At-scale industrial continuous twin screw wet granulation process was analyzed and optimized via design of experiment (DoE). The Box-Behnken method was selected to investigate the influence of key process variables on granule properties and tablet properties. The effects of the key process variables were analyzed. The experimental results have demonstrated that both the granule properties and tablet properties are influenced by the throughput, the screw speed and the screw element. Particularly, the screw element type and the milling process were found having significant effects on tablet tensile strength and disintegration time. The design space (DS) based on volume average granule diameter (Y-4 < 800 mu m) and tablet disintegration time (Y-8 < 4 min) was determined using Monte Carlo simulations. Validation experiments have shown the robustness of the DS. A case study of the DS application is presented. It was demonstrated how to select optimum working conditions of key process parameters based on the DS. (C) 2019 Elsevier Ltd. All rights reserved.