Waters Xevo TQ Absolute: An extremely sensitive LCMSMS for quantification of low concentration of seven Nitrosamine impurities

Significance of Nitrosamine Analysis in Drug Safety

Nitrosamine impurities are recognized carcinogens that can form during pharmaceutical manufacturing. Detecting these compounds at trace levels is essential to safeguard patient health and meet strict regulatory requirements. Advances in analytical sensitivity are needed to quantify nitrosamines at concentrations far below existing limits.

Objectives and Study Overview

This study aimed to develop and validate an ultra-sensitive LC-MS/MS method for quantifying seven nitrosamine impurities in metformin drug substance. The goal was to achieve detection limits 30- to 60-fold lower than the regulatory threshold of 0.03 ppm, ensuring reliable monitoring of nitrosamines at sub-part-per-billion levels.

Methodology and Used Instrumentation

• Sample Preparation: Simple extraction of metformin spiked with seven nitrosamines at 0.0005 ppm.
• Chromatography: Acquity UPLC H-Class Plus system equipped with HSS T3 column for high-polarity separation.
• Mass Spectrometry: Waters Xevo TQ Absolute featuring a removable source shield, low-noise off-axis StepWave Ion Guide, and XDR photomultiplier detector.

Main Findings and Discussion

• Linearity was established from 0.00025 to 0.25 ppm for all analytes.
• Limit of quantification (LOQ) reached 0.0005 ppm, with signal-to-noise ratios exceeding 10.
• Spiked recoveries ranged between 88 % and 111 %, demonstrating accuracy.
• Chromatographic separation effectively resolved NDMA from metformin despite their high polarity.

These results confirm the method’s robustness and its capability to overcome matrix interferences in metformin analysis.

Practical Benefits and Applications

• Enables routine quality control testing of metformin and related pharmaceuticals for trace nitrosamines.
• Ensures compliance with regulatory requirements by detecting impurities well below allowable limits.
• Offers a streamlined sample preparation workflow, reducing analysis time and resource consumption.

Future Trends and Applications

• Implementation of automated sample preparation and data processing to boost laboratory throughput.
• Adaptation of the method to additional drug products and complex formulation matrices.
• Continuous improvements in ion source and detector technologies to enhance sensitivity further.
• Use of real-time monitoring systems to detect nitrosamine formation during manufacturing processes.

Conclusion

The presented LC-MS/MS approach, leveraging the high sensitivity of the Xevo TQ Absolute and Acquity UPLC HSS T3 column, delivers reliable quantification of seven nitrosamine impurities at sub-ppb levels. This method supports stringent quality assurance and regulatory compliance in pharmaceutical analysis.

References

1. Kumar KP, Taposh KG, Wagh P. Waters Xevo TQ Absolute: An extremely sensitive LC-MS/MS for quantification of low concentration of seven nitrosamine impurities. Waters Corporation; March 2023.