Physical stability of bevacizumab solutions for intravitreal injections: influence of the packaging device and storage conditions

Introduction
The treatment of several retinal pathologies requires the off-label use of intravitreal medications prepared by hospital pharmacies in medical 3 pieces syringes. These syringes are generally lubricated with silicone oil which has been shown to be able to leach out into the content and contaminate the medication, thus promoting monoclonal antibody physical instabilities (1). Recently, new types of syringes devoid of silicone oil have been developed. The aim of this work was to investigate and compare the physical stability of bevacizumab stored in syringes made of polypropylene lubricated with silicone oil (PP-SOL) or in novel Cyclic Olefin Copolymer with crosslinked silicone at the surface of the barrel and no silicone oil (COC-CLS).

Methods
0.2 mL of bevacizumab solutions (25 mg/mL) were conditioned in both types of 1 mL syringes and the physical stability and particles or aggregate generation was followed after 3 days, 1 month and 3 months of storage, under two different storage conditions: refrigerated temperature (5±3°C) and heat stress temperature (35±2°C), assimilated to an accelerated study condition. The assays that where employed were aggregation index measurements (AI), size exclusion chromatography (SEC), subvisible particular counting and dynamic light scattering analysis (DLS). Results are presented as mean ± 95% confidence interval.

Results
Whilst the AI remained unchanged for the solutions stored at 5°C, for solutions stored in PP-SOL syringes at 35°C it increased by 16.2 ± 3.4 % compared to only 2.7 ± 0.5 % with COC-CLS syringes after 3 months of storage. SEC results showed a faster decrease of bevacizumab monomer peak for the solutions stored in PP-SOL compared to COC-CLS, especially at 35°C (13.42 ± 4.9 decrease versus 2.76 ± 0.1 %). High molecular weight products and fragment also appeared faster in PP-SOL syringes. The COC-CLS syringes also generated less subvisible particles than the PP-SOL ones, especially when under thermal stress. DLS results did not show any significant size variation of the main particle population. However, polydispersity index raised from 0.0 to 0.4 after 3 months at 35°C in PP-SOL versus 0.2 in COC-CLS

Discussion/Conclusion
Overall, the physical stability of bevacizumab solutions seemed to be superior with COC-CLS syringes than with the PP-SOL syringes, especially when stored for 3 months after conditioning and when stressed. The difference is likely due to the presence of the silicone oil in PP-SOL syringes with could promote aggregation and particle generation. This work shows that even for short to medium storage periods, choosing the right packaging materials for primary packaging devices destined to contain monoclonal antibodies remains primordial in order to maximise patient therapeutic safety.

(1) Kannan et al. Adsorption and Aggregation of Monoclonal Antibodies at Silicone Oil-Water Interfaces. Mol Pharm. 5 avr 2021;18(4):1656‑65.