Impact of Closed System Transfer Device (CSTD) Handling Procedure for Low-Transfer-Volume Dose Preparation of Biologic Drug Products

Abstract

Many challenges have been identified for ensuring compatibility of closed system transfer devices (CSTDs) with biologic drug products. One challenge is large hold-up volumes (HUVs) of CSTD components, which can be especially problematic with early-stage biologics when low transfer volumes smaller than the nominal fill volume may be used to achieve a wide range of doses with a single drug product configuration. Here, we identified possible CSTD handling techniques during dose preparation of a drug product requiring small volume transfers during reconstitution, intermediate dilution, and dilution in an IV bag, and systematically evaluated the impact of these handling procedures on the ability to deliver an accurate dose to the next step. We show that small changes to CSTD procedures can have a major impact on dose accuracy, depending on both CSTD HUVs and drug product-specific transfer volumes. We demonstrate that it is possible to craft CSTD instructions for use to mitigate these issues, and that the dose accuracy for specific drug product/CSTD combinations can be estimated using theoretical equations. Finally, we explored potential downsides of these mitigations. Our results emphasize key factors for consideration by both drug and CSTD manufacturers when assessing compatibility and providing CSTD instructions for use with biologics requiring low transfer volumes during dose preparation.

Keywords: Biologic drug product(s); Clinical trial simulation(s); Closed system transfer devices (CSTDS); Dose accuracy; Drug delivery system(s); Drug transfer; Physical stability; Product loss; Protein formulation(s).