From Sequence Design to a Manufacturable Biologic: A Translation Framework for Expression, Folding, Modification, Purification, and Stability

Sequence design can optimize biologics for target engagement, specificity, format, and predicted structure, but sequence-level promise does not establish efficient expression, productive folding, consistent modification, robust purification, formulation, or stability. This non-empirical article proposes a sequence-to-product translation framework for recombinant therapeutic proteins, particularly antibodies and antibody-derived formats. Manufacturability is treated as a conditional interaction among sequence, host, cellular processing, bioprocess, product heterogeneity, purification, formulation, and intended use. The framework introduces translation debt for liabilities carried into later development; non-compensatory gates that prevent strength in one domain from masking failure in another; and conditional manufacturability readiness as a multidimensional judgement. Validation escalates from computational applicability and host-relevant expression to orthogonal molecular-quality, purification, formulation, scale-transfer, and prospective stage-gate evidence. The framework organizes reasoning and progression; it is not a validated predictive model, universal standard, clinical recommendation, or regulatory pathway.