Simulated moving bed chromatographic separation method and simulated moving bed chromatographic separation system

Abstract

This simulated moving-bed chromatographic separation method comprises: separating, with use of an eluent, a component weakly-adsorptive to an adsorbent, a component strongly-adsorptive to adsorbent, and an intermediately-adsorptive component having an absorptivity that is intermediate between said two components, all of which contained in a raw solution, by using a circulation system which has at least three unit filled columns filled with the adsorbent and linked in series and endlessly by pipes and which is divided into at least three sections that are annularly continuous from the upstream side to the downstream side such that each of the sections has at least one of the unit filled columns. There is a particular relationship between a position where the raw solution is fed, a position where a weakly-adsorptive fraction is extracted, a position where an intermediately-adsorptive fraction is extracted, and a position where a strongly adsorbed fraction is extracted. This chromatographic separation system is suitable for carrying out the chromatographic separation method.

Description

[Technical field]

[0001] The present invention relates to a simulated moving bed chromatographic separation method and a simulated moving bed chromatographic separation system. [Background technology]

[0002] In the chromatographic separation by the simulated moving bed method, a plurality of unit packed towers (hereinafter, simply referred to as "packed towers" or "columns") packed with an adsorbent capable of selectively adsorbing a specific component among two or more components contained in the raw solution are connected in series via piping, and the most downstream packed tower is connected to the most upstream packed tower to construct an endless circulation system. The raw solution and the eluent are supplied to this circulation system, and a fraction with a fast moving speed (weakly adsorbent fraction), a fraction with a slow moving speed (strongly adsorbent fraction), and, if necessary, a fraction with an intermediate moving speed (medium adsorbent fraction) are extracted from different positions in the circulation system. Next, the raw solution supply position, the eluent supply position, the weakly adsorbent fraction extraction position, the medium adsorbent fraction extraction position, and the strong adsorbent fraction extraction position are moved toward the fluid circulation direction of the circulation system while maintaining a constant positional relationship. By repeating this operation, a moving bed treatment operation that can continuously supply the raw solution is realized in a simulated manner.

[0003] For example, Patent Document 1 describes a system in which an endless serial circulation flow path is formed by using a number of unit packed beds filled with an adsorbent, and this circulation flow path is provided so as to be capable of circulating and blocking. In this system, a raw material fluid containing three or more components having different affinities to the adsorbent is passed through the many unit packed beds, forming adsorption zones separated in sequence from components having weak affinities to the adsorbent to components having strong affinities. In this system, the circulation of the system is blocked at a position upstream of an adsorption zone formed by a component previously selected from among the components having weak affinities, while the raw material fluid is supplied to the system at a position downstream of this blocking. Both methods describe a method for separating a multi-component system, which is characterized by repeating the following steps as one cycle: a first step of extracting from the system an enriched fraction of a predetermined component among the components forming an adsorption zone upstream of the cut-off position; and a second step of supplying a desorbent fluid from upstream of the adsorption zone while circulating the system without supplying a raw material fluid, thereby separately extracting enriched fractions of each component separated into the adsorption zone that were not extracted in the first step, and sequentially moving the supply position of the desorbent fluid and the extraction position of each of the fractions downstream of the circulating flow in accordance with the movement of the adsorption zone.

[0004] Since the chromatographic separation using the simulated moving bed method can continuously obtain the target purified substance with high purity, its application to the medical field and the like is also being considered. For example, in the production of antibody drugs, in addition to the target antibody, the extract or culture solution of cultured cells producing the antibody contains fragments of the antibody that do not function sufficiently as an antibody, which are generated by cleavage or the like, and giant aggregates of the antibody that have aggregated. In general, the fragments have few interaction sites with the adsorbent and are weakly adsorbent. Conversely, aggregates are strongly adsorbent. Therefore, when the chromatographic separation using the simulated moving bed method is applied to the purification of antibody drugs, the target antibody needs to be separated as a medium-adsorbent fraction that shows intermediate adsorption to the adsorbent. On the other hand, both the weakly adsorbent fraction and the strongly adsorbent fraction need to be sufficiently removed with a high removal rate. For example, Patent Document 2 describes a simulated moving bed chromatographic separation method that uses a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly via piping to separate, using two or more eluents, a weakly adsorbent component, a strongly adsorbent component, and a medium adsorbent component having an intermediate adsorption property between the two components, which are contained in a stock solution. The piping of the circulation system is provided with a stock solution supply port F, two or more eluent supply ports D corresponding to each of the two or more eluents, an outlet A for a weakly adsorbent fraction containing the weakly adsorbent component, an outlet B for a medium adsorbent fraction containing the medium adsorbent component, and an outlet C for a strongly adsorbent fraction containing the strongly adsorbent component, and the stock solution supply port F, the outlet A, the outlet B, and the outlet C are positioned in a specific positional relationship. The simulated moving bed chromatographic separation method describes that a component to be purified in the stock solution can be separated and isolated with high purity using a smaller amount of adsorbent. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 7-24724 [Patent Document 2] JP 2020-085881 A Summary of the Invention [Problem to be solved by the invention]

[0006] In the past, in the SMB chromatographic separation, several techniques have been proposed to improve the purification efficiency of the target component by devising the supply position and timing of the raw solution or eluent, and the extraction position and timing of each fraction. On the other hand, the components to be separated are diverse, and the impurities in the sample containing the components are also diverse. Therefore, when a SMB chromatographic separation technique that is effective for separating and purifying a certain component in a certain raw sample is applied to the separation and purification of a specific component in another raw sample, the specific component may not be separated with a sufficiently high purity and high efficiency. Therefore, in order to expand the application range of SMB chromatographic separation, it is desirable to increase the variety of techniques that can purify a specific component to a high purity. In addition, in a conventional simulated moving bed chromatographic separation method as described in Patent Document 2, after one cycle of operation is completed, the raw solution supply port, eluent supply port, and each fraction extraction port are simultaneously moved downstream. However, it has been found that this method may result in insufficient separation of the target purification target depending on the target purification target.

[0007] Therefore, an object of the present invention is to provide a chromatographic separation method that makes it possible to separate and isolate the components to be purified in a raw solution with high purity, while using a method that differs from conventional methods in terms of the supply position and timing of the raw solution or eluent, and the withdrawal position and timing of each fraction. Another object of the present invention is to provide a chromatographic separation system suitable for carrying out the above-mentioned chromatographic separation method. [Means for solving the problem]

[0008] The above-mentioned object of the present invention has been achieved by the following means. [1] A simulated moving bed chromatographic separation method comprising: using a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping; dividing the circulation system into at least three continuous sections in a circular ring shape from upstream to downstream such that each section has at least one unit packed tower; and separating, using an eluent, a weakly adsorbent component, a strongly adsorbent component, and a medium adsorbent component having an intermediate adsorbability between the two components, which are contained in a raw solution; the method comprising repeating a cycle consisting of the following first and second processes: <First process> a process comprising a step of cutting off circulation of the circulation system at a cutoff position upstream of the section enriched in the weakly adsorbable component, supplying the raw liquid to a section downstream of the cutoff position, and withdrawing a moderately adsorbable fraction enriched in the moderately adsorbable component from the section upstream of the cutoff position; <Second process> a process comprising a step of extracting a strongly adsorbent fraction enriched in the strongly adsorbent component by controlling the supply of the eluent and the blocking of the circulation system without supplying the stock solution, and moving a supply position of the eluent to the circulation system and a withdrawal position of the strongly adsorbent fraction downstream in accordance with the movement of the strongly adsorbent fraction; A simulated moving bed chromatographic separation method in which the extraction position of the strongly adsorbent fraction within the cycle is moved downstream by at least two sections, and the downstream movement is not the same distance as the [number of sections]. [2] A simulated moving bed chromatographic separation method comprising: using a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping; dividing the circulation system into at least three continuous sections in a circular ring shape from upstream to downstream such that each section has at least one unit packed tower; and separating, using an eluent, a weakly adsorbent component, a strongly adsorbent component, and a medium adsorbent component having an adsorbability intermediate between the two components, which are contained in a raw solution; the simulated moving bed chromatographic separation method comprising repeating a cycle consisting of the following steps (A) and (B): <Step (A)> a sub-step (A1) of blocking circulation in the circulation system by setting a position upstream of the section enriched in the weakly adsorbable component as a blocking position, supplying the stock solution to a section downstream of the blocking position and extracting a weakly adsorbable fraction enriched in the weakly adsorbable component from the circulation system at a further downstream position, and supplying an eluent for desorbing the moderately adsorbable component to a section upstream of the blocking position and extracting a moderately adsorbable fraction enriched in the moderately adsorbable component from the circulation system at a downstream position thereof; A sub-step (A2) of supplying an eluent for desorbing the weakly adsorbable component instead of supplying the stock solution, and continuing the extraction of the weakly adsorbable fraction and the extraction of the moderately adsorbable fraction; A substep (A3) of moving the blocking position upstream, supplying an eluent for desorbing the strongly adsorbent component upstream of the moved blocking position while continuing to extract the weakly adsorbent fraction, and extracting a strongly adsorbent fraction enriched in the strongly adsorbent component at a downstream position thereof; and a sub-step (A4) of withdrawing the weakly adsorbing fraction by shifting the withdrawal position of the weakly adsorbing fraction downstream and withdrawing the weakly adsorbing fraction while not withdrawing the medium adsorbing fraction and not withdrawing the strongly adsorbing fraction; the steps in this order; <Step (B)> A step of performing step α at least once, in which the weakly adsorbing fraction not extracted in step (A) is extracted separately by controlling the supply of eluent and the blockage position without supplying the original solution, while leaving the extraction position of the weakly adsorbing fraction unchanged, and then the extraction position of the weakly adsorbing fraction is moved downstream to extract only the weakly adsorbing fraction. [3] The piping of the circulation system is provided with a raw solution supply port F, an eluent supply port D, an outlet A for a weakly adsorbing fraction, an outlet B for a moderately adsorbing fraction, and an outlet C for a strongly adsorbing fraction, In the step (A), the positions of the raw liquid supply port F, the outlet A, the outlet B, and the outlet C are set as follows (a) to (c): (a) providing the withdrawal outlet A on the downstream side of the raw liquid supply port F across at least one section; (b) providing the withdrawal outlet B in a pipe having the raw liquid supply port F; (c) providing the outlet C on the upstream side of the outlet B across at least one section; In the step (B), the positions of the extraction outlet A and the extraction outlet C are set as follows (d): (d) providing the outlet A downstream of the outlet C across at least two sections; The simulated moving bed chromatographic separation method according to [2] above. [4] The simulated moving bed chromatographic separation method according to [2] or [3], wherein the number of times of the process α performed in the step (B) is [number of sections-2] times, or [number of sections] times or more. [5] A simulated moving bed chromatographic separation method using a circulation system in which four or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, the circulation system being divided into four continuous sections in a circular shape from the upstream side to the downstream side such that each section has at least one unit packed tower, wherein sub-steps (A1) to (A4) in step (A) are the following sub-steps (A1-1) to (A4-1), and in step (B), the following sub-steps (B1-1) to (B3-1) and the following sub-steps (B1'-1) to (B3'-1) are carried out in this order: <Sub-step (A1-1)> The upstream end of section 1 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as a moderately adsorbent fraction outlet B, and the moderately adsorbent fraction is extracted from said outlet B; the upstream end of section 3 is designated as a stock solution supply port F, and the stock solution is supplied from said stock solution supply port F; and the downstream end of section 4 is designated as a weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A; The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through sections 3 and 4 is made weaker than the desorption power of the eluent flowing through sections 1 and 2; <Sub-step (A2-1)> The upstream end of section 1 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as a moderately adsorbent fraction outlet B, and the moderately adsorbent fraction is extracted from said outlet B; the upstream end of section 3 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV; and the downstream end of section 4 is designated as a weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A; The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through sections 3 and 4 is made weaker than the desorption power of the eluent flowing through sections 1 and 2; <Sub-step (A3-1)> the upstream end of section 1 is designated as an eluent supply port DI, eluent dI is supplied from said eluent supply port DI; the downstream end of section 1 is designated as a strongly adsorbing fraction outlet C, and the strongly adsorbing fraction is extracted from said outlet C; the upstream end of section 2 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the upstream end of section 3 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III; the upstream end of section 4 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV; and the downstream end of section 4 is designated as a weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A; The desorption force of the eluent flowing through Section 1 is maximized. The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption power of the eluent flowing through section 4 is made weaker than the desorption power of the eluent flowing through section 3; <Sub-step (A4-1)> The upstream end of section 2 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 4 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made equal to the desorption force of the eluent flowing through section 4; <Sub-step (B1-1)> The upstream end of section 2 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 4 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A, The desorption power of the eluent flowing through sections 2 and 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through sections 2 and 3; The desorption power of the eluent flowing through section 1 is made weaker than the desorption power of the eluent flowing through section 4; <Sub-step (B2-1)> the upstream end of section 2 is designated as an eluent supply port DI, eluent dI is supplied from said eluent supply port DI; the downstream end of section 2 is designated as a strongly adsorbing fraction outlet C, and the strongly adsorbing fraction is extracted from said outlet C; the upstream end of section 3 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the upstream end of section 4 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III; the upstream end of section 1 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV; and the downstream end of section 1 is designated as a weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption power of the eluent flowing through section 1 is made weaker than the desorption power of the eluent flowing through section 4; <Sub-step (B3-1)> The upstream end of section 3 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 4 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is set to be the same as the desorption force of the eluent flowing through section 1. <Substep (B1'-1)> The upstream end of section 3 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A, The desorption power of the eluent flowing through sections 3 and 4 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through sections 3 and 4; The desorption power of the eluent flowing through section 2 is made weaker than the desorption power of the eluent flowing through section 1; <Substep (B2'-1)> the upstream end of section 3 is designated as an eluent supply port DI, eluent dI is supplied from said eluent supply port DI; the downstream end of section 3 is designated as a strongly adsorbing fraction outlet C, and the strongly adsorbing fraction is extracted from said outlet C; the upstream end of section 4 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the upstream end of section 1 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III; the upstream end of section 2 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV; and the downstream end of section 2 is designated as a weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A; The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption power of the eluent flowing through section 2 is made weaker than the desorption power of the eluent flowing through section 1; <Substep (B3'-1)> The upstream end of section 4 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 3 is designated as weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 4 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is set to be the same as the desorption force of the eluent flowing through section 2. [6] A simulated moving bed chromatographic separation method using a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, the circulation system being divided into three continuous sections in a circular ring shape from the upstream side to the downstream side such that each section has at least one unit packed tower, wherein sub-steps (A1) to (A4) in step (A) are the following sub-steps (A1-2) to (A4-2), and in step (B), the following sub-steps (B1-2) and (B2-2) are carried out in this order: <Sub-step (A1-2)> The upstream end of section 1 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the downstream end of section 2 is designated as a moderately adsorbent fraction outlet B, and the moderately adsorbent fraction is extracted from said outlet B, the upstream end of section 3 is designated as a raw solution supply port F, and the raw solution is supplied from said raw solution supply port F, and the downstream end of section 3 is designated as a weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A, The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through section 3 is made weaker than the desorption power of the eluent flowing through sections 1 and 2; <Sub-step (A2-2)> The upstream end of section 1 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as a moderately adsorbent fraction outlet B, and the moderately adsorbent fraction is extracted from said outlet B; the upstream end of section 3 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV; and the downstream end of section 3 is designated as a weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A; The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through section 3 is made weaker than the desorption power of the eluent flowing through sections 1 and 2; <Sub-step (A3-2)> the upstream end of section 1 is designated as an eluent supply port DI, eluent dI is supplied from said eluent supply port DI; the downstream end of section 1 is designated as a strongly adsorbing fraction outlet C, and the strongly adsorbing fraction is extracted from said outlet C; the upstream end of section 2 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the upstream end of section 3 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III; and the downstream end of section 3 is designated as a weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A; The desorption force of the eluent flowing through Section 1 is maximized. The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption power of the eluent flowing through section 3 is made weaker than the desorption power of the eluent flowing through section 2; <Sub-step (A4-2)> The upstream end of section 2 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as weakly adsorbing fraction outlet A, and a weakly adsorbing fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption power of the eluent flowing through section 1 is made weaker than the desorption power of the eluent flowing through section 3; <Sub-step (B1-2)> the upstream end of section 2 is designated as an eluent supply port DI, eluent dI is supplied from said eluent supply port DI; the downstream end of section 2 is designated as a strongly adsorbing fraction outlet C, and the strongly adsorbing fraction is extracted from said outlet C; the upstream end of section 3 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the upstream end of section 1 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III; and the downstream end of section 1 is designated as a weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption power of the eluent flowing through section 1 is made weaker than the desorption power of the eluent flowing through section 3; <Sub-step (B2-2)> The upstream end of section 3 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1. [7] The simulated moving bed chromatographic separation method according to any one of [1] to [6] above, wherein the medium adsorptive component is a biopolymer. [8] A simulated moving bed chromatographic separation system uses a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, the circulation system is divided into at least three continuous sections in a circular ring shape from upstream to downstream so that each section has at least one unit packed tower, and separates, using an eluent, weakly adsorbing components, strongly adsorbing components, and intermediately adsorbing components having adsorption properties intermediate between the two components, contained in a raw solution, the system having a means for repeating a cycle consisting of the following first and second processes: <First process> a process comprising a step of cutting off circulation of the circulation system at a cutoff position upstream of the section enriched in the weakly adsorbable component, supplying the raw liquid to a section downstream of the cutoff position, and withdrawing a moderately adsorbable fraction enriched in the moderately adsorbable component from the section upstream of the cutoff position; <Second process> a process comprising a step of extracting a strongly adsorbent fraction enriched in the strongly adsorbent component by controlling the supply of the eluent and the blocking of the circulation system without supplying the stock solution, and moving a supply position of the eluent to the circulation system and a withdrawal position of the strongly adsorbent fraction downstream in accordance with the movement of the strongly adsorbent fraction; A simulated moving bed chromatographic separation system in which the strongly adsorbent fraction is withdrawn from the cycle by at least two sections downstream, and the downstream movement is not the same distance downstream as the [number of sections]. [9] A simulated moving bed chromatographic separation system using a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, the circulation system being divided into at least three continuous sections in a circular ring shape from upstream to downstream such that each section has at least one unit packed tower, and using an eluent to separate components contained in a raw solution that are weakly adsorbable to the adsorbent, strongly adsorbable, and a medium adsorbable component having an adsorbability intermediate between the two components, the simulated moving bed chromatographic separation system having a means for repeating a cycle consisting of the following steps (A) and (B): <Step (A)> a sub-step (A1) of blocking circulation in the circulation system by setting a position upstream of the section enriched in the weakly adsorbable component as a blocking position, supplying the stock solution to a section downstream of the blocking position and extracting a weakly adsorbable fraction enriched in the weakly adsorbable component from the circulation system at a further downstream position, and supplying an eluent for desorbing the moderately adsorbable component to a section upstream of the blocking position and extracting a moderately adsorbable fraction enriched in the moderately adsorbable component from the circulation system at a downstream position thereof; A sub-step (A2) of supplying an eluent for desorbing the weakly adsorbable component instead of supplying the stock solution, and continuing the extraction of the weakly adsorbable fraction and the extraction of the moderately adsorbable fraction; A substep (A3) of moving the blocking position upstream, supplying an eluent for desorbing the strongly adsorbent component upstream of the moved blocking position while continuing to extract the weakly adsorbent fraction, and extracting a strongly adsorbent fraction enriched in the strongly adsorbent component at a downstream position thereof; and a sub-step (A4) of withdrawing the weakly adsorbing fraction by shifting the withdrawal position of the weakly adsorbing fraction downstream and withdrawing the weakly adsorbing fraction while not withdrawing the medium adsorbing fraction and not withdrawing the strongly adsorbing fraction; the steps in this order; <Step (B)> A step of performing step α at least once, in which the weakly adsorbing fraction not extracted in step (A) is extracted separately by controlling the supply of eluent and the blockage position without supplying the original solution, while leaving the extraction position of the weakly adsorbing fraction unchanged, and then the extraction position of the weakly adsorbing fraction is moved downstream to extract only the weakly adsorbing fraction.

[0009] In this specification, the terms "upstream" and "downstream" are used with respect to the direction of fluid flow in the circulatory system. That is, the "upstream side" of a certain part of the circulatory system means the side from which the fluid flows toward that part, and the "downstream side" means the side from which the fluid flows out of that part. In this specification, the term "strongly adsorbent component" refers to a component that has a strong adsorption force to an adsorbent among the multiple components contained in the stock solution, the term "weakly adsorbent component" refers to a component that has a weak adsorption force to an adsorbent among the multiple components contained in the stock solution, and the term "moderately adsorbent component" refers to a component that has a weaker adsorption force to an adsorbent than the strongly adsorbent component, but has a stronger adsorption force to an adsorbent than the weakly adsorbent component. In other words, the terms "strongly adsorbent", "moderately adsorbent", and "weakly adsorbent" indicate the relative strength of adsorption force when comparing the adsorption force of each component contained in the stock solution to an adsorbent. The above-mentioned "strongly adsorptive component", "moderately adsorptive component" and "weakly adsorptive component" may each be composed of a single component or multiple components. Furthermore, the multiple components may have the same or different adsorptive powers. The grouping of each component in the stock solution into "strongly adsorbent", "medium adsorbent" and "weakly adsorbent" can be appropriately set according to the purpose. For example, when the stock solution contains four types of components, two components in order of the strongest adsorption power to the adsorbent can be combined to form a strong adsorbent, the component with the third strongest adsorption power to the adsorbent can be positioned as a medium adsorbent, and the component with the weakest adsorption power to the adsorbent can be positioned as a weak adsorbent. In addition, the component with the strongest adsorption power to the adsorbent can be positioned as a strong adsorbent, the component with the second strongest adsorption power to the adsorbent and the third component can be positioned as a medium adsorbent, and the component with the weakest adsorption power to the adsorbent can be positioned as a weak adsorbent. In addition, the component with the strongest adsorption power to the adsorbent can be positioned as a strong adsorbent, the component with the second strongest adsorption power to the adsorbent can be positioned as a medium adsorbent, and the component with the third strongest adsorption power to the adsorbent and the weakest adsorption power to the adsorbent can be positioned as a weak adsorbent. When the stock solution contains five or more types of components, separation and purification based on various groupings can be performed in the same manner. In the present invention, the "desorption power" of an eluent means the strength of the action of desorbing a component adsorbed to an adsorbent from the adsorbent. Effect of the Invention

[0010] According to the simulated moving bed chromatographic separation method of the present invention, a component to be purified in a raw solution can be separated with high purity. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 is a system diagram showing an example of a simulated moving bed chromatographic separation system of the present invention. [Diagram 2] FIG. 2 is a flow diagram of each of the sub-steps constituting steps (A) and (B) in one embodiment of the simulated moving bed chromatographic separation method of the present invention. [Diagram 3] FIG. 3 is a flow diagram of each of the sub-steps constituting steps (A) and (B) in the next cycle after steps (A) and (B) shown in FIG. 2 are completed. [Figure 4]FIG. 4 is a flow diagram of each of the sub-steps constituting steps (A) and (B) in another embodiment of the simulated moving bed chromatographic separation method of the present invention. [Diagram 5] FIG. 5 is a flow diagram of each of the sub-steps constituting steps (A) and (B) in the next cycle after steps (A) and (B) shown in FIG. 4 are completed.

[0012] A preferred embodiment of the simulated moving bed chromatographic separation method of the present invention (hereinafter, also simply referred to as the "method of the present invention") will be described.

[0013] The method of the present invention is carried out using a circulation system in which a plurality of unit packed towers packed with an adsorbent are connected in series and endlessly via piping. The circulation system used in the simulated moving bed method is known per se, and reference can be made to, for example, JP 2009-36536 A and JP 4606092 A. The circulatory system will be described below with reference to the drawings, but the present invention is not limited to these embodiments except as defined in the present invention. The drawings mentioned below are explanatory diagrams for facilitating understanding of the present invention, and the sizes and relative size relationships of each component may be changed for the convenience of explanation, and do not directly represent the actual relationships. Furthermore, matters other than those stipulated in the present invention are not limited to the shapes, relative positional relationships, etc. shown in these drawings. Furthermore, conditions other than those specified in the present invention, such as the capacity of the unit packed tower, the inner cross-sectional area and length of the piping, and the flow rate of the liquid supplied to the circulation system, can be appropriately set depending on the purpose.

[0014] A preferred embodiment of the circulation system used in the method of the present invention is shown in Figure 1. The circulation system 100 shown in Figure 1 includes four unit packed towers (columns) packed with an adsorbent Ab (unit packed towers 10a, 10b, 10c, and 10d), the outlet of each unit packed tower being connected to the inlet of the adjacent unit packed tower via a pipe 1, and the unit packed towers are connected in series as a whole. The outlet of the rearmost unit packed tower (for example, unit packed tower 10d) is connected to the inlet of the frontmost unit packed tower (for example, unit packed tower 10a) via piping 1, and all unit packed towers are connected in an endless manner (ring-shaped). With this configuration, it is possible to circulate a fluid within the circulation system 100. The unit packed towers 10a to 10d may be the same or different in terms of internal shape, size, and adsorbent filling amount. It is preferable to use unit packed towers 10a to 10d that are equivalent (preferably the same) in terms of internal shape, size, and adsorbent filling amount.

[0015] A circulation pump P1 for circulating the fluid in the direction of the arrow can be disposed in the circulation system 100. The circulation pump P1 is preferably a metering pump. In the circulation system 100, a pipe 1 between two adjacent unit packed towers is provided with shutoff valves R1, R2, R3, and R4 capable of shutting off the flow of the fluid to the downstream unit packed tower.

[0016] Between each of the shutoff valves R1 to R4 and the outlet of each of the unit packed towers 10a to 10d located upstream thereof, weakly adsorbent fraction withdrawal lines 2a, 2b, 2c, and 2d are branched out to withdraw a fraction containing a large amount of a weakly adsorbent component for the adsorbent Ab (referred to herein as a "weakly adsorbent fraction for the adsorbent Ab" or simply as a "weakly adsorbent fraction"). Each of the weakly adsorbent fraction withdrawal lines 2a, 2b, 2c, and 2d is provided with a weakly adsorbent fraction withdrawal valve A1, A2, A3, and A4 capable of opening and closing each of the weakly adsorbent fraction withdrawal lines. Each of the weakly adsorbent fraction withdrawal lines 2a, 2b, 2c, and 2d is joined together to form a single weakly adsorbent fraction joining pipe 2J.

[0017] Similarly, between each of the shutoff valves R1 to R4 and the outlet of each of the unit packed towers 10a to 10d located upstream thereof, medium adsorbent fraction withdrawal lines 3a, 3b, 3c, and 3d are branched and disposed to withdraw a fraction containing a large amount of a medium adsorbent component for the adsorbent Ab (referred to herein as a "medium adsorbent fraction for the adsorbent Ab" or simply as a "medium adsorbent fraction"). Each of the medium adsorbent fraction withdrawal lines 3a, 3b, 3c, and 3d is provided with a medium adsorbent fraction withdrawal valve B1, B2, B3, and B4 capable of opening and closing each of the medium adsorbent fraction withdrawal lines. Each of the medium adsorbent fraction withdrawal lines 3a, 3b, 3c, and 3d is joined together to form a single medium adsorbent fraction joining pipe 3J.

[0018] Similarly, between each of the shutoff valves R1 to R4 and the outlet of each of the unit packed towers 10a to 10d located upstream thereof, strongly adsorbent fraction extraction lines 4a, 4b, 4c, and 4d are branched and arranged to extract a fraction containing a large amount of strongly adsorbent components for the adsorbent Ab (referred to as a "strongly adsorbent fraction for the adsorbent Ab" or simply as a "strongly adsorbent fraction" in this specification). Each of the strongly adsorbent fraction extraction lines 4a, 4b, 4c, and 4d is provided with a strongly adsorbent fraction extraction valve C1, C2, C3, and C4 capable of opening and closing each of the strongly adsorbent fraction extraction lines. Each of the strongly adsorbent fraction extraction lines 4a, 4b, 4c, and 4d is joined together and combined into a single strongly adsorbent fraction joining pipe 4J.

[0019] In the processes and steps described below, any one of the weakly adsorbent fraction withdrawal valves A1, A2, A3, and A4 is in an open state. The connection portion between the weakly adsorbent fraction withdrawal line in which the opened weakly adsorbent fraction withdrawal valve is installed and the piping 1 serves as an outlet A for the weakly adsorbent fraction in the processes and steps described below. In the processes and steps described below, any one of the medium adsorbent fraction withdrawal valves B1, B2, B3, and B4 is in an open state. The connection portion between the medium adsorbent fraction withdrawal line in which the opened medium adsorbent fraction withdrawal valve is installed and the piping 1 becomes the medium adsorbent fraction withdrawal port B in the processes and steps described below. In the processes and steps described below, any one of the strongly adsorbent fraction withdrawal valves C1, C2, C3, and C4 is in an open state. The connection portion between the strongly adsorbent fraction withdrawal line in which the opened strongly adsorbent fraction withdrawal valve is installed and the piping 1 serves as an outlet C for the strongly adsorbent fraction in the processes and steps described below.

[0020] In order to prevent the pressure in the circulation system 100 from increasing too much, a safety valve (or a relief valve) (not shown) may be provided at an appropriate position in the circulation system 100. In addition, it is preferable to provide check valves T1, T2, T3, and T4 for preventing backflow between two adjacent unit packed towers.

[0021] As shown in Fig. 1, the circulation system 100 is configured to be capable of supplying a stock solution 7 contained in a stock solution tank 6. The circulation system 100 is also configured to be capable of supplying three or more types of eluent. Fig. 1 shows an example in which four types of eluent are supplied. The raw liquid 7 is supplied through the raw liquid supply line 11 by the raw liquid supply pump P2 whose supply flow rate can be controlled. The raw liquid supply pump P2 is preferably a metering pump. The raw liquid supply line 11 is branched into four raw liquid supply branch lines 11a, 11b, 11c, and 11d as shown in FIG. 1, and the raw liquid can be supplied to the inlets of the unit packed towers 10a, 10b, 10c, and 10d through the raw liquid supply branch lines 11a, 11b, 11c, and 11d. The raw liquid supply branch lines 11a, 11b, 11c, and 11d are provided with raw liquid supply valves F1, F2, F3, and F4 that can be opened and closed, and the raw liquid is supplied to the unit packed tower connected downstream through the raw liquid supply branch line having the raw liquid supply valve that is opened. In the process and steps described below, any one of the raw solution supply valves F1, F2, F3, and F4 is in an open state. The connection portion between the raw solution supply branch line in which the opened raw solution supply valve is installed and the piping 1 becomes the raw solution supply port F in the process and steps described below.

[0022] FIG. 1 shows a form in which four types of eluents with different desorption powers are supplied. The eluent 9a contained in the eluent tank 8a is supplied to the eluent supply line 12 by the eluent supply pump P3, the supply flow rate of which can be controlled. The eluent 9b contained in the eluent tank 8b is supplied to the eluent supply line 13 by the eluent supply pump P4, the supply flow rate of which can be controlled. The eluent 9c contained in the eluent tank 8c is supplied to the eluent supply line 14 by the eluent supply pump P5, the supply flow rate of which can be controlled. Furthermore, the eluent 9d contained in the eluent tank 8d is supplied to the eluent supply line 15 by the eluent supply pump P6, the supply flow rate of which can be controlled. The eluent supply pumps P3 to P6 are preferably metering pumps. The eluent supply line 12 is branched into four eluent supply branch lines 12a, 12b, 12c, and 12d as shown in FIG. 1, and the eluent can be supplied to the inlets of the unit packed towers 10a, 10b, 10c, and 10d through the eluent supply branch lines 12a, 12b, 12c, and 12d. The eluent supply branch lines 12a, 12b, 12c, and 12d are provided with openable and closable eluent supply valves E1a, E2a, E3a, and E4a, and the eluent is supplied to the unit packed tower connected downstream through the eluent supply branch line having the open eluent supply valve. Similarly, the eluent supply line 13 is branched into four eluent supply branch lines 13a, 13b, 13c, and 13d, the eluent supply line 14 is branched into four eluent supply branch lines 14a, 14b, 14c, and 14d, and the eluent supply line 15 is branched into four eluent supply branch lines 15a, 15b, 15c, and 15d, so that each eluent can be supplied to the inlet of each unit packed tower 10a, 10b, 10c, and 10d. The eluent supply branch lines 13a, 13b, 13c, and 13d are provided with openable and closable eluent supply valves E1b, E2b, E3b, and E4b, respectively, the eluent supply branch lines 14a, 14b, 14c, and 14d are provided with openable and closable eluent supply valves E1c, E2c, E3c, and E4c, respectively, and the eluent supply branch lines 15a, 15b, 15c, and 15d are provided with openable and closable eluent supply valves E1d, E2d, E3d, and E4d, respectively. In the processes and steps described below, a connection portion between the eluent supply branch line in which an opened eluent supply valve is installed and the pipe 1 serves as an eluent supply port D. In the processes and steps described below, a plurality of eluent supply valves are opened. That is, in the processes and steps described below, the number of eluent supply ports D exists according to the type of eluent used.

[0023] Next, the operation of the circulatory system when carrying out the method of the present invention using the above-mentioned circulatory system will be described, but the present invention is not limited to these embodiments except as specified in the present invention.

[0024] In the method of the present invention, the circulation system includes three or more unit packed towers packed with an adsorbent, which are connected in series and endlessly via piping. The circulation system is divided into at least three continuous sections in a circular ring shape from the upstream side to the downstream side, each section having at least one unit packed tower. That is, one section may have multiple unit packed towers. The method of the present invention can separate weakly adsorbable components, strongly adsorbable components, and moderately adsorbable components having intermediate adsorption properties between the two components, contained in the raw solution, using an eluent, by repeating a cycle consisting of the first and second processes described below, or a cycle consisting of steps (A) and (B) described below. The first and second processes described below are operations characteristic of the present invention, focusing on the movement of the extraction position of the strongly adsorbable component, and steps (A) and (B) described below are operations characteristic of the present invention, focusing on the movement of the extraction position of the weakly adsorbable component.

[0025] In the present invention and this specification, "repeating a cycle consisting of the first process and the second process" or "repeating a cycle consisting of steps (A) and (B)" means that after completion of the second process or step (B) (completion of one cycle), a position upstream of the section enriched with the weakly adsorbable component (preferably the upstream end of the section enriched with the weakly adsorbable component) is set as a cut-off position, and the cycle is repeated by newly starting the supply of the stock solution in the first process or step (A) to the section downstream of the cut-off position.

[0026] Furthermore, in the present invention and this specification, as a form of "repeating a cycle consisting of steps (A) and (B)", after the end of step (B) (after the end of one cycle), the position at which the weakly adsorbing fraction is withdrawn remains the same, and step (A) of the next cycle can be started with the position at which the stock solution is supplied, the position at which the eluent for desorbing the moderately adsorbing component is supplied, and the position at which the moderately adsorbing fraction enriched in the moderately adsorbing component is withdrawn, as specified in step (A) (sub-step (A1)) based on the withdrawal position of the weakly adsorbing fraction. That is, as described below, if the withdrawal outlet for the weakly adsorbing fraction and the stock solution supply port are constructed one section apart in sub-step (A1) of the previous cycle, the withdrawal outlet for the weakly adsorbing fraction and the stock solution supply port are also constructed one section apart in sub-step (A1) of the next cycle, regardless of the position of the withdrawal outlet for the weakly adsorbing fraction.

[0027] In the method of the present invention, the sum of the amount of the raw solution supplied and the amount of the eluent supplied is equal to the sum of the amount of the weakly, moderately and strongly adsorbing fractions extracted. In other words, when liquid is supplied into the circulating system, the same amount of liquid is extracted from the circulating system. More specifically, when a liquid is supplied from a certain supply port (X) and is withdrawn from a certain outlet (Y) downstream of the supply port, if no liquid is supplied from downstream of X and upstream of Y, the amount of liquid withdrawn from Y is the same as the amount of liquid supplied from X. Also, when liquid is supplied from downstream of X and upstream of Y, the amount of liquid withdrawn from Y is the same as the sum of the amount of liquid supplied from X and the amount of liquid supplied from downstream of X and upstream of Y. For example, in substep (A1-1) of FIG. 2, the amount of eluent supplied from eluent supply port D2 is the same as the amount of the moderately adsorbing fraction withdrawn from the moderately adsorbing fraction outlet B. Also, in the same substep (A1-1), the amount of stock solution supplied from stock solution supply port F is the same as the amount of the weakly adsorbing fraction withdrawn from the weakly adsorbing fraction outlet A.

[0028] In the method of the present invention, it is preferable to use three or more eluents having different desorption strengths, it is more preferable to use three to six eluents having different desorption strengths, and it is particularly preferable to use three or four eluents having different desorption strengths. The type of eluent is not particularly limited, and is appropriately set depending on the type of adsorbent and the type of components in the raw solution. For example, when an ion exchange resin is used as the adsorbent, multiple eluents with different desorption powers can be prepared by changing the salt concentration of the eluent. For example, when a cation exchange resin is used as the adsorbent, multiple eluents with different NaCl concentrations can be used.

[0029] The first and second processes, or steps (A) and (B) described below in the method of the present invention do not specify the first implementation (first cycle) of the first and second processes, or steps (A) and (B), but assume a steady state after the first and second processes, or steps (A) and (B) are sequentially performed at least once (preferably two or more times, more preferably three or more times, even more preferably four or more times, and even more preferably five or more times). For example, as shown in the flow diagram of FIG. 2, in the first implementation (first cycle), in substep (A1-1), the raw liquid is supplied from upstream of section 3, so that no medium adsorbent is present in sections 1 and 2. Therefore, in substep (A1-1) in the first implementation, the medium adsorbent fraction enriched with the medium adsorbent is not extracted from the extraction outlet B for the medium adsorbent fraction. However, by performing the following steps (A) and (B) in this order at least once as specified in the method of the present invention, in the subsequent cycles, a medium adsorbable fraction enriched in the medium adsorbable component will be extracted from the extraction port B for the medium adsorbable fraction in substep (A1-1).

[0030] In one embodiment of the present invention, the operation of the circulatory system characteristic of the present invention can be specified by regarding the cycle consisting of the following first and second processes as one cycle. <First process> A process comprising the steps of blocking the circulation of the circulation system at a position upstream of the section enriched in the weakly adsorbable component (preferably the upstream end of the section enriched in the weakly adsorbable component) as a blocking position, supplying the raw liquid to the section downstream of the blocking position, and withdrawing a medium adsorbable fraction enriched in the medium adsorbable component from the section upstream of the blocking position from the circulation system. <Second process> A process comprising a step of extracting a strongly adsorbent fraction enriched in the strongly adsorbent component by controlling the supply of the eluent and the blocking of the circulation system without supplying the stock solution, and moving the supply position of the eluent to the circulation system and the extraction position of the strongly adsorbent fraction downstream in accordance with the movement of the strongly adsorbent fraction.

[0031] In addition, when the cycle in the present invention is specified by the first process and the second process, the strongly adsorbing fraction is moved downstream of the extraction position in the cycle by two or more sections, and the downstream movement is not the same as the [number of sections]. The number of sections is the total number of sections in the circulation system. For example, in the method of the present invention, when the number of sections used in the circulation system is four, the strongly adsorbing fraction is moved downstream of the extraction position in one cycle by two or three sections, or by five or more sections.

[0032] The position for supplying the stock solution in the first process, the position for supplying the eluent for desorbing the moderately adsorbent, and the position for extracting the moderately adsorbent fraction enriched with the moderately adsorbent are constructed based on a cutoff position upstream of the section enriched with the weakly adsorbent in the immediately preceding process (preferably the upstream end of the section enriched with the weakly adsorbent). Note that in the first cycle, any position can be set as the cutoff position. In the first and second processes, it is preferable that the weakly adsorbing fraction is always extracted from the section enriched in the weakly adsorbing component. In addition, the position at which the weakly adsorbing fraction is extracted can be referenced to the description of the positions at which the weakly adsorbing fraction is extracted in steps (A) and (B) described below.

[0033] In another embodiment of the present invention, the operation of the circulatory system characteristic of the present invention can also be specified by considering a cycle consisting of the following steps (A) and (B) as one cycle. <Step (A)> In step (A), the following sub-steps (A1) to (A4) are carried out in this order. a substep (A1) of blocking circulation in the circulation system at a blockage position upstream of the section enriched in the weakly adsorbable component (preferably, the upstream end of the section enriched in the adsorbable component), supplying the stock solution to a section downstream of the blockage position and extracting a weakly adsorbable fraction enriched in the weakly adsorbable component from the circulation system at a further downstream position, and supplying an eluent for desorbing the moderately adsorbable component to the section upstream of the blockage position and extracting a moderately adsorbable fraction enriched in the moderately adsorbable component from the circulation system at a downstream position thereof; A sub-step (A2) of supplying an eluent for desorbing the weakly adsorbable component instead of supplying the stock solution, and continuing the extraction of the weakly adsorbable fraction and the extraction of the moderately adsorbable fraction; A substep (A3) of moving the blocking position upstream, supplying an eluent for desorbing the strongly adsorbent component upstream of the moved blocking position while continuing to extract the weakly adsorbent fraction, and extracting a strongly adsorbent fraction enriched in the strongly adsorbent component at a downstream position thereof; and and sub-step (A4) of shifting the withdrawal position of the weakly adsorbing fraction downstream to withdraw the weakly adsorbing fraction, while not withdrawing the moderately adsorbing fraction and not withdrawing the strongly adsorbing fraction.

[0034] In the present invention, sub-steps (A1), (A2), (A3) and (A4) are carried out in step (A) as described above. In the present invention, "performing sub-steps W, X, Y, and Z in step (A)" means that step (A) includes sub-steps W, X, Y, and Z. In addition, step (A) may include sub-steps other than sub-steps W, X, Y, and Z. A typical example of the form of "performing substeps W, X, Y, and Z in step (A)" is a form in which substeps W, X, Y, and Z are performed in order as step (A), but the present invention is not limited to this form. That is, "performing substeps W, X, Y, and Z in step (A)" is not limited to a form in which substep X is performed immediately after substep W, substep Y is performed immediately after substep X, substep Z is performed immediately after substep Y, step (B) is performed immediately after substep Z, and substep W is performed immediately after step (B). For example, in a form including the above-mentioned other substeps, other substeps (substeps other than substeps W, X, Y, and Z) can be incorporated before substep W (between step (B) and substep W), between substeps W and X, between substeps X and Y, between substeps Y and Z, and between substeps Z and step (B) within a range that does not impair the effects of the present invention. By adjusting the supply flow rate, flow velocity, eluent strength, etc., the desired effect may be obtained even if additional substeps other than substeps W, X, Y, and Z are included, and this will be naturally understood by a person skilled in the art who has come into contact with this specification. This also applies when step (B) has sub-steps.

[0035] <Substep (A1)> In the sub-step (A1), while the eluent for desorbing the moderately adsorbable component is being supplied, the medium adsorbable fraction is extracted from downstream in an amount equal to the amount of the eluent for desorbing the moderately adsorbable component that is supplied. In this case, it is preferable that at least two sections (unit packed towers) are provided between the supply port for the eluent for desorbing the moderately adsorbable component and the downstream outlet for extracting the medium adsorbable fraction. It is also preferable that no other supply ports exist between them. In the sub-step (A1), while the raw liquid is being supplied, the weakly adsorbing fraction is preferably withdrawn from the downstream in an amount equal to the amount of the raw liquid supplied. In this case, at least one section (unit packed tower) is provided between the raw liquid supply port and the weakly adsorbing fraction withdrawal port downstream. In addition, it is preferable that no other supply port exists between them.

[0036] The position for supplying the stock solution in substep (A1), the position for supplying the eluent for desorbing the moderately adsorbent, and the position for extracting the moderately adsorbent-enriched fraction are constructed based on a position upstream of the section enriched in the weakly adsorbent in the immediately preceding step (preferably the upstream end of the section enriched in the weakly adsorbent), which is set as the cut-off position. Alternatively, they can be constructed based on the position for extracting the weakly adsorbent fraction in the immediately preceding step. Note that in the first cycle, any position can be set as the cut-off position. The position for supplying the raw solution is preferably provided at least one section upstream from the position for extracting the weakly adsorptive fraction. The position for extracting the medium adsorbent fraction enriched in the medium adsorbent component is preferably provided on the same piping as the position for supplying the raw liquid (raw liquid supply port) and upstream of the position for supplying the raw liquid. In other words, it is preferable that no unit packed tower is provided between the position for extracting the medium adsorbent fraction enriched in the medium adsorbent component and the position for supplying the raw liquid. The position where the eluent for desorbing the moderately adsorbable component is supplied is preferably on the same piping as the position where the weakly adsorbable fraction is extracted (the outlet for the weakly adsorbable fraction) and is downstream of the position where the weakly adsorbable fraction is extracted. In other words, it is preferable that no unit packed tower is provided between the position where the eluent for desorbing the moderately adsorbable component is supplied and the position where the weakly adsorbable fraction is extracted.

[0037] <Substep (A2)> In the sub-step (A2), while the eluent for desorbing the weakly adsorbing component is being supplied in place of the stock solution, the weakly adsorbing fraction is extracted from downstream in an amount equal to the amount of the eluent for desorbing the weakly adsorbing component. In the system configuration shown in Fig. 1, the supply port for the stock solution and the supply port for the eluent for desorbing the weakly adsorbing component are different supply ports provided on the same pipe. The position of the outlet for the weakly adsorbing fraction is preferably the same as the position of the outlet for the weakly adsorbing fraction in the sub-step (A1). In the sub-step (A2), the withdrawal of the moderately adsorbent fraction in the sub-step (A1) is continued. That is, the conditions for withdrawing the moderately adsorbent fraction in the sub-step (A2) can be the same as the conditions for withdrawing the moderately adsorbent fraction in the sub-step (A1).

[0038] <Substep (A3)> In the sub-step (A3), it is preferable to provide a supply port for supplying an eluent for desorbing the strongly adsorbent in the same piping as the supply ports for the eluent for desorbing the moderately adsorbent in the sub-steps (A1) and (A2). It is also preferable to supply an eluent for desorbing the moderately adsorbent downstream of the moved blocking position, and further preferable to supply an eluent for desorbing the weakly adsorbent from the downstream side across one section from the supply port for the eluent for desorbing the moderately adsorbent. The position for extracting the strongly adsorbent fraction enriched in the strongly adsorbent component is preferably provided on the same piping as the supply port for the eluent for desorbing the moderately adsorbent component, and upstream of the supply position for the eluent. Also, the position of the outlet for the weakly adsorbent fraction is preferably the same as the position of the outlet for the weakly adsorbent fraction in the substep (A2).

[0039] <Substep (A4)> In the sub-step (A4), it is preferred to leave the supply inlet for the eluent for desorbing the moderately adsorbing component and the supply inlet for the eluent for desorbing the weakly adsorbing component in the sub-step (A3) unchanged, and to shift the position of the outlet for the weakly adsorbing fraction by one section downstream from the outlet for the weakly adsorbing fraction in the sub-step (A3).

[0040] <Step (B)> In step (B), the extraction position of the weakly adsorbing fraction is left unchanged, and the weakly adsorbing fraction and the strongly adsorbing fraction that were not extracted in step (A) are extracted separately by supplying the eluent and controlling the blockage position without supplying the original solution, and then step α is performed at least once, in which the extraction position of the weakly adsorbing fraction is moved downstream and only the weakly adsorbing fraction is extracted.

[0041] In the step (B), it is preferable not to extract the moderately adsorbent fraction. On the other hand, a supply port for an eluent for desorbing the moderately adsorbent can be set in accordance with the movement of the moderately adsorbent in the circulation system. That is, a position upstream of the section enriched with the moderately adsorbent (preferably, the upstream end of the section enriched with the moderately adsorbent) can be set as the supply position for the eluent for desorbing the moderately adsorbent.

[0042] In the step α, the supply port for the eluent for desorbing the strongly adsorbent component is preferably provided on the same pipe as the supply port for the eluent for desorbing the moderately adsorbent component at the end of the immediately preceding step or the immediately preceding step α. That is, for example, when the step α is performed once, the supply port for the eluent for desorbing the strongly adsorbent component in step (B) is preferably provided on the same pipe as the supply port for the eluent for desorbing the moderately adsorbent component at the end of the immediately preceding step, step (A) (substep (A4)). Also, for example, when the step α is performed twice, the supply port for the eluent for desorbing the strongly adsorbent component in the second step α is preferably provided on the same pipe as the supply port for the eluent for desorbing the moderately adsorbent component at the end of the first step α.

[0043] It is preferable to always withdraw the weakly adsorbing fraction during the implementation of step (B). Therefore, even when step (B) is composed of a plurality of sub-steps, it is preferable to always withdraw the weakly adsorbing fraction in the plurality of sub-steps.

[0044] In step α, as described above, the weakly adsorbing fraction and the strongly adsorbing fraction are separately extracted, and then the extraction position of the weakly adsorbing fraction is moved downstream to extract only the weakly adsorbing fraction. Therefore, when step α is repeated, i.e., when step α is performed multiple times, the supply positions of each eluent and the extraction positions of each fraction at the start of the next step α are shifted downstream by at least one section while maintaining the relative positional relationship of each position compared to the supply positions of each eluent and the extraction positions of each fraction at the start of the previous step α. That is, at the start of step α when moving from sub-step (A4) to step α, the extraction position of the weakly adsorbing fraction is the same as the extraction position of the weakly adsorbing fraction in sub-step (A4). In step α, the extraction position of the weakly adsorbing fraction is moved downstream, so that at the start of the next step α, the extraction position of the weakly adsorbing fraction moved downstream in the previous step α (the extraction position of the weakly adsorbing fraction at the end of the previous step α) remains the extraction position of the weakly adsorbing fraction. The supply positions of each eluent other than the extraction position of the weakly adsorbing fraction in the next step α and the extraction position of the strongly adsorbing fraction are reconstructed according to the provisions of step α, based on the extraction position of the weakly adsorbing fraction at the start of the next step α. Therefore, by repeating step α, each position is shifted downstream by at least one section.

[0045] With the repetition of steps (A) and (B) (repetition of the cycle), the position for supplying the stock solution, the position for supplying the eluent, and the position for extracting each fraction are preferably moved upstream by one or more sections compared to the previous cycle while maintaining their relative positions. In this way, by moving each of the positions while maintaining their relative positions between the previous cycle and the following cycle, it is possible to avoid the stock solution always being supplied from the same supply port, and to prevent the same supply port from being excessively contaminated by the stock solution. The number of sections to move upstream when the cycle is repeated can be determined by the number of sections and the number of times step α is repeated.

[0046] In the step (A), it is preferable that the raw solution supply port F for supplying the raw solution, the outlet A for withdrawing the weakly adsorbing fraction, the outlet B for withdrawing the moderately adsorbing fraction, and the outlet C for withdrawing the strongly adsorbing fraction in the piping of the circulation system are provided at positions that satisfy the following (a) to (c). That is, in the repetition of steps (A) and (B), it is preferable that the relative positional relationship between the raw solution supply port F, the outlet A for the weakly adsorbing fraction, the outlet B for the moderately adsorbing fraction, and the outlet C for the strongly adsorbing fraction in step (A) always satisfies the above (a) to (c).

[0047] (a) A weakly adsorbent fraction withdrawal port A is provided downstream of the raw solution supply port F, with at least one section in between.

[0048] (b) A middle adsorptive fraction withdrawal outlet B is provided in a pipe having a raw solution supply inlet F. Here, "the medium adsorbent fraction outlet B is provided in a pipe having a raw solution supply port F" means that no unit packed tower is disposed between the medium adsorbent fraction outlet B and the raw solution supply port F. In addition, when "the medium adsorbent fraction outlet B is provided in a pipe having a raw solution supply port F", the medium adsorbent fraction outlet B is provided upstream of the raw solution supply port F in the same pipe. This applies to all relationships between an outlet and a supply port provided in the same pipe. In other words, in a circulation system, when a certain outlet and a supply port are provided in the same pipe (when an outlet and a supply port are provided without a unit packed tower), the outlet is disposed upstream of the supply port in the same pipe. This is to prevent the supplied liquid from being withdrawn from the outlet before it reaches the downstream unit packed tower.

[0049] (c) A strongly adsorbent fraction outlet C is provided upstream of the moderately adsorbent fraction outlet B, with at least one section in between.

[0050] In step (B), it is preferable that outlet A for withdrawing the weakly adsorbing fraction and outlet C for withdrawing the strongly adsorbing fraction in the piping of the circulation system are provided at positions that satisfy the following (d). That is, in the repetition of steps (A) and (B), it is preferable that the relative positional relationship between outlet A for the weakly adsorbing fraction and outlet C for the strongly adsorbing fraction in step (B) always satisfies the above-mentioned (d).

[0051] (d) A weakly adsorbent fraction outlet A is provided downstream of a strongly adsorbent fraction outlet C, with at least two sections in between.

[0052] In step (B), the strongly adsorbent fraction outlet C is preferably provided in a pipe having an inlet for an eluent for desorbing the moderately adsorbent. That is, the strongly adsorbent fraction outlet C is preferably provided upstream of the inlet for the eluent for desorbing the moderately adsorbent in the same pipe.

[0053] It is preferable that the number of times of the process α in the step (B) is [the number of sections-2] times or more than [the number of sections] times. The number of sections is the total number of sections in the circulatory system. For example, in the embodiment shown in FIG. 2 and FIG. 3, the number of sections is four, so the number of times of the process α is two, and in the embodiment shown in FIG. 4 and FIG. 5, the number of sections is three, so the number of times of the process α is one.

[0054] A preferred embodiment of the combination of sub-steps in the above steps (A) and (B) will be described below. These embodiments can be implemented using the system of FIG. 1 or a system capable of implementing the desired embodiment similar to the system of FIG. 1. The following embodiment is an example of the present invention, and for example, from the viewpoint of relative desorption power, two or more types of eluents positioned as the following eluent dI can be prepared, and the type of eluent dI used can be changed between the sub-steps of supplying the eluent dI. This also applies to the eluents d-II to d-IV. That is, in the present invention, when "eluent dI" is used in different substeps in an embodiment, the "eluent dI" used in the different substeps may be the same or different. This also applies to eluents d-II to d-IV.

[0055] -Embodiment 1- In the first embodiment, a circulation system having four or more unit packed towers is used. This circulation system is assumed to be divided into four sections 1 to 4 that are continuous in a circular ring shape from the upstream side to the downstream side, with each section having at least one unit packed tower. In addition, four types of eluents dI to d-IV with controlled desorption power are used as eluents. In this embodiment 1, the following sub-steps (A1-1), (A2-1), (A3-1) and (A4-1) are carried out in step (A).

[0056] <Sub-step (A1-1)> The upstream end of section 1 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as the outlet B, and a moderately adsorbable fraction is extracted from said outlet B; the upstream end of section 3 is designated as the raw solution supply port F, and a raw solution is supplied from said raw solution supply port F; and the downstream end of section 4 is designated as the outlet A, and a weakly adsorbable fraction is extracted from said outlet A; The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through sections 3 and 4 is made weaker than the desorption power of the eluent flowing through sections 1 and 2. In substep (A1-1), the supply of each of the above liquids and the withdrawal of the weakly adsorbing fraction are continuously carried out (i.e., in substep (A1-1), the supply of each of the above liquids and the withdrawal of the weakly adsorbing fraction are always carried out continuously). The same applies to each of the substeps described below. Furthermore, in the present invention and this specification, the explanation of the strength of the desorption force of the eluent described in each substep refers to the strength of the desorption force of the eluent in that substep, and does not explain the strength of the desorption force of the eluent in a different substep. For example, if it is explained that the desorption force of the eluent flowing through section 1 is maximized in one substep constituting step (A), and it is also explained that the desorption force of the eluent flowing through section 1 is maximized in another substep constituting step (A), the desorption force of the eluent flowing through section 1 in that one substep and the desorption force of the eluent flowing through section 1 in that other substep may be the same or different.

[0057] <Sub-step (A2-1)> The upstream end of section 1 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as the outlet B, and a moderately adsorbent fraction is extracted from said outlet B; the upstream end of section 3 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV; and the downstream end of section 4 is designated as the outlet A, and a weakly adsorbent fraction is extracted from said outlet A; The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through sections 3 and 4 is made weaker than the desorption power of the eluent flowing through sections 1 and 2. The eluent supply port D-IV in this sub-step (A2-1) is provided in the same piping as the raw solution supply port F in the above sub-step (A1-1).

[0058] <Sub-step (A3-1)> the upstream end of section 1 is designated as an eluent supply port DI, eluent dI is supplied from the eluent supply port DI, the downstream end of section 1 is designated as the outlet C, and a strongly adsorbent fraction is extracted from the outlet C; the upstream end of section 2 is designated as an eluent supply port D-II, and eluent d-II is supplied from the eluent supply port D-II; the upstream end of section 3 is designated as an eluent supply port D-III, and eluent d-III is supplied from the eluent supply port D-III; the upstream end of section 4 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from the eluent supply port D-IV; and the downstream end of section 4 is designated as the outlet A, and a weakly adsorbent fraction is extracted from the outlet A; The desorption force of the eluent flowing through Section 1 is maximized. The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption power of the eluent flowing through section 4 is made weaker than the desorption power of the eluent flowing through section 3.

[0059] <Sub-step (A4-1)> The upstream end of section 2 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 4 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as the withdrawal port A, and a weakly adsorbable fraction is withdrawn from said withdrawal port A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is set to be the same as the desorption force of the eluent flowing through section 4.

[0060] An example of the sub-step (A1-1) is a sub-step of carrying out the following sub-step (A1-1ex), but the sub-step (A1-1) is not limited to the sub-step (A1-1ex). In the following example, the desorption power of eluent d4 is described as being weaker than that of eluent d3, but the desorption power of eluent d3 and eluent d4 may be the same. The same applies to the following examples. <Substep(A1-1ex)> The upstream end of section 1 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The downstream end of section 2 is designated as a middle adsorbent fraction outlet B, and the middle adsorbent fraction is extracted from said outlet B; The upstream end of section 3 is a raw liquid supply port F, and the raw liquid is supplied from the raw liquid supply port F. The downstream end of section 4 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from said outlet A.

[0061] An example of the sub-step (A2-1) is a sub-step of carrying out the following sub-step (A2-1ex), but the sub-step (A2-1) is not limited to the sub-step (A2-1ex). <Substep(A2-1ex)> The eluent d2 is supplied from the eluent supply port D2, A middle adsorbent fraction is withdrawn from the middle adsorbent fraction withdrawal port B, The upstream end of section 3 is set as an eluent supply port D4, and an eluent d4 having the weakest desorption power among the four eluents is supplied from the eluent supply port D4; The weakly adsorbent fraction is withdrawn from the weakly adsorbent fraction withdrawal port A. The eluent supply port D4 in this substep (A2-1ex) is provided in the same piping as the raw solution supply port F in the above substep (A1-1ex). In addition, the eluent supply port D2 in this substep (A2-1ex) is the same as the eluent supply port D2 in the above substep (A1-1ex).

[0062] An example of the sub-step (A3-1) is a sub-step of carrying out the following sub-step (A3-1ex), but the sub-step (A3-1) is not limited to the sub-step (A3-1ex). <Substep(A3-1ex)> The upstream end of section 1 is set as an eluent supply port D1, and an eluent d1 having the strongest desorption power among the four eluents is supplied from the eluent supply port D1; The downstream end of section 1 is set as a strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C; The upstream end of section 2 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The upstream end of section 3 is set as an eluent supply port D3, and an eluent d3 having the third strongest desorption power among the four eluents is supplied from the eluent supply port D3; The upstream end of section 4 is set as an eluent supply port D4, and an eluent d4 having the weakest desorption power among the four eluents is supplied from the eluent supply port D4; The weakly adsorbent fraction is withdrawn from the weakly adsorbent fraction withdrawal port A. The eluent supply port D1 in this substep (A3-1ex) is provided in the same piping as the eluent supply port D2 in the above substep (A2-1ex). Also, the eluent supply port D3 in this substep (A3-1ex) is provided in the same piping as the eluent supply port D4 in the above substep (A2-1ex).

[0063] An example of the sub-step (A4-1) is a sub-step of carrying out the following sub-step (A4-1ex), but the sub-step (A4-1) is not limited to the sub-step (A4-1ex). <Substep(A4-1ex)> The eluent d2 is supplied from the eluent supply port D2, The eluent d3 is supplied from the eluent supply port D3, The eluent d4 is supplied from the eluent supply port D4, The downstream end of section 1 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from outlet A. The eluent supply ports D2, D3, and D4 in this substep (A4-1ex) are the same as the eluent supply ports D2, D3, and D4 in the above substep (A3-1ex).

[0064] A flow diagram in which step (A) performs the sub-steps (A1-1ex), (A2-1ex), (A3-1ex), and (A4-1ex) in this order is shown in Figure 2. In Figure 2, each square box indicates one section, and the numbers in the box indicate the section number (numbered from left to right).

[0065] In this embodiment 1, in step (B), the following sub-steps (B1-1), (B2-1) and (B3-1) are considered as one set, and this set is performed twice. In this embodiment, the sub-steps for the second time are respectively denoted as (B1'-1), (B2'-1) and (B3'-1). That is, in step (B), the following sub-steps (B1-1) to (B3-1) and the following sub-steps (B1'-1) to (B3'-1) are performed.

[0066] <Sub-step (B1-1)> The upstream end of section 2 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 4 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as the withdrawal port A, and a weakly adsorbable fraction is withdrawn from said withdrawal port A; The desorption power of the eluent flowing through sections 2 and 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through sections 2 and 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4.

[0067] <Sub-step (B2-1)> the upstream end of section 2 is designated as an eluent supply port DI, eluent dI is supplied from the eluent supply port DI, the downstream end of section 2 is designated as the outlet C, and a strongly adsorbing fraction is extracted from the outlet C; the upstream end of section 3 is designated as an eluent supply port D-II, and eluent d-II is supplied from the eluent supply port D-II; the upstream end of section 4 is designated as an eluent supply port D-III, and eluent d-III is supplied from the eluent supply port D-III; the upstream end of section 1 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from the eluent supply port D-IV; and the downstream end of section 1 is designated as the outlet A, and a weakly adsorbing fraction is extracted from the outlet A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4.

[0068] <Sub-step (B3-1)> The upstream end of section 3 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 4 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as the withdrawal port A, and a weakly adsorbable fraction is withdrawn from said withdrawal port A; The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is set to be the same as the desorption force of the eluent flowing through section 1.

[0069] <Substep (B1'-1)> The upstream end of section 3 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as the withdrawal port A, and a weakly adsorbable fraction is withdrawn from said withdrawal port A; The desorption power of the eluent flowing through sections 3 and 4 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through sections 3 and 4; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1.

[0070] <Substep (B2'-1)> the upstream end of section 3 is designated as an eluent supply port DI, eluent dI is supplied from the eluent supply port DI; the downstream end of section 3 is designated as the outlet C, and a strongly adsorbent fraction is extracted from the outlet C; the upstream end of section 4 is designated as an eluent supply port D-II, and eluent d-II is supplied from the eluent supply port D-II; the upstream end of section 1 is designated as an eluent supply port D-III, and eluent d-III is supplied from the eluent supply port D-III; the upstream end of section 2 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from the eluent supply port D-IV; and the downstream end of section 2 is designated as the outlet A, and a weakly adsorbent fraction is extracted from the outlet A; The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1.

[0071] <Substep (B3'-1)> The upstream end of section 4 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 3 is designated as the withdrawal port A, and a weakly adsorbable fraction is withdrawn from said withdrawal port A; The desorption force of the eluent flowing through section 4 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is set to be the same as the desorption force of the eluent flowing through section 2.

[0072] An example of the sub-step (B1-1) is a sub-step of carrying out the following sub-step (B1-1ex), but the sub-step (B1-1) is not limited to the sub-step (B1-1ex). <Substep (B1-1ex)> The upstream end of section 2 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The upstream end of section 4 is set as an eluent supply port D3, and an eluent d3 having the third strongest desorption power among the four eluents is supplied from the eluent supply port D3; The upstream end of section 1 is set as an eluent supply port D4, and an eluent d4 having the weakest desorption power among the four eluents is supplied from the eluent supply port D4; The downstream end of section 1 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from outlet A. The eluent supply port D2 in this substep (B1-1ex) is the same as the eluent supply port D2 in the above substep (A4-1ex). In addition, the eluent supply port D3 in this substep (B1-1ex) is provided in the same piping as the eluent supply port D4 in the above substep (A4-1ex).

[0073] An example of the sub-step (B2-1) is a sub-step of carrying out the following sub-step (B2-1ex), but the sub-step (B2-1) is not limited to the sub-step (B2-1ex). <Sub-step (B2-1ex)> The upstream end of section 2 is set as an eluent supply port D1, and an eluent d1 having the strongest desorption power among the four eluents is supplied from the eluent supply port D1; The downstream end of section 2 is set as a strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C; The upstream end of section 3 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The eluent d3 is supplied from the eluent supply port D3, The eluent d4 is supplied from the eluent supply port D4, The weakly adsorbent fraction is withdrawn from the weakly adsorbent fraction withdrawal port A. The eluent supply port D1 in this substep (B2-1ex) is provided in the same piping as the eluent supply port D2 in the above substep (B1-1ex). Also, the eluent supply ports D3 and D4 in this substep (B2-1ex) are the same as the eluent supply ports D3 and D4 in the above substep (B1-1ex).

[0074] An example of the sub-step (B3-1) is a sub-step of carrying out the following sub-step (B3-1ex), but the sub-step (B3-1) is not limited to the sub-step (B3-1ex). <Sub-step (B3-1ex)> The eluent d2 is supplied from the eluent supply port D2, The eluent d3 is supplied from the eluent supply port D3, The eluent d4 is supplied from the eluent supply port D4, The downstream end of section 2 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from outlet A. The eluent supply ports D2, D3, and D4 in this substep (B3-1ex) are the same as the eluent supply ports D2, D3, and D4 in the above substep (B2-1ex).

[0075] An example of the sub-step (B1'-1) is a sub-step of carrying out the following sub-step (B1'-1ex), but the sub-step (B1'-1) is not limited to the sub-step (B1'-1ex). <Substep (B1'-1ex)> The upstream end of section 3 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The upstream end of section 1 is set as an eluent supply port D3, and an eluent d3 having the third strongest desorption power among the four eluents is supplied from the eluent supply port D3; The upstream end of section 2 is set as an eluent supply port D4, and an eluent d4 having the weakest desorption power among the four eluents is supplied from the eluent supply port D4; The downstream end of section 2 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from outlet A. The eluent supply port D2 in this substep (B1'-1ex) is the same as the eluent supply port D2 in the above substep (B3-1ex). In addition, the eluent supply port D3 in this substep (B1'-1ex) is provided in the same piping as the eluent supply port D4 in the above substep (B3-1ex).

[0076] An example of the sub-step (B2'-1) is a sub-step of carrying out the following sub-step (B2'-1ex), but the sub-step (B2'-1) is not limited to the sub-step (B2'-1ex). <Substep (B2'-1ex)> The upstream end of section 3 is set as an eluent supply port D1, and an eluent d1 having the strongest desorption power among the four eluents is supplied from the eluent supply port D1; The downstream end of section 3 is set as a strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C; The upstream end of section 4 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The eluent d3 is supplied from the eluent supply port D3, The eluent d4 is supplied from the eluent supply port D4, The weakly adsorbent fraction is withdrawn from the weakly adsorbent fraction withdrawal port A. The eluent supply port D1 in this substep (B2'-1ex) is provided in the same piping as the eluent supply port D2 in the above substep (B1'-1ex). Also, the eluent supply ports D3 and D4 in this substep (B2'-1ex) are the same as the eluent supply ports D3 and D4 in the above substep (B1'-1ex).

[0077] An example of the sub-step (B3'-1) is a sub-step of carrying out the following sub-step (B3'-1ex), but the sub-step (B3'-1) is not limited to the sub-step (B3'-1ex). <Substep (B3'-1ex)> The eluent d2 is supplied from the eluent supply port D2, The eluent d3 is supplied from the eluent supply port D3, The eluent d4 is supplied from the eluent supply port D4, The downstream end of section 3 is used as outlet A for the weakly adsorbent fraction, and the weakly adsorbent fraction is withdrawn from outlet A. The eluent supply ports D2, D3, and D4 in this substep (B3'-1ex) are the same as the eluent supply ports D2, D3, and D4 in the above substep (B2'-1ex).

[0078] A flow diagram in which step (B) performs the sub-steps (B1-1ex), (B2-1ex), (B3-1ex), (B1'-1ex), (B2'-1ex) and (B3'-1ex) in this order is shown in Figure 2. In Figure 2, each square box indicates one section, and the numbers in the box indicate the section number (numbered from left to right).

[0079] After completion of step (B), in which the above substeps (B1-1ex), (B2-1ex), (B3-1ex), (B1'-1ex), (B2'-1ex) and (B3'-1ex) are performed in order, the position of the weakly adsorbing fraction outlet A in substep (B3'-1ex) is left as it is, and the eluent supply port D2, the moderately adsorbing fraction outlet B and the raw solution supply port F are constructed while maintaining the relative positional relationship of each position based on the position of the weakly adsorbing fraction outlet A, and the substep (A1-1ex) of the next cycle is performed. A flow diagram of steps (A) and (B) in the next cycle is shown in Figure 3. Compared to the cycle shown in Figure 2, in the next cycle shown in Figure 3, all the supply ports and outlets have been moved one section upstream (three sections downstream) while maintaining their relative positional relationship.

[0080] -Embodiment 2- In the second embodiment, a circulation system having three or more unit packed towers is used. This circulation system is assumed to be divided into three continuous circular sections 1 to 3 from the upstream side to the downstream side, each section having at least one unit packed tower. In addition, four types of eluents dI to d-IV with controlled desorption power are used as eluents. In this embodiment 2, step (A) includes the following sub-steps (A1-2), (A2-2), (A3-2) and (A4-2) performed in this order.

[0081] <Sub-step (A1-2)> The upstream end of section 1 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the downstream end of section 2 is designated as the outlet B, and a moderately adsorbable fraction is extracted from said outlet B, the upstream end of section 3 is designated as the raw solution supply port F, and a raw solution is supplied from said raw solution supply port F, and the downstream end of section 3 is designated as the outlet A, and a weakly adsorbable fraction is extracted from said outlet A, The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through section 3 is made weaker than the desorption power of the eluent flowing through sections 1 and 2.

[0082] <Sub-step (A2-2)> The upstream end of section 1 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as the outlet B, and a moderately adsorbable fraction is extracted from said outlet B; the upstream end of section 3 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV; and the downstream end of section 3 is designated as the outlet A, and a weakly adsorbable fraction is extracted from said outlet A; The desorption power of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through section 3 is made weaker than the desorption power of the eluent flowing through sections 1 and 2. The eluent supply port D-IV in this sub-step (A2-2) is provided in the same piping as the raw solution supply port F in the above sub-step (A1-2).

[0083] <Sub-step (A3-2)> The upstream end of section 1 is designated as an eluent supply port DI, and eluent dI is supplied from the eluent supply port DI; the downstream end of section 1 is designated as the outlet C, and a strongly adsorbing fraction is extracted from the outlet C; the upstream end of section 2 is designated as an eluent supply port D-II, and eluent d-II is supplied from the eluent supply port D-II; the upstream end of section 3 is designated as an eluent supply port D-III, and eluent d-III is supplied from the eluent supply port D-III; and the downstream end of section 3 is designated as the outlet A, and a weakly adsorbing fraction is extracted from the outlet A; The desorption force of the eluent flowing through Section 1 is maximized. The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2.

[0084] <Sub-step (A4-2)> The upstream end of section 2 is designated as an eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as an eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as an eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as the withdrawal port A, and a weakly adsorbable fraction is withdrawn from said withdrawal port A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 3.

[0085] An example of the sub-step (A1-2) is a sub-step of carrying out the following sub-step (A1-2ex), but the sub-step (A1-2) is not limited to the sub-step (A1-2ex). In the following example, the desorption power of eluent d4 is described as being weaker than that of eluent d3, but the desorption power of eluent d3 and eluent d4 may be the same. The same applies to the following examples. <Substep(A1-2ex)> The upstream end of section 1 is designated as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D1; The downstream end of section 2 is designated as a middle adsorbent fraction outlet B, and the middle adsorbent fraction is extracted from said outlet B; The upstream end of section 3 is a raw liquid supply port F, and the raw liquid is supplied from the raw liquid supply port F. The downstream end of section 3 is used as outlet A for the weakly adsorbent fraction, and the weakly adsorbent fraction is withdrawn from outlet A.

[0086] An example of the sub-step (A2-2) is a sub-step of carrying out the following sub-step (A2-2ex), but the sub-step (A2-2) is not limited to the sub-step (A2-2ex). <Substep(A2-2ex)> The eluent d2 is supplied from the eluent supply port D2, A middle adsorbent fraction is withdrawn from the middle adsorbent fraction withdrawal port B, The upstream end of section 3 is set as an eluent supply port D4, and an eluent d4 having the weakest desorption power among the four eluents is supplied from the eluent supply port D4; The weakly adsorbent fraction is withdrawn from the weakly adsorbent fraction withdrawal port A. The eluent supply port D4 in this substep (A2-2ex) is provided in the same piping as the raw solution supply port F in the above substep (A1-2ex). In addition, the eluent supply port D2 in this substep (A2-2ex) is the same as the eluent supply port D2 in the above substep (A1-2ex).

[0087] An example of the sub-step (A3-2) is a sub-step of carrying out the following sub-step (A3-2ex), but the sub-step (A3-2) is not limited to the sub-step (A3-2ex). <Substep(A3-2ex)> The upstream end of section 1 is set as an eluent supply port D1, and an eluent d1 having the strongest desorption power among the four eluents is supplied from the eluent supply port D1; The downstream end of section 1 is set as a strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C; The upstream end of section 2 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The upstream end of section 3 is set as an eluent supply port D3, and an eluent d3 having the third strongest desorption power among the four eluents is supplied from the eluent supply port D3; The weakly adsorbent fraction is withdrawn from the weakly adsorbent fraction withdrawal port A. The eluent supply port D1 in this substep (A3-2ex) is provided in the same piping as the eluent supply port D2 in the above substep (A2-2ex). Also, the eluent supply port D3 in this substep (A3-2ex) is provided in the same piping as the eluent supply port D4 in the above substep (A2-2ex).

[0088] An example of the sub-step (A4-2) is a sub-step of carrying out the following sub-step (A4-2ex), but the sub-step (A4-2) is not limited to the sub-step (A4-2ex). <Substep(A4-2ex)> The eluent d2 is supplied from the eluent supply port D2, The eluent d3 is supplied from the eluent supply port D3, The upstream end of section 1 is set as an eluent supply port D4, and an eluent d4 having the weakest desorption power among the four eluents is supplied from the eluent supply port D4; The downstream end of section 1 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from outlet A. The eluent supply ports D2 and D3 in this substep (A4-2ex) are the same as the eluent supply ports D2 and D3 in the above substep (A3-2ex).

[0089] A flow diagram in which step (A) performs the sub-steps (A1-2ex), (A2-2ex), (A3-2ex), and (A4-2ex) in this order is shown in Figure 4. In Figure 4, each square box indicates one section, and the numbers in the box indicate the section number (numbered from left to right).

[0090] In this embodiment 2, the following sub-steps (B1-2) and (B2-2) are carried out in step (B).

[0091] <Sub-step (B1-2)> The upstream end of section 2 is designated as an eluent supply port DI, and eluent dI is supplied from the eluent supply port DI; the downstream end of section 2 is designated as the outlet C, and a strongly adsorbing fraction is extracted from the outlet C; the upstream end of section 3 is designated as an eluent supply port D-II, and eluent d-II is supplied from the eluent supply port D-II; the upstream end of section 1 is designated as an eluent supply port D-III, and eluent d-III is supplied from the eluent supply port D-III; and the downstream end of section 1 is designated as the outlet A, and a weakly adsorbing fraction is extracted from the outlet A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 3.

[0092] <Sub-step (B2-2)> The upstream end of section 3 is designated as an eluent supply port D-II, and an eluent d-II is supplied from the eluent supply port D-II. The upstream end of section 1 is designated as an eluent supply port D-III, and an eluent d-III is supplied from the eluent supply port D-III. The downstream end of section 2 is designated as the outlet A, and a weakly adsorbable fraction is extracted from the outlet A. The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1.

[0093] An example of the sub-step (B1-2) is a sub-step of carrying out the following sub-step (B1-2ex), but the sub-step (B1-2) is not limited to the sub-step (B1-2ex). <Substep (B1-2ex)> The upstream end of section 2 is set as an eluent supply port D1, and an eluent d1 having the strongest desorption power among the four eluents is supplied from the eluent supply port D1; The downstream end of section 2 is set as a strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C; The upstream end of section 3 is set as an eluent supply port D2, and an eluent d2 having the second strongest desorption power among the four eluents is supplied from the eluent supply port D2; The upstream end of section 1 is set as an eluent supply port D3, and an eluent d3 having the third strongest desorption power among the four eluents is supplied from the eluent supply port D3; The downstream end of section 1 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from outlet A. The eluent supply ports D1, D2, and D3 in this substep (B1-2ex) are provided in the same piping as the eluent supply ports D2, D3, and D4 in the above substep (A4-2ex), respectively.

[0094] An example of the sub-step (B2-2) is a sub-step of carrying out the following sub-step (B2-2ex), but the sub-step (B2-2) is not limited to the sub-step (B2-2ex). <Sub-step (B2-2ex)> The eluent d2 is supplied from the eluent supply port D2, The eluent d3 is supplied from the eluent supply port D3, The upstream end of section 2 is set as an eluent supply port D4, and an eluent d4 having the weakest desorption power among the four eluents is supplied from the eluent supply port D4; The downstream end of section 2 is used as outlet A for the weakly adsorbing fraction, and the weakly adsorbing fraction is withdrawn from outlet A. The eluent supply ports D2 and D3 in this substep (B2-2ex) are the same as the eluent supply ports D2 and D3 in the above substep (B1-2ex).

[0095] A flow diagram in which step (B) performs the sub-steps (B1-2ex) and (B2-2ex) in sequence is shown in Figure 4. In Figure 4, each square box indicates one section, and the numbers in the box indicate the section number (numbered from left to right).

[0096] After completion of step (B), in which the above substeps (B1-2ex) and (B2-2ex) are performed in order, the position of the weakly adsorbing fraction outlet A in substep (B2-2ex) is left as it is, and the eluent supply port D2, the moderately adsorbing fraction outlet B, and the raw solution supply port F are constructed while maintaining the relative positional relationship of each position based on the position of the weakly adsorbing fraction outlet A, and the substep (A1-2ex) of the next cycle is performed. A flow diagram of steps (A) and (B) in the next cycle is shown in Figure 5. Compared to the cycle shown in Figure 4, in the next cycle shown in Figure 5, all the supply ports and outlets have been moved one section upstream (two sections downstream) while maintaining their relative positional relationship.

[0097] In the method of the present invention, the target liquid can be supplied to the target location and withdrawn from the target location by appropriately adjusting the operation of pumps and opening and closing of valves at various locations in the circulation system. That is, the method of supplying the target fluid and withdrawing the target fraction in the circulation system is known per se. In addition, the supply flow rate and withdrawal flow rate of each liquid can be appropriately set depending on the purpose such as the treatment efficiency.

[0098] In the method of the present invention, the component to be purified may be any of a strongly adsorbent component, a moderately adsorbent component, and a weakly adsorbent component, but the method is particularly suitable for purifying a moderately adsorbent component. The method of the present invention can be suitably used for purifying, for example, proteins. Since the method of the present invention can obtain a highly pure moderately adsorbent component, it is a suitable method for obtaining a highly pure target protein from a raw solution that contains not only the target protein but also its degradation products and aggregates. The protein is not particularly limited, and may be, for example, a biopolymer such as an antibody, a peptide, a nucleic acid, or a fusion protein. The method of the present invention is preferably used for purifying an antibody. The term "antibody" refers to an intact antibody or a binding fragment thereof that competes with the intact antibody for specific binding. Binding fragments include, but are not limited to, F(ab), F(ab'), F(ab')2, Fv, and single chain antibodies. In the present invention, the term "antibody" may refer to a naturally occurring antibody, a chimeric antibody, or an antibody fragmented by an enzyme or the like (for example, F(ab')2 fragment, Fab' fragment, Fab fragment). It also includes single-chain antibodies, dimers (diabodies) or trimers (triabodies), or minibodies. It may also be a single domain antibody. Note that these are merely examples, and all proteins or derivatives thereof that have specific binding ability to an antigen are included in the concept of antibody in the present invention. The antibody highly purified by the method of the present invention can be used as an antibody drug. That is, a method for producing an antibody drug can be provided by applying the method of the present invention to separate the antibody contained in the stock solution. More specifically, according to the method of the present invention, an antibody drug can be obtained by using a culture solution of antibody-producing cells and / or an extract of antibody-producing cells as a stock solution and separating the antibody contained therein. In the present invention, the term "culture solution of antibody-producing cells" and "extract of antibody-producing cells" include the culture solution of antibody-producing cells and the extract of antibody-producing cells that have been subjected to various treatments such as centrifugation and chromatographic separation, and have been fractionated or purified to a certain degree.

[0099] In the method of the present invention, the adsorbent packed in the unit packed tower is appropriately selected depending on the component to be purified, and various adsorbents can be used. For example, strongly acidic cation exchange resins, weakly acidic cation exchange resins, strongly basic anion exchange resins, weakly basic anion exchange resins, synthetic adsorbents, zeolites, silica gel, and functional group-modified silica gel (preferably octadecylsilyl-modified silica gel), as well as other gel filtration chromatography materials and affinity adsorbents can be used as the adsorbent. When the component to be purified is a protein, the adsorbent is preferably an ion exchange resin, and among these, a cation exchange resin can be preferably used.

[0100] The simulated moving bed chromatographic separation system of the present invention is a system for carrying out the method of the present invention, that is, the simulated moving bed chromatographic separation system of the present invention is a system having the above-mentioned circulatory system configuration, and the circulatory system can sequentially repeat the above-mentioned operation of the first process and the operation of the second process, or the operation of step (A) and the operation of step (B). EXAMPLES

[0101] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.

[0102] [Preparation of stock solution] Cells producing human immunoglobulin G1 (IgG1) were cultured, and the supernatant of the culture medium was adjusted for pH and conductivity to obtain a stock solution. The content of antibodies and impurities in this supernatant is as shown in Table 1 below. In the following table, the antibody is defined as the protein contained in the fraction with a molecular weight of 50,000 or more and less than 300,000 with a peak around 150,000. Those contained in the fraction with a molecular weight of less than 50,000 are designated as LMW, and those contained in the fraction with a molecular weight of 300,000 or more are designated as HMW. Further, among the LMW fractions, the fraction with a larger molecular weight is designated as LMW-1, and the fraction with a smaller molecular weight is designated as LMW-2. Similarly, among the HMW fractions, the fraction with a larger molecular weight is designated as HMW-1, and the fraction with a smaller molecular weight is designated as HMW-2. The following component composition was determined by high-performance liquid chromatography (HPLC) using an analytical column (Tosoh TSKgel G3000SWXL).

[0103]

Table 1

[0104] [Adsorbent used for single-unit packed column (column)] A cation exchange resin (trade name: POROS® XS Resin, manufactured by Thermo Fisher Scientific) was used as the adsorbent.

[0105] [Eluent] Eluents d1 to d4 were prepared using the following Solution A and Solution B to have the conductivity shown in Table 2 below. The conductivity of the stock solution (F) was 5.0 mS / cm, and the pH was 6.0. <Solution A> 50 mM MES buffer pH 6.0 <Solution B> 50 mM MES buffer pH 6.0 containing NaCl at a concentration of 2.0 M (117 g / L)

[0106]

Table 2

[0107] -Example 1- <Operating conditions> Steps 1 to 10 shown in Table 3 below were carried out in order. A flow diagram of steps 1 to 10 is shown in Figure 2. In Figure 2, steps 1 to 10 below correspond to sub-steps (A1-1) to (B3'-1), respectively. In Table 3 below, the stock solution (F) was supplied from stock solution supply port F, and eluents d1 to d4 were supplied from eluent supply ports D1 to D4.

[0108] [Table 3]

[0109] <Result> - Recovery rate - The antibody concentration, antibody amount, purity, and recovery rate of the antibody in the intermediately adsorptive fraction collected in the fifth cycle are shown in Table 4 below. The antibody concentration was calculated from the area value of the antibody in HPLC, which was prepared by preparing a calibration curve for each antibody amount by high performance liquid chromatography (HPLC) using an analytical column (trade name: TSKgel G3000SWXL, manufactured by Tosoh Corporation). The antibody amount was calculated by multiplying the antibody concentration obtained by the above calculation by the amount of the collected liquid. The antibody recovery rate was calculated by 100 x [amount of antibody in the fraction] / [amount of antibody in the original solution]. The purity of the antibody was calculated by the area value of the antibody in high performance liquid chromatography (HPLC) using an analytical column (trade name: TSKgel G3000SWXL, manufactured by Tosoh Corporation) / area value of all components.

[0110] [Table 4]

[0111] As is clear from Table 4, it was demonstrated that highly purified antibodies could be recovered with high efficiency.

[0112] Example 2 A combination of sub-steps shown in FIG. 4 was adopted to attempt chromatographic separation of the raw solution by the simulated moving bed method. That is, three unit packed towers were used, and the above steps 1 to 4, 6, and 7 (however, in steps 3 and 6, eluent d4 was not supplied from eluent supply port D4) were performed in order. The above steps 1 to 4, 6, and 7 (however, in steps 3 and 6, eluent d4 was not supplied) correspond to sub-steps (A1-2) to (B2-2) shown in FIG. 4, respectively. As a result of performing chromatographic separation by adjusting (optimizing) the flow rate and supply time of each liquid, it was found that in this embodiment as well, an antibody purified to a high purity (purity of 98% or more) can be recovered with high efficiency (recovery rate of 96% or more) as in Example 1.

[0113] Although the present invention has been described in conjunction with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless specifically stated otherwise, and believe that the appended claims should be construed broadly without departing from the spirit and scope of the invention as set forth in the appended claims.

[0114] This application claims priority based on Patent Application No. 2022-045536, filed in Japan on March 22, 2022, the contents of which are incorporated herein by reference as part of the present specification. [Explanation of symbols]

[0115] 100 Circulatory system 10a, 10b, 10c, 10d Unit packed columns (columns) Ab adsorbent R1, R2, R3, R4 Shut-off valves 2a, 2b, 2c, 2d Weakly Adsorbent Fraction Extraction Lines A1, A2, A3, A4 Weakly Adsorbent Fraction Extraction Valve 3a, 3b, 3c, 3d Medium adsorptive fraction extraction line B1, B2, B3, B4 Middle adsorptive fraction extraction valve 4a, 4b, 4c, 4d Strongly adsorptive fraction extraction lines C1, C2, C3, C4 Strongly Adsorbent Fraction Extraction Valve T1, T2, T3, T4 check valves 1 Piping 2J Weakly Adsorbent Fraction Junction Tube 3J Medium Adsorbent Fraction Junction Tube 4J Strongly Adsorbent Fraction Confluence Tube 6. Stock solution tank 7 Stock solution 8a, 8b, 8c, 8d Eluent tanks 9a, 9b, 9c, 9d eluent 11 Raw solution supply line 11a, 11b, 11c, 11d Concentrate supply branch lines F1, F2, F3, F4 Stock solution supply valve 12, 13, 14, 15 Eluent supply lines 12a, 12b, 12c, 12d Eluent supply branch lines 13a, 13b, 13c, 13d Eluent supply branch lines 14a, 14b, 14c, 14d Eluent supply branch lines 15a, 15b, 15c, 15d Eluent supply branch lines E1a, E2a, E3a, E4a Eluent supply valve E1b, E2b, E3b, E4b Eluent supply valve E1c, E2c, E3c, E4c Eluent supply valve E1d, E2d, E3d, E4d Eluent supply valve P1 Circulation Pump P2 Stock solution supply pump P3, P4, P5, P6 Eluent supply pumps

Claims

1. A simulated moving bed chromatographic separation method comprising: using a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping; dividing the circulation system into at least three continuous sections in a circular ring shape from upstream to downstream such that each section has at least one unit packed tower; and separating, using an eluent, a weakly adsorbing component, a strongly adsorbing component, and a medium adsorbing component having an intermediate adsorbability between the two components, which are contained in a raw solution; the method comprising repeating a cycle consisting of the following first and second processes: <First process> a process comprising a step of cutting off circulation of the circulation system at a cutoff position upstream of the section enriched in the weakly adsorbable component, supplying the raw liquid to the section downstream of the cutoff position, and withdrawing a moderately adsorbable fraction enriched in the moderately adsorbable component from the section upstream of the cutoff position; <Second process> a process comprising a step of extracting a strongly adsorbent fraction enriched in the strongly adsorbent component by controlling the supply of the eluent and the blocking of the circulation system without supplying the stock solution, and moving a supply position of the eluent to the circulation system and a withdrawal position of the strongly adsorbent fraction downstream in accordance with the movement of the strongly adsorbent fraction; A simulated moving bed chromatographic separation method in which the extraction position of the strongly adsorbent fraction within the cycle is moved downstream by at least two sections, and the downstream movement is not the same distance as the number of sections.

2. A simulated moving bed chromatographic separation method comprising: using a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping; dividing the circulation system into at least three continuous sections in a circular ring shape from upstream to downstream such that each section has at least one unit packed tower; and separating, using an eluent, a weakly adsorbent component, a strongly adsorbent component, and a medium adsorbent component having an adsorbability intermediate between the two components, which are contained in a raw solution; the simulated moving bed chromatographic separation method comprising repeating a cycle consisting of the following steps (A) and (B): <Step (A)> a sub-step (A1) of blocking circulation of the circulation system by setting a position upstream of the section enriched in the weakly adsorbable component as a blocking position, supplying the stock solution to a section downstream of the blocking position and extracting a weakly adsorbable fraction enriched in the weakly adsorbable component from the circulation system at a further downstream position, and supplying an eluent for desorbing the moderately adsorbable component to a section upstream of the blocking position and extracting a moderately adsorbable fraction enriched in the moderately adsorbable component from the circulation system at a downstream position thereof; a sub-step (A2) of supplying an eluent for desorbing the weakly adsorbable component instead of supplying the stock solution, and continuing the extraction of the weakly adsorbable fraction and the extraction of the moderately adsorbable fraction; A substep (A3) of moving the blocking position upstream, supplying an eluent for desorbing the strongly adsorbent component upstream of the moved blocking position while continuing to extract the weakly adsorbent fraction, and extracting a strongly adsorbent fraction enriched in the strongly adsorbent component at a downstream position thereof; a sub-step (A4) of moving the withdrawal position of the weakly adsorbing fraction downstream to withdraw the weakly adsorbing fraction, while not withdrawing the medium adsorbing fraction and not withdrawing the strongly adsorbing fraction; performing the steps in this order; <Step (B)> A step of performing step α at least once, in which the weakly adsorbing fraction not extracted in step (A) is extracted separately by controlling the supply of eluent and the blockage position without supplying the original solution, while leaving the extraction position of the weakly adsorbing fraction unchanged, and then the extraction position of the weakly adsorbing fraction is moved downstream to extract only the weakly adsorbing fraction.

3. the piping of the circulation system is provided with a raw solution supply port F, an eluent supply port D, an outlet A for a weakly adsorbing fraction, an outlet B for a moderately adsorbing fraction, and an outlet C for a strongly adsorbing fraction; In the step (A), the positions of the raw liquid supply port F, the outlet A, the outlet B and the outlet C are set as follows (a) to (c): (a) the withdrawal outlet A is provided on the downstream side of the raw liquid supply port F across at least one section; (b) providing the withdrawal outlet B in a pipe having the raw liquid supply port F; (c) providing the outlet C on the upstream side of the outlet B across at least one section; In the step (B), the positions of the extraction port A and the extraction port C are set to the following (d): (d) providing the withdrawal port A downstream of the withdrawal port C across at least two sections; The simulated moving bed chromatographic separation method according to claim 2.

4. The simulated moving bed chromatographic separation method according to claim 2 or 3, wherein the number of times of the process α performed in the step (B) is [the number of sections-2] times, or [the number of sections] times or more.

5. A simulated moving bed chromatographic separation method according to any one of claims 2 to 4, which uses a circulation system in which four or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, and divides the circulation system into four continuous sections in a circular ring shape from the upstream side to the downstream side such that each section has at least one unit packed tower, wherein substeps (A1) to (A4) in step (A) are the following substeps (A1-1) to (A4-1), and in step (B), the following substeps (B1-1) to (B3-1) and the following substeps (B1'-1) to (B3'-1) are carried out in this order: <Sub-step (A1-1)> The upstream end of section 1 is designated as an eluent supply port D-II, and an eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as a moderately adsorbable fraction outlet B, and the moderately adsorbable fraction is extracted from said outlet B; the upstream end of section 3 is designated as a stock solution supply port F, and the stock solution is supplied from said stock solution supply port F; and the downstream end of section 4 is designated as a weakly adsorbable fraction outlet A, and the weakly adsorbable fraction is extracted from said outlet A; The desorption force of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through sections 3 and 4 is made weaker than the desorption power of the eluent flowing through sections 1 and 2; <Sub-step (A2-1)> the upstream end of section 1 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the downstream end of section 2 is designated as a moderately adsorbable fraction outlet B, the moderately adsorbable fraction is extracted from said outlet B, the upstream end of section 3 is designated as an eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 4 is designated as a weakly adsorbable fraction outlet A, and the weakly adsorbable fraction is extracted from said outlet A; The desorption force of the eluent flowing through sections 1 and 2 is maximized. The desorption power of the eluent flowing through sections 3 and 4 is made weaker than the desorption power of the eluent flowing through sections 1 and 2; <Sub-step (A3-1)> the upstream end of section 1 is designated as eluent supply port D-I, eluent d-I is supplied from said eluent supply port D-I, the downstream end of section 1 is designated as strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C, the upstream end of section 2 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 4 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 4 is designated as weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 1 is maximized. The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; <Sub-step (A4-1)> the upstream end of section 2 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 4 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as weakly adsorbing fraction outlet A, and a weakly adsorbing fraction is withdrawn from said outlet A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made equal to the desorption force of the eluent flowing through section 4; <Sub-step (B1-1)> the upstream end of section 2 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 4 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as weakly adsorbing fraction outlet A, and a weakly adsorbing fraction is withdrawn from said outlet A; The desorption force of the eluent flowing through sections 2 and 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through sections 2 and 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; <Sub-step (B2-1)> the upstream end of section 2 is designated as eluent supply port D-I, eluent d-I is supplied from said eluent supply port D-I, the downstream end of section 2 is designated as strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C, the upstream end of section 3 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 4 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; <Sub-step (B3-1)> the upstream end of section 3 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 4 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is withdrawn from said outlet A; The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is set to be the same as the desorption force of the eluent flowing through section 1. <Sub-step (B1'-1)> the upstream end of section 3 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as weakly adsorbing fraction outlet A, and a weakly adsorbing fraction is withdrawn from said outlet A; The desorption force of the eluent flowing through sections 3 and 4 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through sections 3 and 4; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; <Sub-step (B2'-1)> the upstream end of section 3 is designated as eluent supply port D-I, eluent d-I is supplied from said eluent supply port D-I, the downstream end of section 3 is designated as strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C, the upstream end of section 4 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as eluent supply port D-IV, and eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 4 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; <Substep (B3'-1)> the upstream end of section 4 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 3 is designated as weakly adsorbing fraction outlet A, and a weakly adsorbing fraction is withdrawn from said outlet A; The desorption force of the eluent flowing through section 4 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 4; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is set to be the same as the desorption force of the eluent flowing through section 2.

6. A simulated moving bed chromatographic separation method according to any one of claims 2 to 4, which uses a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, and divides the circulation system into three continuous sections in a circular ring shape from the upstream side to the downstream side such that each section has at least one unit packed tower, wherein substeps (A1) to (A4) in step (A) are the following substeps (A1-2) to (A4-2), and in step (B), the following substeps (B1-2) and (B2-2) are carried out in this order: <Sub-step (A1-2)> The upstream end of section 1 is designated as an eluent supply port D-II, and an eluent d-II is supplied from said eluent supply port D-II; the downstream end of section 2 is designated as a moderately adsorbable fraction outlet B, and the moderately adsorbable fraction is extracted from said outlet B; the upstream end of section 3 is designated as a stock solution supply port F, and a stock solution is supplied from said stock solution supply port F; and the downstream end of section 3 is designated as a weakly adsorbable fraction outlet A, and the weakly adsorbable fraction is extracted from said outlet A; The desorption force of the eluent flowing through sections 1 and 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through sections 1 and 2; <Sub-step (A2-2)> the upstream end of section 1 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the downstream end of section 2 is designated as a moderately adsorbent fraction outlet B, and the moderately adsorbent fraction is extracted from said outlet B, the upstream end of section 3 is designated as an eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 3 is designated as a weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A, The desorption force of the eluent flowing through sections 1 and 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through sections 1 and 2; <Sub-step (A3-2)> the upstream end of section 1 is designated as an eluent supply port D-I, eluent d-I is supplied from said eluent supply port D-I, the downstream end of section 1 is designated as a strongly adsorbing fraction outlet C, and the strongly adsorbing fraction is extracted from said outlet C, the upstream end of section 2 is designated as an eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as an eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, and the downstream end of section 3 is designated as a weakly adsorbing fraction outlet A, and the weakly adsorbing fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 1 is maximized. The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1; The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; <Sub-step (A4-2)> the upstream end of section 2 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 3 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 1 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 1 is designated as weakly adsorbing fraction outlet A, and a weakly adsorbing fraction is withdrawn from said outlet A; The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption power of the eluent flowing through section 1 is made weaker than the desorption power of the eluent flowing through section 3; <Sub-step (B1-2)> the upstream end of section 2 is designated as eluent supply port D-I, eluent d-I is supplied from said eluent supply port D-I, the downstream end of section 2 is designated as strongly adsorbent fraction outlet C, and the strongly adsorbent fraction is extracted from said outlet C, the upstream end of section 3 is designated as eluent supply port D-II, and eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, and eluent d-III is supplied from said eluent supply port D-III, and the downstream end of section 1 is designated as weakly adsorbent fraction outlet A, and the weakly adsorbent fraction is extracted from said outlet A, The desorption force of the eluent flowing through section 2 is maximized. The desorption force of the eluent flowing through section 3 is made weaker than the desorption force of the eluent flowing through section 2; The desorption power of the eluent flowing through section 1 is made weaker than the desorption power of the eluent flowing through section 3; <Sub-step (B2-2)> the upstream end of section 3 is designated as eluent supply port D-II, eluent d-II is supplied from said eluent supply port D-II, the upstream end of section 1 is designated as eluent supply port D-III, eluent d-III is supplied from said eluent supply port D-III, the upstream end of section 2 is designated as eluent supply port D-IV, eluent d-IV is supplied from said eluent supply port D-IV, and the downstream end of section 2 is designated as weakly adsorbing fraction outlet A, and a weakly adsorbing fraction is withdrawn from said outlet A; The desorption force of the eluent flowing through section 3 is maximized. The desorption force of the eluent flowing through section 1 is made weaker than the desorption force of the eluent flowing through section 3; The desorption force of the eluent flowing through section 2 is made weaker than the desorption force of the eluent flowing through section 1.

7. The simulated moving bed chromatographic separation method according to any one of claims 1 to 6, wherein the medium adsorptive component is a biopolymer.

8. A simulated moving bed chromatographic separation system uses a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, the circulation system is divided into at least three continuous sections in a circular ring shape from upstream to downstream so that each section has at least one unit packed tower, and separates, using an eluent, a weakly adsorbable component, a strongly adsorbable component, and a medium adsorbable component having an intermediate adsorbability between the two components, which are contained in a raw solution, the system having a means for repeating a cycle consisting of the following first and second processes: <First process> a process comprising a step of cutting off circulation of the circulation system at a cutoff position upstream of the section enriched in the weakly adsorbable component, supplying the raw liquid to the section downstream of the cutoff position, and withdrawing a moderately adsorbable fraction enriched in the moderately adsorbable component from the section upstream of the cutoff position; <Second process> a process comprising a step of extracting a strongly adsorbent fraction enriched in the strongly adsorbent component by controlling the supply of the eluent and the blocking of the circulation system without supplying the stock solution, and moving a supply position of the eluent to the circulation system and a withdrawal position of the strongly adsorbent fraction downstream in accordance with the movement of the strongly adsorbent fraction; A simulated moving bed chromatographic separation system in which the extraction position of the strongly adsorbent fraction during the cycle moves downstream by two or more sections, and the downstream movement is not the same amount as the number of sections.

9. A simulated moving bed chromatographic separation system using a circulation system in which three or more unit packed towers packed with an adsorbent are connected in series and endlessly via piping, the circulation system being divided into at least three continuous sections in a circular ring shape from upstream to downstream such that each section has at least one unit packed tower, and separating, using an eluent, a weakly adsorbing component, a strongly adsorbing component, and a medium adsorbing component having an adsorbability intermediate between the two components, which are contained in a raw solution, the simulated moving bed chromatographic separation system having a means for repeating a cycle consisting of the following steps (A) and (B): <Step (A)> a sub-step (A1) of blocking circulation of the circulation system by setting a position upstream of the section enriched in the weakly adsorbable component as a blocking position, supplying the stock solution to a section downstream of the blocking position and extracting a weakly adsorbable fraction enriched in the weakly adsorbable component from the circulation system at a further downstream position, and supplying an eluent for desorbing the moderately adsorbable component to a section upstream of the blocking position and extracting a moderately adsorbable fraction enriched in the moderately adsorbable component from the circulation system at a downstream position thereof; a sub-step (A2) of supplying an eluent for desorbing the weakly adsorbable component instead of supplying the stock solution, and continuing the extraction of the weakly adsorbable fraction and the extraction of the moderately adsorbable fraction; A substep (A3) of moving the blocking position upstream, supplying an eluent for desorbing the strongly adsorbent component upstream of the moved blocking position while continuing to extract the weakly adsorbent fraction, and extracting a strongly adsorbent fraction enriched in the strongly adsorbent component at a downstream position thereof; a sub-step (A4) of moving the withdrawal position of the weakly adsorbing fraction downstream to withdraw the weakly adsorbing fraction, while not withdrawing the medium adsorbing fraction and not withdrawing the strongly adsorbing fraction; performing the steps in this order; <Step (B)> A step of performing step α at least once, in which the weakly adsorbing fraction not extracted in step (A) is extracted separately by controlling the supply of eluent and the blockage position without supplying the original solution, while leaving the extraction position of the weakly adsorbing fraction unchanged, and then the extraction position of the weakly adsorbing fraction is moved downstream to extract only the weakly adsorbing fraction.

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