Physicochemical stability study of a biosimilar of Bevacizumab in vials and after dilution in 0.9% NaCl in polyolefin intravenous bags

Abstract

Abstract Objectives Bevacizumab was first marketed in 2005. Since then, its stability has been extensively studied. The arrival of numerous biosimilars on the market has called into question these stabilities and organisation within reconstitution units. To study the stability of the Bevacizumab biosimilar Alymsys® marketed by Zentiva laboratory in ready-to-use vials at a concentration of 25 mg/mL and following dilution to obtain final concentrations of 1.4 and 16.5 mg/mL and storage in polyolefin IV bags at 4 °C. In parallel, the impact of a storage temperature excursion at 25 °C for three days and storage of the vial before opening at room temperature (25 ± 2 °C) and after opening at 4 °C was studied. Methods The vials were supplied by Zentiva laboratory. The vials (three batches) were diluted to the final concentrations of 1.4 or 16.5 mg/mL in 100 mL IV bags of NaCl. The IV bags and vials were stored at 4 °C and at room temperature throughout the duration of the study. The physico-chemical stability was tested using the following methods: turbidimetry, UV spectrometry and fluorescence, dynamic light scattering, ion exchange and steric exclusion chromatography, pH, osmolality and density. Results Out of all the parameters studied, for the two concentrations and standard storage conditions (90 days at +4 °C) or after a three-day temperature excursion at +25 °C, no modification was detected for the three batches tested with respect to physical and chemical stability. Hence, no signs of physical instability were observed, with, in particular, the absence of formation of submicron or micron sized aggregates and particles. The steric exclusion chromatography profiles did not demonstrate any oligomer formation or molecular structure rupture. Ion exchange chromatography did not demonstrate any significant modification in the distribution of charge variants. Derivative UV and fluorescence spectral analysis did not demonstrate any modification. The thermal denaturation curves were identical, suggesting the absence of thermodynamic destabilisation. Identical results were observed for the vials stored for 60 days at 4 °C after opening. Finally, only ion exchange chromatography demonstrated a slight change after 45 days of storage at 25 °C for vials before opening. Conclusions After dilution in sterile conditions with 0.9% NaCl in polyolefin IV bags, at the usual concentrations of 1.4 and 16.5 mg/mL, the Bevacizumab biosimilar Alymsys® is stable for at least three months at 4 °C protected from light and after a three-day temperature excursion at +25 °C. The same conclusions can be reached for the 25 mg/mL vials stored for 60 days at +4 °C after opening. However, the stability of vials stored at 25 °C before opening is no longer guaranteed beyond 15 days.