A multitude of heterologous proteins is needed in pharmaceutical research. These have to be produced in robust and flexible cultivation systems to allow a fast and cost-effective handling. Moreover, these systems should be scalable and meet quality and regulatory requirements. The baculovirus expression vector system propagated on High Five insect cells is a popular choice for this purpose. For this expression system an efficient, robust and scalable process was developed based on a single-use technology and a medium replacement strategy with cell retention. It is shown that a medium replacement in the Wave bioreactor is feasible and can be scaled up to a 10-L scale without much effort.