<p>Antibody–drug conjugates (ADCs) represent a rapidly expanding class of therapeutics, combining the specificity of monoclonal antibodies with the potency of cytotoxic payloads. Their increasing clinical adoption introduces complex challenges for safe handling, preparation, and administration that extend beyond traditional hazardous drug and monoclonal antibodies – based therapies protocols. These inherent complexities of ADCs necessitate strict controls during handling and administration. This review outlines the current regulatory frameworks and institutional practices guiding ADC’s in-use handling and highlights key limitations within these practice systems. We examine current handling practices, including the regulatory and institutional guidance landscape, engineering controls, aseptic compounding environments, and the use of personal protective equipment (PPE), as well as the integration of closed system transfer devices (CSTDs) into clinical and pharmacy workflows. This paper addresses ADC dosing solution stability and administration material compatibility, highlighting risks such as undesired interaction with IV bag materials, tubing, and other administration components while identifying potential gaps in compatibility information availability and accessibility. In addition, the effectiveness of closed-system transfer devices (CSTDs) and their implementation into the clinical workflow are discussed. Finally, we provide recommendations to address the identified gaps to promote safer, more consistent clinical handling practices. Given the complexity of ADC products, the rise of novel ADC constructs, and their expanding application in targeted therapies and alternative administration routes, continued ADC-specific research and regulatory guidance will be essential to achieve safe and effective clinical implementation.</p> Graphical Abstract <p></p>