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A novel two-layer predictive control scheme for a continuous biodiesel transesterification reactor is presented. Based on a validated mechanistic model, the least squares (LS) algorithm is used to identify the finite step response (FSR) process model adapted in the controller. The two-layer predictive control method achieves the steady-state optimal setpoints and resolves the multivariable dynamic control problems synchronously. Simulation results show that the two-layer predictive control strategy leads to a significant improvement of control performance in terms of the optimal set-points tracking and disturbances rejection, as compared to conventional PID controller within a multiloop framework.