Manufacturing companies face increasing pressure to adapt to shorter product life cycles and higher product variety. Currently, manufacturing systems are typically designed with a conservative, project-based approach, primarily focused on a shorter payback period in an attempt to avoid the impact of future demand uncertainty. Consequently, manufacturing companies are faced with (1) low utilization (e.g. ramp up and ramp down) and limited reuse potential of systems (e.g. mix changes, new product variants); and (2) frequent and costly system redesign actions resulting in a struggle to minimize their overall manufacturing system lifecycle cost. The industrial target group are (1) high-mix, low-volume (HMLV) manufacturers that deal with significant product demand uncertainty and operate at least semi-automated manufacturing processes; (2) their machine builders and system integrators; and (3) simulation (-as-a-service) providers of advanced digital design tools. The AGEAS innovation goal is to develop a design framework for cost-efficient manufacturing systems that can accommodate product demand uncertainty. This framework targets a reduction in the manufacturing system lifecycle costs of 30% while halving the engineering effort and ensuring at least a similar productivity and time-to-decision compared with current practice. Three reusable results will be developed: (1) Lifecycle cost assessment tool; (2) Supporting tools for MSD digital model generation and evaluation; and (3) Optimization framework for MSD exploration. Framework verification and validation will be based on Manufacturing System Design (MSD) configurations, performance and cost data of the last 10 years from a research case within the (virtual) InfraFlex and Heal research infrastructure and from several small validation cases of user group companies. As frontrunners, the user group companies will pave the way for a lot of other companies in Flanders with similar challenges. The project consortium will actively disseminate (intermediate) project results towards the broader target group in Flanders.