Dynamic Design Space As An Integrated Component of Quality by Design

The Food and Drug Administration requires from pharmaceutical companies the development of extensive knowledge databases regarding the control of the manufacturing process of a drug product. Through development and validation, drug manufacturers discover their process boundaries and identify a range of process parameters for each unit operation, the design space. However, limited work is done to study the effect of changing raw material on the robustness of the design space. Furthermore, once approved by the FDA, a process cannot be changed without filing post-approval changes that might require adding new experiments to the knowledge space. In the present study, the development of a design space for the creation of Excedrin (acetaminophen, caffeine) tablets through direct compression was investigated. A design of experiment including different excipent ratio of microcrystaline cellulose and lactose, two cros-carmelose sodium levels, and four compression forces was created using an industrial size press to define a knowledge space. Classical critical quality attributes (CQAs) (disintegration time, dissolution, radial tensile strength, friability) were measured and a design space identified. In order to test the robustness of the design space, raw material properties of acetaminophen (particle size) and lactose (ratio anhydrous to monohydrate) were modified. Resulting tablets were analyzed for relevant CQAs (disintegration time and radial tensile strength) to investigate how common variability in the raw material impacts the design space.