Prolonged In-use Stability of Diluted Atezolizumab in Commercial Intravenous Bags

Abstract

The programmed death-ligand 1 checkpoint inhibitor, atezolizumab is a monoclonal antibody that is indicated for the treatment of several cancers. Prior to administration, atezolizumab is diluted in normal saline (0.9% sodium chloride) in polyvinylchloride or polyolefin infusion bags. The objective of the studies reported in this paper was to evaluate the stability of atezolizumab diluted to 2.4 mg/mL and 9.6 mg/mL (Study 1), and 16.8 mg/mL (Study 2) in intravenous bags containing normal saline and stored for up to 12 months. Atezolizumab was withdrawn from commercial vials (1,200 mg/20 mL or 840 mg/14 mL) under aseptic conditions and added to infusion bags containing normal saline with target concentrations of 2.4 mg/mL, 9.6 mg/mL, and 16.8 mg/mL. Bags were stored at 30°C for 24 hours with exposure to ambient light, then at 2°C to 8°C for up to 12 months protected from light. 10-mL samples were withdrawn at selected time points and evaluated by analytical assays for color, opalescence, and clarity; visible and subvisible particulates; pH; protein concentration by ultraviolet spectrophotometric analysis; size-exclusion high-performance liquid chromatography; ion-exchange high-performance liquid chromatography; non-reduced capillary electrophoresis-sodium dodecyl sulfate; and potency assays. No substantial changes in atezolizumab product quality were apparent by any measure related to any analytical assay in either study after 3 months of storage at 2°C to 8°C. No new peaks were observed on size-exclusion high-performance liquid chromatography, ion-exchange high-performance l i qui d chromatography, or non-reduced capillary electrophoresis-sodium dodecyl sulfate profiles of diluted atezolizumab after the extended storage of 12 months at 2°C to 8°C. In Study 1, a decreasing trend in ion-exchange highperformance liquid chromatography main peak area was detected in samples from polyvinylchloride bags containing 2.4 mg/mL atezolizumab; and substantial changes were observed at 12 months in samples from polyvinylchloride bags containing 2.4 mg/mL and 9.6 mg/mL atezolizumab. I n Study 2, decreasi ng trends i n mai n peak areas were detected by si ze-excl usi on hi gh-performance liquid chromatography analyses, ion-exchange high-performance liquid chromatography analyses, and non-reduced capi l l ary el ectrophoresi s-sodi um dodecyl sulfate analyses of samples stored in polyvinylchloride bags, where substantial changes were observed in size-exclusion high-performance liquid chromatography main peak area at 12 months and in ion-exchange high-performance liquid chromatography main peak areas at the 6-month and subsequent time points. Decreasing trends in main peak areas were detected by ion-exchange high-performance liquid chromatography analyses and non-reduced capillary electrophoresis-sodium dodecyl sulfate analyses of samples taken from polyolefin bags, where substantial changes were observed in ion-exchange high-performance liquid chromatography main peak areas at 6 and 12 months. In conclusion, atezolizumab diluted to 2.4 mg/mL to 16.8 mg/mL in 0.9% sodium chloride remains physicochemically stable when stored for 24 hours at 30°C, followed by 3 months at 2°C to 8°C in polyvinylchloride and polyolefin infusion bags.