The manufacturing of large-scale parts needs the implementation of a holistic data management and integrated automation methodology to achieve the desired levels of precision using modular and more flexible equipment. Large-part manufacturing is characterized by the high customization required (built-customer specific). Also, manufacturing of complex large-scale parts involves a variety of subassemblies that must be manufactured and assembled. This high degree of personalization implies a great effort in the design and the posterior verification after manufacturing, to achieve high precision. On the other hand, this customised product-centric design requires an optimisation of the resources of the workshop –i.e. workers, machines, devices— for a responsive, reconfigurable and modular production, targeting the execution of key labour-intensive tasks by preserving industry-specific workers’ knowledge and skills (worker-centric approach). PENELOPE proposes a novel methodology linking product-centric data management and production planning and scheduling in a closed-loop digital pipeline for ensuring an accurate and precise manufacturability from the initial product design. PENELOPE is built over five pillars for developing a common methodology and vision deployed in four industrial-driven pilot lines in strategic manufacturing sectors (Oil&Gas, Shipbuilding, Aeronautics and Bus&Coach) and with potential replicability to other sectors. Moreover, it will be set a pan-European network of Didactic Factories and showrooms, providing training and upskilling capabilities enabling the workforce transition towards Industry 4.0 and general-purpose testbeds for assisting in the industry adoption. PENELOPE envision to highly-increase EU manufacturing sector competitiveness by increasing production performance, quality and accuracy while ensuring workers’ safety and resource efficiency.