Regulatory and Quality Considerations of Antibody-drug Conjugates.

Antibody-Drug Conjugates (ADCs) have become well-established as an important class of oncology therapeutics with 15 FDA-approved ADCs for various cancer types and hundreds more ADCs in clinical development. This chapter highlights the unique regulatory considerations for the development of ADCs in oncology given their dual nature as biologics and small-molecule drugs. Topics covered include the organization of applications in eCTD format, meeting types with FDA, and key considerations for a successful regulatory application with a particular emphasis on the Chemistry, Manufacturing, and Controls (CMC)-related strategy. Regulatory pathways, such as Fast Track and Breakthrough Therapy, are discussed as options to expedite ADC development. In early development, both the antibody and the cytotoxic linker-payload must meet detailed CMC requirements to ensure patient safety. The transition from a Phase 1-enabling process to a validated, commercial-scale manufacturing process for a biologic involves a complex interplay of science, engineering, and regulatory compliance. This transition is often on the critical path, particularly as many novel biologic therapies receive Fast Track and/or Breakthrough Therapy Designation. This paper outlines the critical steps in process development and scale-up, highlighting common gaps encountered when moving from an early-stage process with limited manufacturing experience to a fully validated commercial process. By providing a comprehensive overview of the required regulatory deliverables and a roadmap for sequencing key workstreams, this paper aims to guide readers through the essential steps and potential pitfalls in advancing a biologic therapy from early clinical development to market launch.