Abstract Biorefineries are central to the transition toward a circular bioeconomy; however, their increasing scale and technological heterogeneity, and the integration of biological, chemical, and thermochemical processes introduce complex challenges related to safety, sustainability, and operational reliability. Existing Safe‐and‐Sustainable‐by‐Design (SSbD) frameworks provide valuable guidance for chemicals and materials but offer limited operationalization for process‐based biosystems, which are characterized by biological uncertainty, feedstock variability, and tightly coupled unit operations. This study proposes an integrated biobased SSbD (BioSSbD) framework specifically tailored to biorefineries, embedding safety, environmental sustainability, technoeconomic performance, and operational reliability into both early stage design and continuous improvement. The framework combines a layered safety concept with a Plan–Do–Check–Act (PDCA) cycle and an 11‐step assessment methodology supported by nine safety‐driven design components. It integrates established tools such as hazard identification and risk assessment, inherent safety principles, life cycle assessment (LCA), technoeconomic indicators, and total quality management. The BioSSbD framework is systematically compared with major SSbD approaches developed by European and international organizations – e.g., the European Commission (EC), the European Chemical Industry Council (CEFIC), the Organisation for Economic Co‐operation and Development (OECD), and the World Business Council for Sustainable Development (WBCSD) – demonstrating its added value in addressing process‐level risks, biological hazards, and operational dynamics specific to biorefineries. A literature‐grounded conceptual application to a lignocellulosic bioethanol biorefinery illustrates how early integration of safety and sustainability considerations can guide design decisions, indicating literature‐informed potential reductions of approximately 20% to 40% in relative process‐risk indices and 15% to 20% in life cycle greenhouse‐gas emissions under comparable process conditions. Overall, the proposed framework provides a structured, adaptive, and scalable approach for advancing safe and sustainable biorefinery development, supporting alignment with circular bioeconomy goals and emerging SSbD certification initiatives.
Fernando Ramonet (Wed,) studied this question.