This study presents two designs for a seven-zone SMB (Simulated Moving Bed) and the procedures for establishing the operating conditions for the direct separation of IRC (intermediate retention component) from a feedstock with VSRC (very strong retention component). Normally, the crude extract from natural products or fermented liquid can rarely be directly applied as the feedstock for continuous chromatography due to its multiple components and VSRC. Two SMBs connected in series can usually work to separate a ternary mixture; yet, an additional zone for CIP (cleaning in place) is commonly required to remove the VSRC. By using a seven-zone SMB, this study successfully separates the IRC from two different crude extracts with VSRC. By examining the relative retention of IRC to WRC (weak retention components), this study proposes two SMB designs to separate the IRC. Based on the Triangle theory, a three-step procedure is also proposed, and two crude extracts: an anticancer drug produced by fermentation and astaxanthin extracted from red algae, were used as working examples in this study. Both samples showed that the separation of the IRC with near 90% purity and recovery can be achieved by following the three-step procedure without knowing the adsorption isotherms of the impurities, which will quickly provide useful information for further feasibility studies and scaled-up designs.