Why FDA Complete Response Letters Involve Manufacturing Issues – And What Must Change In Cell Therapy

By Cindy Riggins, Head of CMC Regulatory Affairs, ElevateBio

Examine why manufacturing and quality issues have become the leading cause of FDA Complete Response Letters in cell therapy, highlighting industry data showing that a significant portion of CRLs from 2020–2024 stem from deficiencies in CMC strategy, assay readiness, process robustness, and facility preparedness. These problems rarely emerge suddenly; instead, they originate from development choices made during preclinical and early clinical phases, where pressure to accelerate timelines or cut costs can leave critical gaps unaddressed. As cell therapy programs move toward approval, those early decisions resurface, resulting in delays, additional costs, and jeopardized program trajectories.

Key issues include incomplete CMC packages, assays not built for late‑stage or commercial demands, inconsistent product quality, and scale‑up challenges that undermine comparability and reproducibility. The insights underscore the need for stronger early manufacturing strategy, rigorous analytical foundations, and proactive readiness to meet modern regulatory expectations for complex cell‑based therapeutics.