Taste is routinely cited as one of the major contributing factors that negatively influence pediatric patient compliance. A promising solution is coated microsphere systems, which provide doses of active pharmaceutical ingredients (API) subdivided into a plurality of small dosage units. In this work, the microspheres were coated with Kollicoat® Smartseal, a reverse enteric polymer, which acts to minimize or prevent the release of API in the neutral pH of the oral cavity, which results in a masking effect of the unpleasant taste of the API. A screening of seven key variables in a Wurster coating process was evaluated by D-optimal design and by analysis of variance. The percentage of API released at pH 6.2 was used as a surrogate method for the taste-masking performance evaluation of Kollicoat® Smartseal. The seven studied variables were: product bed temperature, inlet airflow, atomizing air pressure, spray rate (process parameters), coating level, plasticizer level, solids in coating suspension (material attributes), and curing. Results show that coating level, plasticizer level, product bed temperature, and spray rate are the critical process parameters and reinforce the importance of curing to reduce the overall variability within the batch by promoting complete film formation. The link between material attributes, process parameters, and quality attributes were demonstrated to allow a better understanding of the parameters that affect the API release profile at neutral pH (in vitro) while not injuring release at acidic pH (in vitro). It was demonstrated that not only thickness but also coating morphology have an impact on the dissolution in 50mM potassium phosphate buffer, pH 6.2.