CMC Regulatory Considerations for ADCs

Antibody drug conjugates unite the specificity and long circulation time of an antibody with the toxicity of a chemical cytostatic drug using smart linkers to reduce systemic toxicity and increase therapeutic index. This combination of a large biological molecule and a small synthetic molecule creates an inherent increase in complexity. Multiple production processes are required to produce the naked antibody, the drug and the linker, followed by conjugation of aforementioned entities to form the final antibody drug conjugate. The connected processes further increase the number of points of control, resulting in necessity of additional specifications and an increased load of analytical characterization. By combining scientific understanding of the production processes with risk-based approaches, quality should be demonstrated at those points where control is required and redundant comparability studies, specifications or product characterization avoided. Over the product development lifecycle, this will allow process qualification to focus on those areas affected by a change and prevent redundant studies. The structure of a module 3 global technical dossier for an ADC needs to reflect each of the production processes and the combined overall approach to quality. Historically, regulatory authorities have provided varied expectations on its structure. An overview is provided of essential information to be included showing that multiple approaches work as long as adequate cross-referencing is included. This talk outlines the content of a white paper soon to be published by a workstream under the Biomanufacturing Working Group by EFPIA.