Industrial production processes, which utilize mammalian cells for the production of therapeutic proteins are routinely designed to include temperature and pH shifts. The process conditions are shifted away from growth promoting conditions towards a state of decreased metabolic activity. This results in the extension of the cultivation duration and therefore in a higher final product concentration. Although the correct timing of these shifts is essential for peak process performance, not many studies have been investigating this topic. In this work temperature and pH shift were optimized with a mechanistic model to increase the final product concentration in comparison to an established industrial fed-batch process. The major advantage of the mechanistic in comparison to a data-driven approach lies in the reduced number of experiments, which is needed. Therefore process development is faster, which decreases the time of the product to the market. Based on the optimization, an increased final product concentration of 14% was achieved in comparison to an already established industrial fed-batch process with the same cell line. Furthermore, the space-time-yield of the process did increase in comparison, resulting in a 20% increase of the final volumetric product concentration. (C) 2019, The Society for Biotechnology, Japan. All rights reserved.