Two methodological improvements of the design of dynamic experiments (C. Georgakis, Ind Eng Chem Res. 2013) for the modeling and optimization of (semi-) batch processes are proposed. Their effectiveness is evaluated in two representative classes of biopharmaceutical processes. First, we incorporate prior process knowledge in the design of the experiments. Many batch processes and, in particular, biopharmaceutical processes are usually not understood completely to enable the development of an accurate knowledge-driven model. However, partial process knowledge is often available and should not be ignored. We demonstrate here how to incorporate such knowledge. Second, we introduce an evolutionary modeling and optimization approach to minimize the initial number of experiments in the face of budgetary and time constraints. The proposed approach starts with the estimation of only a linear Response Surface Model, which requires the minimum number of experiments. Accounting for the model's uncertainty, the proposed approach calculates a process optimum that meets a maximum uncertainty constraint. (c) 2017 American Institute of Chemical Engineers AIChE J, 63: 2796-2805, 2017