Heating, Ventilation, and Air Conditioning (HVAC) systems can critically affect the ability of a pharmaceutical facility to meet its objective of providing a safe and effective product to the patient. The design of these systems requires a blend of Good Manufacturing Practice (GMP) and Good Engineering Practice (GEP) to help provide a safe and healthy workplace, protect the environment, and manage energy responsibly. The need to update this Guide has become increasingly evident since its original publication in 2009 as options available to HVAC designers and engineers have evolved due to technological advancements and shifting project pressures. The updates reflect these changes, providing readers with a more current perspective on the challenges and resources involved. This Guide aims to clarify GMP HVAC issues that are critical to the safety, identity, strength, purity, and quality of pharmaceuticals, biopharmaceuticals, advanced therapy medicinal products, and medical devices, from raw materials to finished products. It covers HVAC control and monitoring requirements and addresses GEP issues related to sustainability, economics, and environmental health and safety. The Guide provides best practices for implementing international regulatory and industry guidance, with appendices containing industry examples and templates for the reader’s reference. Applicable to HVAC engineers regardless of experience level, this Guide also provides Quality professionals with an understanding of system parameters important to product quality and patient safety. An overview of HVAC-specific building automation controls and environmental monitoring is presented. Business driven specifications are also discussed, such as redundant systems and custom air handlers. Additional topics include: Supporting information and HVAC practices for different facility types Establishing HVAC Design Criteria Energy Use and Sustainability Considerations System Configurations by Facility Type HVAC and Environmental Controls and Monitoring Commissioning, Qualification, and Quality Risk Management Lifecycle Documentation, Operations, and Maintenance The information provided in this Guide reflects the cumulative knowledge and experiences of the authors, editors, and reviewers with input from members of the ISPE HVAC Community of Practice (COP).