Hydrophobic interaction and ion exchange chromatography are basic steps in purification of fermentative biopharmaceuticals. An optimization by statistical design of experiments requires a huge amount of feed. An alternative approach is the combination of model parameter determination using small scale experimental model parameter determination (1-mL columns) and rigorous process modeling. Applicability for the prediction of the separation of a fermentation mixture of CHO mammalian cell culture is validated and hence IgG is purified from cell culture supernatant. Hydrophobic interaction chromatography directly combined with ion exchange chromatography is optimized. Any direct integration of those two main unit operations in purification processes is a methodological first step towards total process optimization. The potential for cost reduction and overall yield improvement is demonstrated and this leads to the conclusion that single step optimization is a feigned and not a real optimum.