QSRR; N-nitrosamine impurity; Pharmaceuticals; LC-MS/MS; ICH Q2(R2) guidelines; Quantification; Call for review
Abstract :
[en] To address regulatory concerns regarding N-nitrosamine contamination in pharmaceutical products, generic LC- MS/MS methods for determining N-nitrosamines were developed using an innovative in silico approach based on Quantitative Structure Retention Relationship modeling (QSRR). The development process included screening and optimization phases, offering flexibility in targeting N-nitrosamines and addressing the challenges related to the matrix effect. This methodology represents a significant advancement in method development. Among the developed methods, a highly sensitive and accurate LC-MS/MS method was successfully validated to simultaneously determine 5 small-molecule N-nitrosamine impurities in tablets, which was used in the present proof-of-concept study. The validation followed the ICH Q2 (R2) guidelines, employing a combined approach for accuracy and precision based on total error risk-based methodology. The method was validated to function as both an impurity limit test and a quantitative method. Validation results demonstrated adequate quantitative performance of the method, establishing a validated dosing range from 1 to 30 ng/mL for all N-nitrosamines. The estimated detection limit ranged from 0.75 pg/mL to 0.02 ng/mL. The detection and quantification limits for each N-nitrosamine met the EMA N-nitrosamine investigation approach requirements. Moreover, both are always below 10 % of their respective acceptable limit in the studied finished product formulation. This proposed method is suitable for investigating small-molecule N-nitrosamines in pharmaceutical products and also provides a starting point for further method development, particularly for the determination of newly identified small-molecule N-nitrosamines and drug substance-related N-nitrosamines.
Research Center/Unit :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Zhang, Yue ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Houari, Sabah ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Van Laethem, Thomas ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Dispas, Amandine ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Ziemons, Eric ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Hubert, Philippe ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Hubert, Cédric ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Language :
English
Title :
Innovative QSRR modeling approach for the development of an ultra-sensitive LC-MS/MS method for trace analysis of N-nitrosamines
Publication date :
June 2025
Journal title :
Journal of Pharmaceutical and Biomedical Analysis Open
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