The goal of our study was to develop a rational in silico scale-up and process transfer approach for hot melt extrusion processes occurring in the pharmaceutical and other industries. To that end, we performed high-fidelity simulations of individual twin-screw extruder elements via the Lagrangian-based Smoothed Particle Hydrodynamics (SPH) method. To parametrize a mechanistic 1D hot-melt extrusion (HME) model, the data generated by the SPH simulations was used together with the material properties. Two co-rotating twin-screw extruder setups were compared: the Coperion ZSK18 and the Leistritz MIC27 extruders. The pressure and power characteristics of the two extruders with different screw elements and geometries were obtained and compared. The impact of the HME process parameters (throughput, screw speed and barrel temperature) on the filling degree, melt temperature, axial specific mechanical energy consumption (SMEC) and residence time distribution in the two extruders was established. The torque and SMEC values obtained in silico were then compared to experiments to ensure that the 1D HME simulations were set up correctly. Next, scale-up methods from the literature were evaluated, yielding an unsatisfactory set of process parameters that might lead to material degradation. Finally, a rational scale-up approach was proposed. Based on this novel method alternative parameter settings on the MIC27 extruder were established, assuring equivalent thermo-mechanical load on the product compared to the process using the ZSK18 extruder. (C) 2019 Elsevier Ltd. All rights reserved.