Background/Objectives: Health and social care systems around the globe are currently undergoing a transformation towards personalized, preventive, predictive, participative precision medicine (5PM), considering the individual health status, conditions, genetic and genomic dispositions, etc., in personal, social, occupational, environmental, and behavioral contexts. This transformation is strongly supported by technologies such as micro- and nanotechnologies, advanced computing, artificial intelligence, edge computing, etc. Methods: To enable communication and cooperation between actors from different domains using different methodologies, languages, and ontologies based on different education, experiences, etc., we have to understand the transformed health ecosystem and all its components in terms of structure, function and relationships in the necessary detail, ranging from elementary particles up to the universe. In this way, we advance design and management of the complex and highly dynamic ecosystem from data to knowledge level. The challenge is the consistent, correct, and formalized representation of the transformed health ecosystem from the perspectives of all domains involved, representing and managing them based on related ontologies. The resulting business viewpoint of the real-world ecosystem must be interrelated using the ISO/IEC 21838 Top Level Ontologies standard. Thereafter, the outcome can be transformed into implementable solutions using the ISO/IEC 10746 Open Distributed Processing Reference Model. Results: The model and framework for this system-oriented, architecture-centric, ontology-based, policy-driven approach have been developed by the first author and meanwhile standardized as ISO 23903 Interoperability and Integration Reference Architecture. The formal representation of any ecosystem and its development process including examples of practical deployment of the approach, are presented in detail. This includes correct systems and standards integration and interoperability solutions. A special issue newly addressed in the paper is the correct and consistent formal representation Conclusions: of all components in the development process, enabling interoperability between and integration of any existing representational artifacts such as models, work products, as well as used terminologies and ontologies. The provided solution is meanwhile mandatory at ISOTC215, CEN/TC251 and many other standards developing organization in health informatics for all projects covering more than just one domain.