Recent trends in the pharmaceutical sector are changing the way processes are designed and executed, moving from: allowing the process to operate in a fixed point, to allowing a permissible region in the operating space (a.k.a. design-space) This trend is driving product development to design quality into the manufacturing process (Quality by Design) and not to rely solely on testing quality in the product These changes address the presence of uncertainties entering the process and their negative effect on product quality if the operating conditions are not free to compensate for these disturbances. This work provides a review of methods to address the presence of these uncertainties, ranging from the establishment of multivariate specifications for incoming product, to feed-forward process control. It also presents the development of a feed-forward controller to compensate the process for the observed changes in the properties of the incoming material. The development and testing of this controller is illustrated with a wet-granulation process. The performance of the multiple control strategies is back-propagated to the changes in the acceptance regions for the raw materials Ultimately, the controller and its model are used to define an integrated design-space that accounts for the network of complex relationships between materials, process conditions and product. This work proposes and demonstrates that the use of mathematics is the only way to reach the maximum potential of the Quality by Design by providing a tool to specify an integral Design Space. (C) 2010 Elsevier Ltd All rights reserved