Solutions for Nitrosamine Analysis in Pharmaceuticals

by | May 2, 2024

Discover the latest Waters resources providing up-to-date information on tools and techniques for nitrosamine analysis.

[eBook] Nitrosamines Analysis with LC-MS/MS

N-nitrosamines are a potentially mutagenic class of impurities. Human exposure to these impurities (above certain levels and for extended periods) can pose a risk of cancer. To ensure safety and quality, pharmaceutical manufacturers strive to control and mitigate the presence of these impurities in their products. This eBook provides a comprehensive overview of nitrosamine analysis, including history, formation, and method development. It also reveals how Waters automated technologies, workflows, expertise, and solutions can help overcome challenges in nitrosamine analysis.

[App Note] Suggested Approaches for Minimizing Background Chemical Noise in Low Mass MRM Transitions for Trace Level Quantification of N-Nitrosamines

Health authorities have mandated measures to control nitrosamines in medications due to their carcinogenic potential since 2018, when N-nitroso-dimethylamine (NDMA) was detected in a valsartan active pharmaceutical ingredient (API). Tandem quadrupole mass analyzers within LC-MS/MS systems offer precise detection, but background noise can affect sensitivity. This study describes the use of ultra-performance liquid chromatography (UPLC) with atmospheric pressure chemical ionization (APCI) and tandem quadrupole mass spectrometry for the trace analysis of nitrosamines. Background noise is mitigated by various strategies including evaluation of the cone gas and the use of high-purity mobile phases.

[App Note] Quantitation of N-Nitroso-Propranolol in Drug Substance using LC-MS/MS

Recently, the EMA and FDA revised acceptable intake (AI) value determination methods, introducing an expanded structure-activity relationship (SAR) approach based on carcinogenicity data. A beta-blocker recall in 2022, due to the detection of N-nitroso-propanolol, led to the development of a method using ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-ESI) and the Xevo™ TQ-S micro Tandem Quadrupole Mass Spectrometer for detecting N-nitroso-propranolol. This method meets regulatory requirements for trace-level detection, accuracy, and reproducibility.

[App Note] High Sensitivity Quantification of Nitrosamines in Metformin Using Xevo™ TQ Absolute Tandem Quadrupole Mass Spectrometer With an ACQUITY™ Premier System

Using UPLC coupled with tandem quadrupole mass spectrometry, this research successfully detects and quantifies nine nitrosamine impurities in metformin, an anti-diabetic drug. Key instruments include the Atlantis™ Premier™ BEH C18 AX Column used for the chromatographic separation and the ACQUITY Premier System with the Waters Xevo TQ Absolute Mass Spectrometer for accurate quantification. The method provides highly sensitive detection with limits ranging from 0.01 to 0.1 ng/mL and accurate quantification at 0.025 ng/mL concentration, with recoveries of 85–110%. 

[Webinar] Managing the complexities of NDSRI method development: The N-nitroso propranolol case story

Analytical testing is crucial for ensuring compliance with nitrosamine regulatory thresholds. In this webinar, Marian Twohig, Ph.D., from Waters Corporation, discusses recent advancements in N-nitrosamine regulations. Dr. Twohig explores the development of an analytical methodology for quantifying N-nitroso propranolol in propranolol, addressing challenges and optimization beyond regulatory requirements. Key objectives include aligning method optimization with regulatory guidance, emphasizing high-quality chromatographic methods for API and impurity resolution, and leveraging tandem quadrupole mass spectrometry for peak investigation and method optimization.

Presenter: Dr. Marian Twohig, Principal Scientist, Waters Corporation

Marian Twohig is a scientist with a passion for problem solving using analytical instrumentation. She has over 18 years of experience supporting quantitative and qualitative applications in the pharmaceutical, food, environmental, and materials science industries. She works as a Principal Scientist for Waters Corporation where she has previously held several Senior Scientist positions.


Cover of PFAS analysis magazineThis article is featured in our May 2024 publication, Pharmaceutical Purity and Precision. Find out what’s happening in the world of pharmaceutical impurity analysis and learn about the latest topics and techniques.

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