Streamlining Analytical Method Development for NDSRIs and Mutagenic Impurities in Pharmaceutical Formulations Using Single-Quadrupole LC-MS

User Benefits

- LabSolutions MD enables simple and efficient development of LC conditions, such as mobile phases, columns, and gradient programs. - Using a single-quadrupole LC-MS, NDSRIs in drug products can be quantified with high sensitivity and precision. - Simultaneous screening of NDSRIs and mutagenic impurities can be performed.

Introduction

In September 2024, the FDA issued the second edition of “Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry.” This guidance classifies nitrosamines into two categories: “small-molecule nitrosamines” and “nitrosamine drug substance-related impurities (NDSRIs).” NDSRIs are formed through the reaction (nitrosation) of the active pharmaceutical ingredient (API) or API-related impurities with nitrites and related species. Unlike small-molecule nitrosamines, NDSRIs have structures similar to that of the API and exhibit a wide variety of API-derived structures. As a result, their toxicity varies depending on their structure. To address this issue, the FDA and EMA have developed the Carcinogenic Potency Categorization Approach (CPCA), which estimates the carcinogenic risk of NDSRIs based on partial structural information and establishes acceptable intake limits (AI limits). Under the CPCA, NDSRIs are classified into Categories 1 to 5 according to their predicted toxicity, and different AI limits are assigned to each category. Furthermore, because NDSRIs differ in structure depending on the API, analytical methods need to be developed for each target NDSRI. Atenolol is a β-blocker used to treat mild to moderate hypertension, angina pectoris, and arrhythmia (premature beats), and its maximum daily dose is 100 mg/day. The NDSRI potentially formed from atenolol, N-nitrosoatenolol, is classified as Category 4 under the CPCA, with an AI limit of 1,500 ng/day. In this application, single-quadrupole LC-MS was used to analyze the API and NDSRI in an atenolol drug product, along with atenolol impurity D, a mutagenic impurity. LabSolutions MD (analytical method development support software) enabled efficient development of LC conditions, while the LCMS-2050 enabled simple, highly sensitive, and highly accurate analysis.

August 17, 2026 GMT