ADCs: Why the Most Exciting Modality in Oncology Is Also the Most CMC-Demanding

A Pharmefex Thought Leadership Article

ADCs have become a defining modality of oncology investment. The global market reached $13.5 billion in 2025, with 15 FDA-approved products and more than 400 programs in development. BioNTech committed up to $7.6 billion in milestones for a single collaboration. Eli Lilly pledged $5 billion to dedicated ADC manufacturing infrastructure. The clinical results are supporting the enthusiasm: Enhertu's expansion into HER2-low disease added 200,000 newly treatable patients in the U.S. with a single regulatory action.

What makes ADCs work is an antibody targeting a tumor-specific antigen, a linker engineered to stay stable in circulation, and a cytotoxic payload released only after internalization. Payloads are 100 to 1,000 times more toxic than conventional chemotherapy, delivered with precision systemic treatment cannot match.

What makes them difficult to develop is that they carry the full CMC complexity of both a biologic and a small molecule, plus a third layer: conjugation chemistry that neither framework was designed to address. The antibody requires biologic-grade process control. The linker-payload must meet HPAPI containment standards. And conjugation must produce a consistent drug-to-antibody ratio across batches, clinical phases, and sites. No single analytical method covers all of this. FDA data shows 11 of 32 Complete Response Letters for biologic programs were attributed to CMC deficiencies. ADCs face that same scrutiny with no ADC-specific CMC guideline from FDA or EMA.

Programs that treat CMC as a Phase 2 problem consistently find that it becomes a Phase 3 crisis.

At Pharmefex, we support ADC programs with integrated oversight across antibody production, linker-payload synthesis, and conjugation as a single workflow, with specialists who think across both the biologic and small molecule sides of the equation. The full article explores what that means in practice.

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