Toward end-to-end continuous biopharmaceutical manufacturing: Current advances and prospects

End-to-end continuous biopharmaceutical manufacturing extends process intensification from improved standalone unit operations to integrated process trains designed for long-duration operation with minimal pooling. This review synthesizes recent progress across upstream and downstream processing and frames end-to-end continuity as a system-level integration and interface-engineering problem in which throughput, residence-time behavior, and quality are jointly managed. Upstream perfusion sustains high viable cell density and productivity, but it tightens constraints on critical process parameters and demands robust monitoring to deliver a consistent feed. In downstream processing, continuous capture and polishing, continuous conditioning, and continuous-compatible viral clearance steps are increasingly feasible. However, long-duration robustness, cyclic dynamics, and sensitivity to feed variability remain central considerations. Across integration case studies, the dominant barrier is not missing unit operations but unresolved interface mismatches, especially between steady upstream harvest and cyclic downstream operations, that drive surge and hold requirements unless engineered out through residence-time and cycle-time synchronization, in-line conditioning, and long-duration filtration performance management. In addition, process analytical technologies and digital twins underpin real-time observability and control, while ultra scale-down and high-throughput development workflows accelerate operating-window definition and generate data for model calibration and control design. Overall, practical end-to-end continuity depends on coordinated advances in interface engineering, platform-level integration, and credible validation strategies for extended continuous operation.