Chromatography techniques rarely follow linear processes. Two-level factorial designs cannot evaluate nonlinearity, and thus assume linearity with only two points. This defect leads to false conclusions about the method development, the optimization, and where actual design spaces exist (robustness zones). Some chromatographic separations actually follow a polynomial equation, or exponential equation, based on the application of varying critical quality attributes (CQA). When only two levels are applied, the deviation from linearity then leads to false conclusions