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

Area of Science:

• Pharmaceutical science
• Biotechnology
• Drug delivery systems

Background:

• Closed System Transfer Devices (CSTDs) are widely used in oncology for safe handling of hazardous drugs.
• The impact of CSTDs on the stability and integrity of biologics, such as monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), and fusion proteins, is not fully understood.
• Particle formation during preparation and administration can affect drug efficacy and patient safety.

Purpose of the Study:

• To investigate particle formation in three experimental biologics (mAb, ADC, fusion protein) when processed using seven different CSTD models.
• To identify the composition of generated particles and correlate particle formation with CSTD design and fluid dynamics.
• To assess the influence of CSTD fluid path geometry on protein stability.

Main Methods:

• Preparation and mock administration of three experimental biologics using seven CSTD models.
• Analysis of visible and subvisible particle formation.
• Characterization of particle composition using techniques like X-ray micro-computed tomography.
• Computational fluid dynamics (CFD) analysis to evaluate shear stress and solution residence time within CSTD fluid paths.
• Control experiments involving silicone oil spiking.

Main Results:

• A wide range of visible and subvisible particle formation was observed across different CSTD models.
• Particles were identified as consisting of silicone oil and protein.
• X-ray micro-computed tomography revealed highly tortuous fluid paths in most CSTDs.
• CFD analysis showed a 154-fold difference in maximum shear stress and significant variations in residence time between high- and low-particle-forming CSTDs.
• Silicone oil exposure alone did not account for the majority of particle formation.

Conclusions:

• The geometry of CSTD fluid paths significantly influences particle formation during biologic drug preparation and administration.
• CSTD design can negatively impact protein stability, leading to the formation of silicone oil and protein particles.
• Further research into CSTD design is warranted to ensure the integrity of biologic therapeutics.