Facing an increased pressure for sustainable manufacturing, the resource demanding but essential process of cleaning-in-place (CIP) requires further optimization. This study aims to understand the mechanisms involved in CIP by designing a process that emulates industrial pasteurization. Whey protein fouling was generated on a stainless-steel metal surface and cleaned the use of an alkaline solution. Cleaning was monitored with optical and UV–Vis spectroscopy measurements recording the fouling thickness and dissolved protein mass in the effluent respectively. Experimental results reveal the mechanisms at play during cleaning, showing a two-stage behavior. The first stage is dominated by the diffusion of NaOH and reaction within the fouling. During the second stage, a drag force peels the fouling from its front edge, assisting removal. The cleaning rate increased with the increase of liquid velocity and temperature. The cleaning rate also depended on the axial location. The cleaning time between two positions 10 cm apart differed by 1.2 min, with a total cleaning time of 5.8 min (at a Reynolds number of 5500 and 70 °C). By developing a model based on observed mechanisms, the study explores using effluent concentration to indicate residual fouling mass and estimate the required cleaning time.