Scaling-up the extrusion-spheronization process involves the separate scale-up of each of the five process steps: dry mixing, granulation, extrusion, spheronization, and drying. The aim of the study was to compare two screw extrusion systems regarding their suitability for scaling-up. Two drug substances of high- and low-solubility in water were retained at different concentrations as formulation variables. Different spheronization times were tested. The productivity of the process was followed up using the extrusion rate and yield. Pellets were characterized by their size and shape, and by their structural and mechanical properties. A response surface design of experiments was built to evaluate the influence of the different variables and their interactions on each response, and to select the type of extrusion which provides the best results in terms of product quality, the one which shows less influence on the product after scale-up ("scalability") and when the formula used changes ("robustness"), and the one which allows the possibility to adjust pellet properties with spheronization variables ("flexibility"). Axial system showed the best characteristics in terms of product quality at lab and industrial scales, the best robustness at industrial scale, and the best scalability, by comparison with radial system. Axial system thus appeared as the easiest scaled-up system. Compared to lab scale, the conclusions observed at industrial scale were the same in terms of product quality, but different for robustness and flexibility, which confirmed the importance to test the systems at industrial scale before acquiring the equipment.