A CFD‐Based Digital Framework for Scaling Optimization of Orbital Rocking Bioreactors

Robust scale‐up of bioreactor systems requires hydrodynamic similarity across scales to ensure consistent cell culture performance. This study presents a computational fluid dynamics (CFD)‐guided digital framework for optimizing the scale‐up of a novel orbital rocking bioreactor, CELBIC, from CELBIC5 (working volume 1–2 L) to CELBIC50 (working volume 10–20 L). Using lattice Boltzmann‐based simulations, key hydrodynamic parameters, including velocity, shear stress, and energy dissipation rate, were evaluated across various working volumes, inclination angles, and agitation speeds. Compared with conventional scale‐up criteria, such as average P/V, we propose a comprehensive and digitalized scale‐up optimization framework: a root mean square error (RMSE)‐based method comparing the full spatial and temporal distributions of various CFD variables to quantify similarities among scaled‐up conditions. This approach allows identification of the best‐matching scaled‐up condition and further refinement using response surface analysis. The optimized condition (10 L, 7°, and 19 rpm) exhibited the lowest combined RMSE relative to the reference condition (CELBIC5 at 1 L, 6°, and 30 rpm), suggesting substantial hydrodynamic equivalence. Overall, this study demonstrates how integrating CFD‐ and RMSE‐based analyses enables rational scale‐up of orbital rocking bioreactors, offering a systematic strategy for digital process development in single‐use systems.