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

By combining the unique targeting ability of monoclonalantibodieswith the cancer-killing ability of cytotoxins, antibody-drugconjugates (ADCs) exhibit unique properties that preclude them frombeing viewed strictly as either a biologic or a small molecule. Instead,they are more accurately considered as hybrid compounds with uniqueattributes. In the absence of a formal regulatory guidance for Chemistry,Manufacturing, and Controls (CMC) development specific to ADCs, biopharmaceuticalindustry companies and regulatory agencies follow existing regulatoryguidelines for small molecule drugs and monoclonal antibodies. Conventionalregulatory strategies involve the need to understand material attributesand their potential impact to downstream quality. Control strategiesfor both small and large molecule development should consider theorigin and significance of impurities as they relate to the finalADC drug substance. This understanding is also used to help designatea starting material (SM) for CMC regulatory filings. While historicallyregulatory authorities have treated the drug-linker as a drug substance,it is in fact an intermediate in the ADC process. This paper discusseshow the principles of ICH Q11 for SM designation for drug substance(e.g., the ADC) can be applied to the drug-linker moiety to supportidentification of suitable SMs for ADCs. It also highlights key ADCfactors, including the structure of the hybrid conjugate and specificmanufacturing steps such as the post-conjugation purification by ultrafiltration/diafiltration,that should be incorporated into the SM designation process and theoverall control strategy for small molecule impurities.