For improving quality and safety of healthcare as well as efficiency and efficacy of care processes, health systems turn toward personalized, preventive, predictive, participative precision medicine. The related pHealth ecosystem combines different domains represented by a huge variety of different human and non-human actors belonging to different policy domains, coming from different disciplines. Those actors deploy different methodologies, terminologies, and ontologies, offering different levels of knowledge, skills, and experiences, acting in different scenarios and accommodating different business cases to meet the intended business objectives. Core challenge is the formal representation and management of multiple domains' knowledge. For correctly modeling such systems and their behavior, a system-oriented, architecture-centric, ontology-based, policy-driven approach is inevitable, thereby following established Good Modeling Best Practices. The ISO Interoperability Reference Architecture model and framework offers such approach. The paper describes and classifies the ongoing paradigm changes. It presents requirements and solutions for designing and implementing advanced pHealth ecosystems, thereby correctly adopting and integrating existing pHealth interoperability standards, specifications and projects.