Biologic drugs are promising therapeutics, and their efficient production is essential for a competitive pharma industry. Dynamic flux balance analysis (dFBA) enables the dynamic simulation of the extracellular bioreactor environment and intracellular fluxes in microorganisms, but it is rarely used for model-based optimization of biopharmaceutical manufacturing in Pichia pastoris. To bridge this gap, we present a model-based optimization approach based on dFBA to produce biologics in P. pastoris that combines ideas from bilevel optimization, penalization schemes, and direct dynamic optimization. As a case study, we consider the production of recombinant erythropoietin in P. pastoris growing on glucose, and predict a 66% improvement in the productivity of erythropoietin. We show that this improvement could be obtained by implementing an almost constant optimal feeding strategy which is different from typical exponential feeding strategies and that a high activity of most pathways in the central carbon metabolism is crucial for a high productivity. (C) 2018 Elsevier Ltd. All rights reserved.