their potential genotoxic and carcinogenic risks. Among the potential NDSRIs, N-nitroso-desmethyl-nintedanib has received particular regulatory attention owing to its predicted carcinogenic potency. In the present study, a highly sensitive and selective liquid chromatography tandem mass spectrometry method was developed and validated for the trace-level determination of impurity in Nintedanib drug substance and drug product. Based on the Carcinogenic Potency Categorization Approach, impurity was assigned to Potency Category 3 with an acceptable intake limit of 400 ng/day, corresponding to a specification limit of 1.33 ppm based on the maximum daily dose of Nintedanib. Chromatographic separation was achieved using an InertSustain C18 column with a gradient elution of formic acid in water and acetonitrile, followed by positive electrospray ionization and multiple reaction monitoring detection. The method demonstrated satisfactory specificity, sensitivity, precision, accuracy, linearity, and robustness in accordance with regulatory requirements. The method range extended from 0.133 to 1.995 ppm, with a limit of quantification of 0.133 ppm. The developed method is therefore suitable for sensitive routine monitoring and control of the impurity in nintedanib pharmaceutical products.
