Identification of an Oxidizing Leachable from a Clinical Syringe Rubber Stopper

• Published in: Journal of pharmaceutical sciences Vol. 110; no. 10; pp. 3410 - 3417
• Main Authors: Schröter, Ariane, Peter, Sonja, Mahler, Hanns-Christian, Zerr, Andreas, Danton, Ombeline, Chalus, Pascal, Koulov, Atanas V., Huwyler, Jörg, Jahn, Michael
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2021
• Subjects: Analysis; Degradation product; Injectable(s); Interactions; Mass spectrometry; Oxidation; Polymer synthesis; Polymers; Proteins; Solubilization; Surfactants; UV/Vis spectroscopy; Abbreviations: API; PS; HS; Solubilization; DP; Proteins; FTIR; m/z; Oxidation; Polymers; TBME; Injectable(s); Surfactants; UV/Vis spectroscopy; FOX; DCM; TIC; NMR; XIC; Analysis; Polymer synthesis; TCE; Interactions; HSQC; Degradation product; Mass spectrometry; ATR
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2021.05.017

Leaching of toxic or reactive chemicals from polymeric materials can adversely affect the quality and safety of biopharmaceuticals. It was therefore the aim of the present study to analyze leachables from a disposable clinical administration syringe using a polysorbate-containing surrogate solution and to assess their chemical reactivity. Analytical methods did include (headspace) GC-MS, Fourier-transform-infrared spectroscopy, a ferrous oxidation-xylenol orange assay, and nuclear magnetic resonance analysis. In the syringe leachables solution, the carcinogenic 1,1,2,2-tetrachloroethane (TCE) was detected in concentrations above the ICH M7-derived analytical evaluation threshold. TCE was shown to be an oxidation product of dichloromethane used during sample preparation. Since TCE was only isolated from incubations with the contained rubber stopper, we hypothesized that a stopper-derived leachable acted as a reactive oxidant promoting this chemical reaction. Subsequently, the leachable was identified to be the polymerization initiator Luperox® 101. Combining different analytical approaches led to the structural elucidation of a chemical reactive oxidant, which has the potential to interact and alter drug products. We conclude that chemically reactive compounds, such as the newly identified rubber stopper leachable Luperox® 101, may be of concern and therefore should be routinely considered if a prolonged exposure of polymers with drug products can be anticipated.