BACKGROUND Polyhydroxyalkanoate-type polymers (PHAs) are claimed as an alternative for replacing conventional plastics; but the economic feasibility of its production should still be assured in order to accomplish such a massive goal. In a previous work on fed-batch production of PHAs, it was shown that the process yield and the properties of the biopolymer obtained highly depend on the type of feeding strategy applied. Such results evidenced the need for implementing optimization-based control strategies to control the process in real-time, rather than implementing pre-defined feeding policies. RESULTS In this study, real-time optimization for the fed-batch production of PHAs at pilot plant scale from a low-cost substrate (vinasses-molasses mixture) is presented. Two optimization-based control strategies were developed to calculate the optimal feed flow rate. One strategy considered only the process productivity as an objective, whereas the other incorporated not only productivity but also a profitability-oriented objective. The latter resulted in a productivity of 0.364 g/L h and a maximal polymer concentration of 62.03% cell dry weight,versus0.043 g/L h and 6.25% attained by applying a traditional feedback control law. CONCLUSION Implementation of closed-loop based-optimal control policies in PHA production has led to higher yield and polymer concentration, confirming that an improved operation of fed-batch bioprocesses is reached when the feeding policy is updated in real-time, according to an optimization goal. Despite implementation costs, applying this approach might be the best alternative for simultaneously facing uncertainties and achieving optimal operation at an industrial scale, especially when living microorganisms are used as factories. (c) 2020 Society of Chemical Industry