Analysis of Five Nitrosamine Impurities in Drug Products and Drug Substances Using Agilent GC/MS/MS Instrumentation

Importance of the Topic

The presence of trace nitrosamine impurities in angiotensin receptor blocker drugs has triggered global recalls and strict regulatory limits. Sensitive and specific analytical methods are required to ensure patient safety and compliance with guidelines.

Objectives and Overview of the Study

This study evaluates the capability of Agilent 7890B or 8890 gas chromatographs coupled to a 7010B triple quadrupole GC/MS system with high efficiency source to detect and quantify five nitrosamines (NDMA NDEA NEIPA NDIPA NDBA) at levels below current regulatory limits. The goal is to demonstrate improved sensitivity and robustness for routine quality control.

Methodology and Instrumentation

Sample Preparation

• Accurately weigh 500 mg of API or drug product and add internal standard solution (50 ng/ml NDMA C13 d6 in dichloromethane).
• For poorly soluble samples vortex and centrifuge then filter the organic layer through 0.45 µm nylon into GC vials.

Instrumentation Used

• Agilent 7890B or 8890 GC with 7693A autosampler and 7697A headspace sampler connected to multimode inlet.
• Agilent 7010B triple quadrupole GC/MS with high efficiency source (HES).
• J W VF WAXms column 30 m × 0.25 mm 1.0 µm.
• Carrier gas helium 1 ml/min under pulsed splitless conditions.

Main Results and Discussion

Chromatographic separation of all five nitrosamines achieved baseline resolution with retention times matching regulatory data. Calibration curves showed excellent linearity with R2 above 0.999 for each analyte. Repeatability tests at 40 ng/ml yielded RSD values below 2% across six injections. Limits of quantitation were lowered by factors of 2 to 20 relative to FDA criteria with signal to noise ratios exceeding 150 at LOQ levels.

Benefits and Practical Applications

High sensitivity and precision enable confident detection of nitrosamines well below regulatory thresholds. The 8890 GC touchscreen interface and monitoring alerts facilitate method setup and instrument diagnostics. This protocol supports quality control in pharmaceutical and biopharmaceutical laboratories ensuring compliance and patient safety.

Future Trends and Applications

Advances may include integration with laboratory information management systems for automated data handling real time process monitoring and coupling with complementary separation or ionization techniques. Further miniaturization and ambient ionization approaches could expand applicability to other drug classes and low volume samples.

Conclusion

The Agilent 7890B 7010B and 8890 7010B GC/MS/MS configurations with HES provide robust and ultra sensitive analysis of five nitrosamine impurities in sartans. The method delivers linearity repeatability and LOQs surpassing regulatory requirements without extensive parameter changes.

References

• https://www.fda.gov/media/123409/download
• https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and-irbesartan