Considerations for Starting Material Designation for Drug-Linkers in Antibody–Drug Conjugates

By combining the unique targeting ability of monoclonal antibodies with the cancer-killing ability of cytotoxins, antibody–drug conjugates (ADCs) exhibit unique properties that preclude them from being viewed strictly as either a biologic or a small molecule. Instead, they are more accurately considered as hybrid compounds with unique attributes. In the absence of a formal regulatory guidance for Chemistry, Manufacturing, and Controls (CMC) development specific to ADCs, biopharmaceutical industry companies and regulatory agencies follow existing regulatory guidelines for small molecule drugs and monoclonal antibodies. Conventional regulatory strategies involve the need to understand material attributes and their potential impact to downstream quality. Control strategies for both small and large molecule development should consider the origin and significance of impurities as they relate to the final ADC drug substance. This understanding is also used to help designate a starting material (SM) for CMC regulatory filings. While historically regulatory authorities have treated the drug-linker as a drug substance, it is in fact an intermediate in the ADC process. This paper discusses how the principles of ICH Q11 for SM designation for drug substance (e.g., the ADC) can be applied to the drug-linker moiety to support identification of suitable SMs for ADCs. It also highlights key ADC factors, including the structure of the hybrid conjugate and specific manufacturing steps such as the post-conjugation purification by ultrafiltration/diafiltration, that should be incorporated into the SM designation process and the overall control strategy for small molecule impurities.