The biopharmaceutical industry has adapted to reflect available technologies such as single-use technologies and modular construction methodologies, products with more focused patient populations, evolving regulatory conditions, unrelenting pressures on costs, and increased focus on robust product supply while maintaining high-quality standards. This Guide presents concepts that reflect how these changes affect biopharmaceutical manufacturing facilities without sacrificing product quality, by reducing risk and enhancing the manufacturing control strategy. This third edition of the ISPE Baseline Guide: Biopharmaceutical Manufacturing Facilities intends to further reinforce the concepts described in the second edition of the Guide, provide examples of how these concepts can be put into practice, and detail the value and benefits of the approaches described. In addition, this revision includes new topics and details regarding Quality Risk Management (QRM), Contamination Control Strategies (CCS), and the impact of closed processes on facility design. The globally recognized concepts around product protection, driven by aseptic and low bioburden practices and closed system designs, provide the foundation for a risk-based approach that examines the relationship between product, process, and facility. This Guide is intended to provide individuals and teams with the tools to make informed decisions about layouts, area classifications, segregation strategies, project delivery approaches, and operational approaches, all aimed at creating compliant, cost-effective biomanufacturing facility assets.