Determination of genotoxic nitrosamines in Valsartan with gas chromatography and mass spectrometry

Importance of the Topic

• Valsartan is a widely prescribed antihypertensive whose safety has been impacted by genotoxic nitrosamine contamination (NDMA, NDEA).
• Regulators (FDA, EMA, C-FDA) classified these impurities as probable human carcinogens and established strict limits (0.3 ppm for NDMA, 0.08 ppm for NDEA).
• Analytical detection at trace levels in complex drug matrices presents a significant challenge for sensitivity, selectivity, and throughput.

Objectives and Study Overview

• Evaluate and compare three Thermo Scientific GC-MS configurations against C-FDA and US-FDA recommended methods for nitrosamine analysis in Valsartan.
• Assess performance in terms of sensitivity, linearity, repeatability, resolution and compliance with regulatory limits.
• Provide a flexible analytical portfolio to suit different laboratory needs for routine quality control.

Methodology and Instrumentation

• Liquid-injection GC-MS (C-FDA): Single quadrupole ISQ 7000, methanol extraction of Valsartan, splitless injection.
• Headspace GC-MS (US-FDA): TriPlus 500 autosampler, DMSO dissolution, single quadrupole analysis with TRACE 1310 GC.
• Direct injection GC-MS/MS (US-FDA): TSQ 9000 triple quadrupole, DCM extraction, SRM transitions for NDMA and NDEA.

Main Results and Discussion

1. Liquid-injection GC-MS achieved LOQs of 0.6 ppb (NDMA) and 0.8 ppb (NDEA), R2>0.998, resolution >2.5, S/N>10, recoveries 93–105%, detected nitrosamines below regulatory limits.
2. Headspace GC-MS delivered LOQs equivalent to 1.5 ppb (NDMA) and 3.1 ppb (NDEA), R2>0.999, RSD <3%, recoveries 92–104%, quantification within specification.
3. GC-MS/MS provided superior sensitivity (LOQs 0.5 ppb for NDMA, 0.16 ppb for NDEA), R2>0.998, RSD <3%, recoveries 84–108%, detected NDMA (2.6 ppb) and NDEA (1.5 ppb) well below limits.

Benefits and Practical Applications

• All methods meet or exceed regulatory criteria for nitrosamine detection in pharmaceutical quality control.
• GC-MS/MS offers highest sensitivity and selectivity, particularly beneficial for trace NDEA analysis.
• Vacuum interlock design enables rapid maintenance, minimizing downtime and maximizing throughput.

Future Trends and Opportunities

• Development of even lower detection limits for emerging nitrosamine analogues.
• Integration of fully automated headspace and triple quadrupole workflows for high-throughput screening.
• Extension of validated protocols to other drug substances and complex matrices.
• Implementation of advanced data management systems to ensure compliance with evolving regulatory standards.

Conclusion

• Thermo Scientific GC-MS and GC-MS/MS platforms provide robust, compliant, and flexible solutions for quantification of genotoxic nitrosamines in Valsartan.
• Laboratories can select the most appropriate configuration based on required sensitivity, selectivity, and throughput.

Reference

1. Chinese Pharmacopoeia, Determination of nitrosamines in Valsartan, 2018.
2. US FDA, GC-MS Headspace Method for NDMA in Valsartan Drug Substance, 2018.
3. US FDA, Combined NDMA and NDEA Impurity Assay by GC-MS Headspace, 2018.
4. US FDA, Combined Direct Injection NDMA and NDEA Impurity Assay by GC-MS/MS, 2018.