Strategies for UF/DF-Based Impurity Removal in the Post-conjugation Purification of Antibody–Drug Conjugates
Lara Fernandez‐Cerezo, Melissa Holstein, Srinath Thirumalairajan, Dante W. Romanini, Pavlo Kos, Thomas Raglione, Paul G. Bulger
Abstract
Antibody–drug conjugates (ADCs) are increasingly prevalent as investigational and marketed treatments for a variety of cancers and other diseases. The structures of most ADCs comprise a small-molecule component (the drug-linker) chemically conjugated to a monoclonal antibody, and this hybrid construct presents a number of challenges for Chemistry, Manufacturing, and Controls (CMC) development. A Small Molecule Considerations for ADC Development Working Group (WG) has been established within the IQ Consortium to serve as a forum for biopharmaceutical industry companies to discuss development strategies for ADCs, with a focus on the drug-linker portion. The preceding paper from the WG presented results from a benchmarking survey of IQ member companies on a number of topics relating to drug-linker development. One of the key findings was that ultrafiltration/diafiltration (UF/DF) is used by all responding companies for purification of the ADC following the conjugation step and is a critical operation for control of small-molecule impurities in the ADC drug substance. UF/DF is well established in monoclonal antibody processing, but to date, there are relatively few literature reports detailing its application to ADCs. To help address this gap, this manuscript presents results and analysis from a more focused survey of IQ member companies on the application of UF/DF for post-conjugation purification of ADCs. Insight is provided into practical considerations such as common operating parameters, relative efficiency of removal of different types of impurities, technical challenges, and application of emerging technologies. In addition, recommendations are offered on where to start when developing a UF/DF process for a new ADC. The overall goals are to provide an overview of current industry practices for UF/DF purification of ADCs and to spur further communication and innovation in this area.