Physicochemical stability of carmustine-containing medicinal products after reconstitution and after dilution to ready-to-administer infusion solutions stored refrigerated or at room temperature

Abstract

Introduction The aim of this study was to determine and compare the physicochemical stability of two carmustine-containing medicinal products licensed and marketed in Europe as Carmustin Obvius (Medac GmbH) and Carmubris (Tillomed Pharma GmbH). Reconstituted stock solutions and diluted ready-to-administer infusion solutions of the two products were investigated. Methods Reconstituted carmustine stock solutions (3.3\u2009mg/mL) and ready-to-administer infusion solutions (0.2\u2009mg/mL, 1.0\u2009mg/mL) prepared in prefilled 5% glucose injection solution PP/PE bags were stored at 22°C or 2–8°C over a maximum period of 66 hours protected from light. Samples were taken immediately after reconstitution or dilution and after 3.5, 6, 8.5 and 11 hours when stored at 22°C or after (12), 24, 48 and 60 hours when stored at 2–8°C, followed by 3- and 6-hour storage at 22°C (60+3 hours, 60+6 hours). Physicochemical stability was determined by reversed-phase high-performance liquid chromatography with UV detection, measurement of pH, osmolarity and inspection for visible particles or colour changes. Results Carmustin Obvius and Carmubris reconstituted stock solutions were physicochemically stable for at least 48 hours when stored at 2–8°C. Carmustin Obvius and Carmubris infusion solutions 0.2\u2009mg/mL were physicochemically stable for at least 8.5\u2009hours and 60 hours when stored at 22°C and 2–8°C, respectively. After subsequent storage of the 60-hour refrigerated test solutions for 3\u2009hours at 22°C, the carmustine concentrations averaged the 90% limit and fell below the 90% limit after 6\u2009hours. Carmustin Obvius infusion solutions 1.0\u2009mg/mL were physicochemically stable for at least 8.5\u2009hours when stored at 22°C and for 60 hours when stored at 2–8°C. Conclusion According to the physicochemical stability data, the shelf life (95% limit) of the refrigerated stock solutions is 48 hours and the shelf life (90% limit) of ready-to-administer infusion solutions (0.2\u2009mg/mL, 1.0\u2009mg/mL) is 60 hours at 2–8°C or 8.5\u2009hours at 22°C under light protection. These results facilitate the use of both medicinal products in a pharmacy-based centralised cytotoxic preparation unit.