"Control from root design": a proactive strategy for green and sustainable API process research and development

We detail the concept, implementation, and illustrative applications of the "control from root design"(CRD) strategy for developing safe, environmentally benign, simple, health-protective, quality-assured, and cost-efficient (six CRD criteria) manufacturing processes for active pharmaceutical ingredients (APIs). Unlike conventional approaches, in which synthetic routes are typically established first, and sustainability is optimized retrospectively, CRD integrates synthetic route design and sustainability evaluation from project inception. Drawing on both the principles of green and sustainable chemistry and practical experience from industrial innovation and implementation, CRD embeds a “green gene” foundation into the core technology before regulatory lock-in occurs, thereby resolving the API industry’s persistent process lock-in problem. While established green metrics provide some quantitative guidance, CRD offers a structured, case-specific decision approach that incorporates these metrics into early-stage route design and evaluation. We demonstrate the efficacy and versatility of the CRD strategy through several API R&D case studies, including VV116, molnupiravir, and tecovirimat. By aligning regulatory requirements and sustainability objectives from the outset, CRD streamlines API process research and development and reduces both post-approval modifications and overall lifecycle costs.