Closed system transfer devices (CSTD) are broadly used in healthcare settings as an adjunct engineering control to limit personnel exposure to hazardous drugs (HD). Mechanistic and material differences between CSTD and traditional in-use devices warrant assessment of their impact to product quality and deliverable dose. A lyophilized antibody-drug conjugate (ADC) product was assessed for holdup volume and material compatibility with 14 diverse CSTD sets in a simulated dose compounding scheme. Transient exposure to CSTD showed no negative impact to product quality attributes; however, 6 CSTD sets showed a substantial increase in subvisible particles with a morphology consistent with silicone oil. CSTD led to variable but consistently reduced recovery of dose from the product. In addition, devices with high holdup volumes resulted in dilution of reconstituted drug product and protein concentrations below the target. Given the complexities and potential implications for efficacy and patient safety, this study illustrates the need for proactive assessment and risk mitigation, as well as increased awareness from clinicians, pharmaceutical manufacturers, device developers, and relevant regulatory authorities.