This study aimed to establish a robust process for producing uniformly sized nanoparticles, a key quality attribute for sustained-release tirzepatide injections. Tirzepatide, a dual GLP-1/GIP receptor agonist, is effective for type 2 diabetes and obesity. While current products are administered once weekly, longer dosing intervals are desired to improve patient convenience and adherence. Microparticles made with biodegradable PLGA gradually degrade in vivo, enabling sustained release. In this study, drug-loaded microparticles were fabricated using a W/O/W double-emulsion solvent evaporation method. To obtain a uniform particle size(350–450nm), sonication time and intensity during emulsification were selected as Critical Process Parameters. Following Quality by Design(QbD) principles, Design of Experiments (DoE) was applied to statistically optimize these CPPs and define robust conditions. The optimized microparticles showed a narrow size distribution within the target range and a polydispersity index(PDI ≤ 0.15), confirming excellent process control and reproducibility. In conclusion, this study established a reproducible method for generating nanoparticles for sustained-release tirzepatide. The results provide a foundation for future optimization of formulations and are expected to contribute to the ultimate development of sustained-release injections, which will significantly improve patient convenience.