This paper is concerned with enhanced process design and control of a multiple-input multiple-output (MIMO) granulation process. The work is based on a first-principles mechanistic three-dimensional population balance model (3D-PBM), which has been previously validated against experiments at the laboratory-scale for various operating conditions and formulations. The main objective of this study is via a novel process design, to control and operate the granulation process under more optimal conditions. Novelty of the work lies in the usage of the validated 3D-PBM to extract suitable multiple control-loop pairings from which an overall control loop performance is qualitatively and quantitatively assessed. Results show that for most existing granulation process configurations, enhanced control-loop performance is not achieved and as a result an alternative process design strategy is necessary. The proposed design demonstrates increased efficiency in the control and operation of the granulation process, which is required for further efficient control and operation of subsequent downstream processes. (C) 2011 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.