Process intensification (PI) has the potential to improve existing processes or create new process options, which are needed in order to produce products using more sustainable methods. In principle, an enormous number of process options can be generated but where and how the process should be intensified for the biggest improvement is difficult to identify. In this paper the development of a systematic computer aided model-based synthesis and design methodology incorporating PI is presented. In order to manage the complexities involved, the methodology employs a decomposition-based solution approach. Starting from an analysis of existing processes, the methodology generates a set of process options and reduces their number through several screening steps until from the remaining options, the optimal is found. The application of the methodology is highlighted through a case study involving the chemo-enzymatic synthesis of N-acetyl-D-neuraminic acid (Neu5Ac). (C) 2011 Elsevier Ltd. All rights reserved.