Abstract
The recent detection of potent carcinogenic nitrosamine impurities in several human medicines has triggered product recalls and interrupted the supply of critical medications for hundreds of millions of patients, illuminating the need for increased testing of nitrosamines in pharmaceutical products. However, the development of analytical methods for nitrosamine detection is challenging due to high sensitivity requirements, complex matrices, and the large number and variety of samples requiring testing. Herein, we report an analytical method for the analysis of a common nitrosamine, N-nitrosodimethylamine (NDMA), in pharmaceutical products using full evaporation static headspace gas chromatography with nitrogen phosphorous detection (FE-SHSGC-NPD). This method is sensitive, specific, accurate, and precise and has the potential to serve as a universal method for testing all semi-volatile nitrosamines across different drug products. Through elimination of the detrimental headspace-liquid partition, a quantitation limit of 0.25 ppb is achieved for NDMA, a significant improvement upon traditional LC-MS methods. The extraction of nitrosamines directly from solid sample not only simplifies the sample preparation procedure but also enables the method to be used for different products as is or with minor modifications, as demonstrated by the analysis of NDMA in 10+ pharmaceutical products. The in situ nitrosation that is commonly observed in GC methods for nitrosamine analysis was completely inhibited by the addition of a small volume solvent containing pyrogallol, phosphoric acid, and isopropanol. Employing simple procedures and low-cost instrumentation, this method can be implemented in any analytical laboratory for routine nitrosamine analysis, ensuring patient safety and uninterrupted supply of critical medications.Graphical
Highlights
The discovery of N-nitrosodimethylamine (NDMA), a potent probable carcinogen with very low acceptable intake (AI) limits (e.g., 96 ng/day), in valsartan has triggered industrywide scrutinization of nitrosamine contamination for all pharmaceutical products [1, 2]
Nitrosamines are extracted to the headspace by heating at high temperature and analyzed by gas chromatography (GC)-nitrogen phosphorous detector (NPD)
The extraction time is dependent on the time it takes for the analytes of interest to diffuse from solid to headspace, which can be shortened by reducing the particle size through grinding and increasing the headspace heating temperature
Summary
The discovery of N-nitrosodimethylamine (NDMA), a potent probable carcinogen with very low acceptable intake (AI) limits (e.g., 96 ng/day), in valsartan has triggered industrywide scrutinization of nitrosamine contamination for all pharmaceutical products [1, 2]. Pharmaceutical companies need to perform confirmatory testing across multiple lots if a potential nitrosamine risk is identified in the drug product, which could affect a large portion of the product on the market or in development [9, 10]. This is a rapidly evolving regulatory environment with major regulatory agencies actively revising guidance on the control of nitrosamines in human drugs. This is especially difficult for formulated drug products as extracting nitrosamines from complex matrices is much more difficult compared to drug substances
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call