Closed System Transfer Devices (CSTD) are a supplemental engineering control designed to reduce occupational exposure of hazardous drugs and are currently implemented in accordance to evolving regulations. Due to the novelty and complexity of these devices and their importance in clinical in-use testing, here we evaluated FDA approved CSTD, assessing product quality through stability indicating assays to determine any drug product incompatibilities. Six devices were used in a simulated compounding and administration of a late phase IgG1 Antibody Drug Conjugate (ADC) and the resulting samples were analyzed for visible and subvisible particle counts by light obscuration and micro-flow imaging, physical stability by size exclusion chromatography, and biological activities by relative potency. Potential challenges included improper fit of CSTD components, loss of product to void volume, and material incompatibility. Results showed compatibility of the ADC with the six CSTD evaluated. One CSTD introduced subvisible particles into the ADC during compounding that were identified through morphological assessment as silicone oil. This study highlights the importance of clinical in use testing with new devices and proposes strategies to mitigate the risk of drug product incompatibility with CSTD.