Abstract
Recent advances in computer-aided retrosynthesis (CAR), flow chemistry, and continuous manufacturing collectively offer new opportunities to enable environmentally sustainable development and manufacturing practices across the pharmaceutical development and manufacturing value chain. However, the implementation of these methods and technologies remains scattered and fragmented, preventing full realization of their potential to address one of the most urgent needs in the pharmaceutical and related sectors. This work introduces a holistic digital framework for the design and optimization of an end-to-end manufacturing process for paracetamol (acetaminophen). The framework integrates Green-by-Design synthetic and purification routes of the active pharmaceutical ingredient (API) aims to deliver cost efficiency and robust quality, safety, and environmental sustainability assurance. The approach integrates AI-driven CAR with plant wide modelling, Techno-Economic Analysis (TEA), and prospective cradle-to-gate prospective Life Cycle Assessment (LCA) to evaluate designs options and greener, chemically feasible, and more selective synthetic pathways. An end-to-end mathematical model is implemented in gPROMS Formulated Products® to optimize operating and design parameters and generate inventory data for TEA/LCA. The framework also embeds Quality by Digital Design (QbDD) to identify CPPs and CMAs that influence CQAs, enabling definition of a robust design space. Finally, a multicriteria decision-aiding approach is implemented to determine the best trade-offs among yield, productivity, resource efficiency, cost, and environmental performance, providing a transferable Safe-and-Sustainable-by-Design (SSbD) methodology for developing greener and more resilient pharmaceutical manufacturing systems.