Hollow fiber-based cell retention has emerged to the preferred technology within the continuous manufacturing of complex therapeutic modalities. Nevertheless, filter fouling remains a major bottleneck in current manufacturing scenarios and scale-up. There lies a huge potential to improve performance by optimizing operating parameters and therefore better control the filtration process. This study investigates how to improve Tangential Flow Filtration (TFF) perfusion systems, which are often limited by membrane fouling and product retention—primarily due to the Starling flow effect caused by pressure drops in hollow fiber filters.