By Dr. Guanghui Zhu, Takeda Pharmaceuticals Particle engineering has emerged as a critical frontier in pharmaceutical process development, enabling control over drug formulation and delivery. By manipulating the size, shape, surface properties, and composition of API particles, researchers can significantly enhance drug solubility, bioavailability, and targeted efficacy. This approach allows overcoming traditional challenges such as poor absorption, inconsistent drug release, and limited therapeutic performance, particularly for challenging molecules like poorly water-soluble compounds. Advanced particle engineering techniques, including crystallization, milling, and spray drying, provide powerful tools to optimize drug properties to meet performance requirements. For rapidly advancing developmental compounds, precise control of particle size distribution is essential for both in vivo and in vitro studies. Our research presents an innovative combined experimental and modeling methodology designed to maximize knowledge while minimizing resource expenditure during crystallization and wet milling process development. Population balance modeling and CFD modeling for crystallization enabled consistent scale-up performance, providing reproducible input PSD for subsequent wet milling processes. During wet milling, our findings demonstrate that matching generator configuration and turnover number did not consistently produce transferable results across scales. Notably, flowrate—traditionally not considered a controlled variable—significantly impacts wet milling outcomes. A mechanistic wet mill model was developed to better inform scale-up milling conditions. Furthermore, while certain PSD percentiles (D50 or D90) may align between different mill scales, the overall particle size distribution shapes often differ, sometimes presenting bimodal distribution. We discovered that even with minimal temperature dependence of solubility, an Oswald ripening process can be applied to sharpen the distribution shape, thereby providing enhanced particle property control during scale-up. Finally, we demonstrated that in addition to primary particle size control, secondary particles (agglomerates) can cause content uniformity issues during formulation. We employed Acoustic Mixer to evaluate agglomerate friability and developed an agitated filter drying procedure to reduce agglomeration formation during drying. A final co-milling process was implemented to control agglomerates in the packaged API, ensuring consistent product quality and performance.