Process scale-up is a critical step in the transition of pharmaceutical preparations from research and development to industrial production. Dry granulation, as a key technology for forming traditional Chinese medicine (TCM) solid dosage forms, offers advantages such as a short process flow, minimal impact on active ingredients, high efficiency, and energy savings. However, its process scale-up faces numerous challenges. This article reviews the key technical bottlenecks in the process scale-up of TCM dry granulation, including critical process parameters, thermodynamic effects of the feeding system and equipment, and critical material attributes. The evolution of scale-up strategies is summarized from perspectives of methodological support and strategic evolution, tracing the progression from traditional empirical scale-up to digital modeling-driven multi-scale intelligent scale-up. Among these, gray-box hybrid modeling, population balance model-based integrated process simulation, and process analytical technology-driven closed-loop feedback control offer new approaches to address nonlinear issues during scale-up. In the future, integrating physical fingerprint with digital twin technology to establish a cross-scale scale-up framework will promote the transformation of process development from “experience-driven” to “model-driven” paradigms, thereby facilitating the strategic upgrade of TCM pharmaceutical manufacturing toward intelligent manufacturing.

dry granulation  /  process scale-up  /  physical fingerprint  /  digital modeling  /  continuous manufacturing  /  quality by design