Optimization of biofilm activated sludge (BAS) process via mathematical modelling is an entangle activity since economic, environmental objective and technical decision must be considered. This paper presents a methodology to optimize the operational conditions of BAS process in four steps by combining dynamic simulation techniques with nonlinear optimization methods and with operative decision making criteria. Two set of variables are separately prioritized in the methodology: essential variables related to physical operation to enforce established process performance, and refinement variables related to biological processes that can generate risks of bulking, pinpoint floc and rising sludge. The proposed optimization strategy is applied for the treatment of high COD wastewater under nutrient limitation using an integrated mathematical model for COD removal that include predation, hydrolysis and a simplified approach to the limiting solids flux theory in the secondary clarifier in order to facilitate the convergence of the optimization solver. The methodology is implemented in a full scale wastewater treatment plant for a cellulose and viscose fibre mill obtaining: i) improvement of the effluent quality index (Kg pollution/m 3) up to 62% and, ii) decrease the operating cost index (€/m 3) of the process up to 30% respect the regular working operational conditions of the plant. The proposed procedure can be also applied to other biological treatments treating high COD nutrient-limited industrial wastewater such as from textile and winery production among others. Modelling of biofilm stages and activated sludge provided a better understanding of the intrinsic connections between soluble and particulate compounds, biomass properties and process performance in terms of COD, BOD and TSS (Fan et al. 2017). Commercial simulation platforms, including GPS-X and BioWin can be used to describe the one dimensional (1-D) multi-species biofilm structure and biological behaviour of the treatment process (Li et al. 2016); however, none of these platforms include the description of the predator microorganism which plays a predominant role in a BAS process under certain conditions such as nutrient limited conditions (Revilla et al. 2016a). The authors published recently the mathematical model of BAS process including hydrolysis and predation and uses wastewaters coming from viscose and cellulose production industrial process to validate the model. In Revilla et al. 2016a the whole BAS process was simulated and the evaluation of the role and contribution of predator microorganisms towards COD removal, nutrient requirements and sludge production is displayed. More strict regulations are being imposed regularly in terms of COD, BOD and TSS removal that enforce wastewater treatment technologies to progress (Guerrero et al. 2011; Kamali and Khodaparast 2015). Optimization of an existing facility in terms of cost, operational improvements and removal efficiency is the most effective method of achieving the stricter compliance and the mo...