A Q-TOF LC/MS method for identification and quantitation of Histamine in the antibiotic Gentamicin at ppm level: Validation and uncertainty evaluation

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Adverse reactions have been reported for antibiotics produced via fermentation with fish peptone due to Histamine contamination. Just few micrograms of Histamine can result in adverse reactions when administered intravenously. Thus in this paper a new method for identification and quantitation of Histamine at ppm levels in the antibiotic Gentamicin is described. The method is based on separation of Histamine from Gentamicin and other excipients present in the drug matrix, by hydrophilic interaction liquid chromatography (HILIC) coupled to a Q-TOF/MS detector; quantitation is based on the standard addition approach.The method was validated for repeatability, inter-day precision, specificity, accuracy (relative and absolute bias) linearity, limit of detection and quantitation. Uncertainty was estimated and evaluated by comparison with values expected according to the Horwitz theory. The method showed satisfactory performances and good sensitivity, reaching a limit of quantitation of approximately 1 ppm.The method proposed can be a starting point for the development of Histamine quantitation methods in other antibiotics or even in other medicinal products which active ingredient is produced via fermentation in presence of fish peptone.Graphical abstractHighlightsA method to identify and quantify Histamine contamination in Gentamicin medicinal products and active pharmaceutical ingredients by QTOF LC/MS.Hydrophilic interaction liquid chromatography (HILIC) allowed a perfect separation of Histamine from Gentamicin and preservatives.High resolution Q-TOF mass spectrometry resulted in the best choice to solve a case of Histamine contamination.A detailed description of method validation and measurement uncertainty evaluation was presented.

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