👨‍💻 Nitrosamines Analysis in Solvents by GC-MS/MS

This analytical note highlights a robust and sensitive procedure for the quantification of six nitrosamine impurities NDMA, NDEA, NDIPA, NEIPA, NDPA and NDBA in common (commercial and analytical) solvents used during pharmaceuticals manufacturing at trace levels by GC-MS/MS. The procedure was validated according to USP General Chapters <1225> and <736>

  • LOQ of 0.005 ppm for NDMA, NDEA, NEIPA, NDIPA,
    NDPA in analytical-grade solvents with respect to 100
    mg/mL sample concentration.
  • LOQ of 0.013 ppm for NDBA in analytical-grade solvents
    with respect to 100 mg/mL sample concentration.
  • LOQ of and 0.1 ppm for commercial-grade solvents
    respect to 25 mg/mL sample concentration.
  • Accuracy and precision ≤20%.

@AmandaGuiraldelli @mayank.bhanti

USP App Note - Nitrosamines analysis in Solvents by GC-MS-MS V4.pdf (761.6 KB)


This application note was developed to provide an analytical resource for regulators
and industry to monitor nitrosamine impurities in drug products, drug substances or other matrices. It is intended to serve as a resource for informational purposes only and not as an USP-NF compendial documentary standard. This document was developed by USP staff without a public comment period and does not reflect USP or USP’s Expert Body opinions on future revisions to official text of the USP-NF. Parties relying on the information in this document bear independent responsibility for awareness of, and compliance with, any applicable federal, state, or local laws and requirements.

If any solvant interference with any impurities in that case how to control?

If you have an interferer: game over. This method only unrecovered solvents. If you want to analyze process solvent you must go to a QTOF. There are no easy solutions to difficult problems.

What are Nitrosamines impurities to be recommend to test in fresh solvents and why ?

it is not a closed list. You have to evaluate the possible ones you find. The good thing is that there are a lot of multi-analysis methods for nitrosamines, like the one that the guys from USP give you here.
For clean (fresh) solvents, a GC/MS works incredibly well. The problem is the recovered solvents. By having many contributions from recoveries, such a complex matrix can give false positives. That is when the only solution is to go to a GC QTOF or similar and use the HR-MS to distinguish what is and is not.


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Thank you. Please share if anyone has published white paper on testing of nitrosamine impurities in solvent. I appreciate if you can also share your thought on Cleaning method development for nitrosamine impurity and reference on cleaning method validation.

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