A Rationally Integrated Approach

level: intermediAte Most biopharmaceutical production platforms are based on fed-batch cell culture protocols, which can support high volumetric productivity while maintaining low operational complexity (1). The industry is interested in developing or refining high-titer cell culture processes to meet increasing market demands and reduce manufacturing costs (2). Although advancements in cell engineering have enabled development of highperforming recombinant cell lines (3–6), improvements in cell culture media and process parameter settings are required to realize the maximum production potentials of those cells (7–8). In a fed-batch process, a basal medium supports initial growth and production, and a feed medium prevents depletion of nutrients and sustains the production phase (9). Those media can contain different assortments of nutrients to accommodate the distinct metabolic requirements during different production phases. Process parameter settings — including feeding strategy and control parameters — define the chemical and physical environments suitable for cell growth and protein production. Optimization of a fedbatch process can be achieved by development efforts addressing one or more of three major elements: basal medium, feed medium, and process settings. Given the large sets of variables in these systems, establishing a costand time-efficient approach for process optimization is desired but challenging. Through a study aiming to upgrade a fed-batch process, we observed that basal and feed media have interrelated impacts on process outcomes (a “pairing effect”). So we required a combined optimization of basal and feed media to fulfill our objective. Here we discuss a rationally integrated approach that best serves the practices of fed-batch cell culture process optimization.