The effect of light in combination with shocks on the physical stability of infusion bags with monoclonal antibodies

Abstract

Aim: It is known that incorrect storage or mishandling of monoclonal antibodies (mAbs) could lead to aggregation and in the worst case to immunogenic reactions. Therefore, conditions as temperature, light exposure, and exposure to shocks during manufacturing and storage are well monitored and the effect of it is known. Little is known about the effect of these stress factors during administration, for instance when a patient goes on an outside walk. For that reason, the aim of this study was to investigate the effect of light in combination with shocks on the physical stability of infusion bags with monoclonal antibodies. Materials and methods: Infusion bags were prepared with leftover reconstituted vials of infliximab and pembrolizumab. They were exposed to several types of stress, namely light, shocks and light in combination with shocks. There also was a group of mAb infusion bags that was not stressed (unstressed). Each group also contained 2 NaCl 0.9% infusion bags without anything added to measure background particles. After stressing the infusion bags, they were analysed with dynamic light scattering (DLS), nanoparticle tracking analysis (NTA), size exclusion chromatography (SEC), and micro- flow imaging (MFI). Statistical analysis was done with a one-way ANOVA and Tukey HSD post-hoc test or Brown-Forsythe and Games-Howell post-hoc test depending on the result of Levene’s test for equality of variances. Results and interpretation: In the nanometer range exposure to light seems to negatively influence the physical stability of both infliximab and pembrolizumab based on the results of DLS and SEC. This was only significantly proven for pembrolizumab with SEC (p = 0.007). For NTA no reliable results were obtained. In the micrometer range no general effect could be found for infliximab and pembrolizumab. However, MFI detected significantly higher particle concentrations for shocks (p = 0.002) and light combined with shocks exposure (p = 0.002) compared to unstressed for pembrolizumab. Regarding the requirements of the Pharmacopoeias for parenteral formulations infliximab exposed to any stress factor could still be used, but pembrolizumab exposed to any stress factor could not be used anymore. Despite these requirements further research is needed before administering these products to patients. For example, biological activity should be tested and other analytical techniques that can detect around 1 μm should be used. Conclusion: This study was not elaborated enough to conclude if infliximab and pembrolizumab can still be administered to patients. However, based on this study, it seems that infliximab and pembrolizumab are both potentially sensitive to light in the nanometer range. To say something about the effect of light in combination with shocks on the physical stability of all mAbs more research is necessary. So, the effect of light in combination with shocks on the physical stability of mAbs remains unknown.