Abstract: Serum-free media (SFM) and chemically defined media (CDM) are increasingly important in modern bi-omanufacturing, reducing dependence on undefined serum components and improving raw-material control, reproducibility, and biosafety. However, rational medium development extends beyond replacing serum with defined supplements. This review presents SFM design as a metabolism-guided optimization problem in which nutrient composition, waste-metabolite accumulation, redox balance, lipid homeostasis, and growth-factor signaling jointly determine cell growth, product quality, and process robustness. We trace the evolution and classification of SFM/CDM and map amino acids, carbon sources, vitamins, lipids, trace elements, and sig-naling factors to the metabolic constraints they regulate. We compare cell-type-specific requirements across Chinese hamster ovary (CHO) and human embryonic kidney 293 (HEK293) production cells, mesenchymal stromal cells, induced pluripotent stem cells, chimeric antigen receptor T (CAR-T) and natural killer cells, primary-cell and organoid systems, and viral production platforms. We further examine how metabolomics, high-throughput screening, machine learning, and process analytical technologies support dynamic medium adjustment and closed-loop control. Finally, we consider economic, scalability, regulatory, and sustainability constraints. This framework links measurable cellular states to cell-type-specific medium formulation and feeding strategies for biologics and cell-based manufacturing.

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