Nitrosamines are carcinogenic, even at trace levels. As a result, the FDA has issued guidance regarding monitoring nitrosamine impurities in drugs for human consumption [1]. Under acidic conditions, nitrosamines can form when amines and nitrite are present.

Monitoring nitrite impurities in pharmaceutical products and raw materials can be part of a control strategy for nitrosamines. Ion chromatography (IC) is well suited for the analysis of trace amounts of nitrite.

Since the discovery of N-nitrosodimethylamine (NDMA) in the medication valsartan [2], nitrosamine contaminants have been detected in many other drugs. This has raised safety concerns in the pharmaceutical industry [3]. The FDA has issued monitoring guidance as even low levels of nitrosamines pose a health risk [1]. Furthermore, the ICH has updated its M7(R2) guideline [3,4] and the USP has released General Chapter <1469> on nitrosamine impurities [5].

Under acidic conditions, secondary or tertiary amines can react with nitrite to form nitrosamines. Amines such as dimethylamine are commonly used in the synthesis of active pharmaceutical ingredients (APIs) and excipients. Nitrite can be present as an impurity in raw materials and solvents, or it can be formed during the drug manufacturing process [5].

All three regulatory guidelines recommend a risk assessment to detect the potential inclusion of nitrosamines in pharmaceutical products. Monitoring trace levels of nitrite impurities as a potential source of nitrosamines can be part of a control strategy for pharmaceutical manufacturers.

Ion chromatography (IC) is an excellent method for measuring trace levels of nitrite. Unlike photometric measurements and other testing methods, chloride does not interfere with IC analysis of nitrite. Sample preparation through solid phase extraction (SPE) or pre-derivatization is therefore not necessary with IC. Moreover, IC can simultaneously detect multiple ionic impurities in drug products.

A Metrosep A Supp 10 column (L91 packaging) with UV/VIS detection is the preferred choice for IC analysis of nitrite in pharmaceuticals. Inline sample preparation techniques, such as the Metrohm intelligent Preconcentration Technique with Matrix Elimination (MiPCT-ME), further increase the sensitivity and robustness of the analysis. Preconcentrating the sample increases the sensitivity, allowing even trace amounts of nitrite to be detected. Matrix elimination improves the robustness by removing the interfering sample matrix.

To learn more about this analysis, read our free Application Notes on the determination of nitrite in an API and excipient using IC.

Application Note AN-S-401 – Nitrite in duloxetine hydrochloride API

Application Note AN-S-402 – Nitrite in hydroxypropyl methylcellulose

References

[1] U.S. Department of Health and Human Services Food and Drug Administration; Center for Drug Evaluation and Research (CDER). Control of Nitrosamine Impurities in Human Drugs.

[2] Mansouri, I.; Botton, J.; Semenzato, L.; Haddy, N.; Zureik, M. N‐nitrosodimethylamine‐Contaminated Valsartan and Risk of Cancer: A Nationwide Study of 1.4 Million Valsartan Users. Journal of the American Heart Association 2022, 11 (24), e8067. https://doi.org/10.1161/JAHA.122.026739.

[3] Tuesuwan, B.; Vongsutilers, V. Current Threat of Nitrosamines in Pharmaceuticals and Scientific Strategies for Risk Mitigation. Journal of Pharmaceutical Sciences 2023, 112 (5), 1192–1209. https://doi.org/10.1016/j.xphs.2023.01.028.

[4] International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). M7(R2) – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.

[5] U.S. Pharmacopeia. USP-NF.〈1469〉Nitrosamine Impurities. https://doi.org/10.31003/USPNF_M15715_02_01.