Industry 4.0 emerged in the last decade as the fourth industrial revolution aiming at reaching greater productivity, digitalization and operational efficiency standard. In this new era, if compared to automated assembly systems, manual assembly systems (MASs) are still characterized by wide flexibility but poor productivity levels. To reach acceptable performances in terms of both productivity and flexibility, higher automation levels are required to increase the skills and capabilities of the human operators with the aim to design next-generation assembly systems having higher levels of adaptivity and collaboration between people and automation/information technology. In the current literature, such systems are called adaptive automation assembly systems (A3Ss). For A3Ss, few design approaches and industrial prototypes are available. This paper, extending a previous contribution by the Authors, expands the lacking research in the field and proposes a general framework guiding toward A3S effective design and validation. The framework is applied to a full-scale prototype, highlighting its features together with the technical- and human-oriented improvements arising from its adoption. Specifically, evidence from this study show a set of benefits from adopting innovative A3Ss in terms of reduction of the assembly cycle time (about 30%) with a consequent increase of the system productivity (about 45%) as well as relevant improvements of ergonomic posture indicators (about 15%). The definition of a general framework for A3S design and validation and the integration of the productivity and ergonomic analysis of such systems are missing in the current literature, representing an element of innovation. Globally, this research paper provides advanced knowledge to guide research, industrial companies and practitioners in switching from traditional to advanced assembly systems in the emerging Industry 4.0 era matching current industrial and market features.