Quality by Design principle was applied to optimize the load and wash steps in the chromatographic process of Panax notoginseng extracts. Saponin recovery, saponin purity and saponin yield per unit volume of resin were identified as the process critical quality attributes (CQAs) of the chromatographic process. The critical process parameters (CPPs) were determined by an Ishikawa diagram combined with a Failure Mode and Effect Analysis. Column height/diameter ratio, load rate, load volume, total saponin concentration in loading solution and wash volume were identified as CPPs for the load and wash steps. The models between CPPs and process CQAs were developed according to the data obtained from central composite designed experiments. Determination coefficients (R-2) were higher than 0.83 for all the models. Loss mechanism of saponins was discussed, overloading may lead to the loss of all the saponins and wash with water may lead to the loss of notoginsenoside R-1, ginsenoside Rg(1) and ginsenoside Re. Design spaces with different acceptable probabilities were calculated using a Monte-Carlo simulation method. Recommended normal operation region is located in height/diameter ratio of 13.5-15.0, load rate of 1.5-1.6 BV/h, load volume of 5.5-6.0 BV, total saponin concentration of 10.4-12.2 mg/g, wash volume of 2.0-2.6 BV when acceptable probability was set to 0.80. The verification experimental values were in a good agreement with the predicted values. The design space is reliable and working within it can attain process CQAs criteria with a high probability. (C) 2015 Elsevier B.V. All rights reserved.