In the Industry 4.0 era, manufacturers strive to remain competitive by using advanced technologies such as collaborative robots, automated guided vehicles, augmented reality support and smart devices. However, only if these technological advancements are integrated into their system context in a seamless way, they can deliver their full potential to a manufacturing organization. This integration requires a system architecture as a blueprint for positioning and interconnection of the technologies. For this purpose, the HORSE framework, resulting from the HORSE EU H2020 project, has been developed to act as a reference architecture of a cyber-physical system to integrate various Industry 4.0 technologies and support hybrid manufacturing processes, i.e., processes in which human and robotic workers collaborate. The architecture has been created using design science research, based on well-known software engineering frameworks, established manufacturing domain standards and practical industry requirements. The value of a reference architecture is mainly established by application in practice. For this purpose, this paper presents the application and evaluation of the HORSE framework in 10 manufacturing plants across Europe, each with its own characteristics. Through the physical deployment and demonstration, the framework proved its goal to be basis for the well-structured design of an operational smart manufacturing cyber-physical system that provides horizontal, cross-functional management of manufacturing processes and vertical control of heterogeneous technologies in work cells. We report on valuable insights on the difficulties to realize such systems in specific situations. The experiences form the basis for improved adoption, further improvement and extension of the framework. In sum, this paper shows how a reference architecture framework supports the structured application of Industry 4.0 technologies in manufacturing environments that so far have relied on more traditional digital technology.