Recent advances in systems engineering approaches to integrated strain and bioprocess development.

Systems engineering has transformed chemical manufacturing, but bioprocessing has lagged in adopting comprehensive approaches. This review explores strategies that successfully engineer integrated upstream and downstream bioprocesses. Our analysis reveals a critical gap: bioprocess subsystems are typically optimized in isolation ('subsystems optimization'), which limits the overall performance. We identify four key leverage points for systems engineering: engineering product accessibility to eliminate cell lysis, modifying strains to remove contaminants, adapting products for simplified purification, and enhancing strain tolerance for improved separation. While these integrative approaches substantially improve process consolidation, our findings show that there remains a significant misalignment between academic research and industrial needs (failing commercially relevant metrics). Embracing a holistic systems perspective is essential for future bioprocesses to have a transformative impact.