Stability study of a biosimilar of Bevacizumab in vials and after dilution in 0.9% NaCl in polyolefin IV bags

V. Vieillard, M. Paul
CHU Henri Mondor, Créteil, France

Background
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.

Objectives
To study the stability of the Bevacizumab biosimilar Alymsys® marketed by Laboratoire Zentiva 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.

Material and methods

The vials were supplied by Laboratoire Zentiva. The vials (three batches) were diluted to the final concentrations of 1.4 mg/mL or 16.5 mg/mL in NaCl. The IV bags and vials were stored at 4°C and at room temperature. 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 after 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 gel 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.

Conclusion
Before opening, vials are stable 15 days at 25°C and 60 days when stored between +2°C and +8°C after opening, protected from light. After dilution in sterile conditions with 0.9% NaCl in polyolefin IV bags, at the usual concentrations of 1.4 mg/mL and 16.5 mg/mL, the Bevacizumab biosimilar Alymsys® is stable for at least three months between +2°C and +8°C protected from light. After a three-day temperature excursion at +25°C followed by a return to temperature between 2°C and 8°C, stability data remained inchanged.

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