The development of alginate microparticles for encapsulation of hydrophilic drug is addressed. The alginate microparticles are produced by the emulsification/gelation process. The objective of this study is to optimize the encapsulation of sunset yellow, a model of small hydrophilic drug, by the means of an agile quality by design (QbD) approach. Five input factors are considered: the alginate concentration (2–7% w/V), the drug/polymer ratio (0.1/1–0.5/1), the cross-linker addition flow rate (1–1.6 mL/min), the cross-linker volume (5–10 mL), and the crosslinking time (15–60 min). Critical quality attributes (and their associated specifications) are the particle size (µ) and polydispersity, the encapsulation efficiency (), and the drug loading (). The implemented agile method follows three successive QbD sprints, each based on a specific design of experiments (DoE). First, a screening of the process parameters is performed using a Plackett-Burman design, followed in a second sprint by the implementation of a central composite Hartley’s design to identify the design space and to extract four eligible control operating regions where the probability to meet the CQA specifications is above 95%. In the last sprint, one of these optimal operating conditions has been qualified by testing eight end points of the region through the application of a full factorial design. This operating region corresponds to a combination of three factors: alginate concentration in [6.7;7]%, drug/polymer ratio in [0.29;0.34]w/w and a curing time in [40;60]min.