Current approaches to downstream process development in the biopharmaceutical industry are commonly based on a combination of platform technology, high-throughput experimentation, and 'rules of thumb'. These empirical strategies conflict with demands for a mechanistic process understanding and a rational definition of design space, issued by the Quality by Design approach (QbD). Model-based process simulation and optimization are options for implementation of QbD. A model-based process optimization approach has to consider the complexity of biopharmaceutical downstream processes, especially the interactions of multiple chromatographic operations. We present a case study on model-based concerted process optimization of two consecutive ion exchange chromatographies (Poros 50HS and QSepharose FF). Our optimization approach includes a process flowsheet optimization, the shape of the salt gradient, and the boundaries of fraction collection for both columns. The superiority of the presented concerted process optimization approach is demonstrated by comparison to a sequential approach that optimizes the two ion exchange chromatographies (IEX) consecutively. Verification is carried out with a set of three model proteins (cytochrome c, chymotrypsin, ribonuclease A). The in silico optimum is reproduced in lab experiments and the modeling tool is successfully employed for the identification and characterization of critical process parameters (CPP). (C) 2014 Elsevier B.V. All rights reserved.