The use of spray drying in the pharmaceutical industry is growing at a fast pace. The need for robust scale-up methods is essential in order to control critical quality attributes and improve powder properties during drug development. Moreover, poor scale-up is likely to lead to considerable losses of expensive materials. Process understanding and simulation is a very powerful tool to support the scale-up of spray drying processes. A scale-up methodology based on scientific principles is proposed in this study. The method is divided in two steps: thermodynamic and atomization & particle formation. The method is relatively straightforward to apply and has been tested in numerous spray-dried formulations across all production scales. An illustrative example is also shown covering the main steps of the proposed methodology.