ε-Poly-l-lysine biomanufacturing advances: From biosynthesis to specification-grade products and applications

ε-Poly-l-lysine (ε-PL) is transitioning from a food preservative to a bio-based cationic functional scaffold with opportunities spanning food, agriculture, and biomaterials. However, progress in the field is hampered by a persistent disconnect between titer-driven manufacturing optimization and performance-driven application development. To bridge this gap, we propose a specification-driven (spec-driven) framework that uses critical quality attributes (CQAs) to link molecular structure, industrial production, and application translation. First, we define a minimal, actionable set of ε-PL CQAs and map their molecular determinants to functional relevance. Next, we delineate the biological feasibility windows and constraints that govern these CQAs under high-throughput biosynthesis. We then synthesize integrated strain, process, and recovery engineering strategies to illustrate how CQAs can be translated into reproducible industrial specifications. Finally, application requirements are reverse-mapped to the CQA combinations most frequently required across use scenarios. We conclude that while titer remains important, further gains in titer alone are insufficient to unlock broad translation. Among the proposed CQAs, chain-length distribution, impurity profile, and manufacturing consistency are particularly critical because they determine functional performance, safety boundaries, and lot-to-lot reproducibility. Accordingly, chain-length control, impurity reduction, and integrated strain-process-downstream control represent key rate-limiting steps for developing specification-grade ε-PL product families.