A systematic study of CSTD-generated stress on different biomolecular modalities

Although Closed System Transfer Devices (CSTDs) are used in oncology for dose preparation and administration, the impact of CSTDs on biologics and other non-small molecular modalities are not fully understood. We investigated particle formation when preparing and mock administering three experimental biologics (mAb, ADC, and fusion protein) using seven models of CSTDs. A wide range of visible and subvisible particle formation was observed among CSTD models. Particles were found to consist of silicone oil and protein. X-ray micro-computed tomographic images of the fluid paths of the CSTDs showed that most have highly tortuous fluid paths. Computational fluid dynamics analysis of dose preparation using the CSTDs that produced the highest and lowest amounts of particles demonstrated a 154-fold difference in maximum shear stress as well as a significant difference in solution residence time. Control experiments with silicone oil spiking showed that exposing the proteins to silicone oil does not account for the majority of visible and subvisible particle formation. These results demonstrate that the geometry of the fluid paths of CSTDs can have a detrimental effect on protein stability.