Qualitative and quantitative analysis of glutathione and related impurities in pharmaceuticals by qNMR.
Qin Shu, Mary Schleiff, Cynthia Sommers, Jingyue Yang, Xiaohui Shen, Jason D Rodriguez, David Keire
Author Information
Qin Shu: Office of Pharmaceutical Quality Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, MO 63110, USA. Electronic address: Qin.Shu@fda.hhs.gov.
Mary Schleiff: Office of Pharmaceutical Quality Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, MO 63110, USA.
Cynthia Sommers: Office of Pharmaceutical Quality Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, MO 63110, USA.
Jingyue Yang: Office of Pharmaceutical Quality Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, MO 63110, USA.
Xiaohui Shen: Office of Compounding Quality and Compliance, Office of Compliance, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
Jason D Rodriguez: Office of Pharmaceutical Quality Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, MO 63110, USA.
David Keire: Office of Pharmaceutical Quality Research, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, St. Louis, MO 63110, USA.
In this study, an alternative method to compendial analytical procedures with enhanced detection and separation capabilities was validated for the quality assessment of glutathione (GSH) drug substance. The related impurities A, B, C, and D present in GSH drug substance were characterized using a one-dimension proton nuclear magnetic resonance (1D H NMR) method on a 600 MHz spectrometer equipped with a liquid nitrogen cryoprobe. Two sample preparations at different pH were optimized to ensure the unambiguous identification of different impurities in the GSH samples. Specifically, impurities A and C in a GSH sample can be tested at pH 3.0, while pH 7.4 is more suitable for testing impurities B and D. The quantitative NMR (qNMR) method was validated following International Council for Harmonisation (ICH) guidelines. The limit of detection (LOD) was less than 0.1% wt for an individual impurity, and the limit of quantitation (LOQ) ranged from 0.14 to 0.24% wt, using about 14 min experimental time per spectrum. Following validation, the qNMR method was applied to assess different commercial GSH bulk substance samples, an in-house compounded GSH drug product, and a GSH dietary supplement product. The method was also applied to monitor GSH degradation (hydrolysis and oxidation) over time to provide quantitative information on GSH degradation and stability. The results suggest that the qNMR method can serve as a highly specific and efficient orthogonal tool for assessing the quality of GSH pharmaceuticals, providing both qualitative and quantitative information on GSH and its related impurities A-D.
