Method for inspecting valves in a chromatography apparatus and a chromatography apparatus

Abstract

To enable inspection of valves of a chromatography device without detaching the valves.SOLUTION: A plurality of first region forming valves D1-D4, DR, DS and pressure regulation means are used to form a first closed region S1 having a higher pressure than a plurality of adjacent regions defined by the plurality of first region forming valves in a portion of a liquid circulation mechanism. Then, whether the pressure in the first region S1 has decreased or not is detected using a pressure gauge PRD to detect whether or not at least one of the plurality of first region forming valves is leaking.SELECTED DRAWING: Figure 4

Description

Technical Field

[0001] The present invention relates to a method for inspecting valves of a chromatograph apparatus and a chromatograph apparatus.

Background Art

[0002] A chromatograph apparatus that separates a plurality of components contained in a stock solution with an eluent is known. The chromatograph apparatus is used for analysis and purification. Particularly in the case of purification applications, a simulated moving bed type chromatograph apparatus that connects a plurality of columns with a circulation line and switches the supply positions of the stock solution and the eluent and the extraction positions of the separated plurality of components over time is used (see, for example, Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] In a simulated moving bed type chromatograph apparatus, a large number of valves are installed in order to switch the supply positions of the stock solution and the eluent and the extraction positions of the separated plurality of components over time. Leakage of the valves may cause mixing of the stock solution, the eluent, and the separated plurality of components, and may result in a decrease in separation efficiency. In order to prevent valve leakage, it is desirable to inspect the valves, but it requires a lot of labor to remove and inspect a large number of valves.

[0005] An object of the present invention is to provide a method for inspecting valves of a chromatograph apparatus that can be inspected without removing the valves.

Means for Solving the Problems

[0006] The present invention relates to a method for inspecting valves in a chromatography apparatus having a liquid flow mechanism and a plurality of valves provided in the liquid flow mechanism, the plurality of which include a plurality of first region-forming valves, wherein the liquid flow mechanism has a plurality of columns, a circulation line sequentially connecting the plurality of columns, and a plurality of liquid lines connected to the circulation line through which liquid supplied to the plurality of columns flows in and liquid processed by the plurality of columns flows out.

[0007] According to one aspect of the present invention, a valve inspection method comprises: forming a closed first region in a part of a liquid flow mechanism, where the pressure is higher than that of a plurality of adjacent regions defined by the plurality of first region-forming valves, using a plurality of first region-forming valves and a pressure regulating means; and detecting whether or not at least one of the plurality of first region-forming valves is leaking by detecting whether or not the pressure in the first region is decreasing using a pressure gauge.

[0008] According to another aspect of the present invention, a valve inspection method comprises: forming a first region defined and closed by a plurality of first region-forming valves in a part of a liquid flow mechanism using a plurality of first region-forming valves and a pressure regulating means; forming a second region adjacent to the first region and having a lower pressure than the first region via a connecting valve, which is one of the plurality of first region-forming valves; and detecting whether or not the connecting valve is leaking by detecting whether or not the pressure in the second region is increasing using a pressure gauge. [Effects of the Invention]

[0009] According to the present invention, a method for inspecting valves in a chromatography apparatus is provided that allows inspection without removing the valves. [Brief explanation of the drawing]

[0010] [Figure 1] This is a schematic diagram of a pseudo-mobile bed chromatography apparatus to which the present invention is applied. [Figure 2] This is a schematic diagram illustrating the principle of a valve inspection method according to the first embodiment of the present invention. [Figure 3]This is a schematic diagram of a pseudo-mobile bed chromatography apparatus to which the first embodiment of the present invention is applied. [Figure 4] This is a schematic diagram illustrating the first embodiment (measurement mode 1-1) of the present invention. [Figure 5] This is a schematic diagram illustrating the first embodiment (measurement mode 1-2) of the present invention. [Figure 6] This is a schematic diagram illustrating the first embodiment (measurement modes 1-3) of the present invention. [Figure 7] This is a schematic diagram illustrating the first embodiment (measurement modes 1-4) of the present invention. [Figure 8] This is a schematic diagram illustrating the first embodiment (measurement modes 1-5) of the present invention. [Figure 9] This is a schematic diagram illustrating the principle of a valve inspection method according to a second embodiment of the present invention. [Figure 10] This is a schematic diagram of a pseudo-mobile bed chromatography apparatus to which a second embodiment of the present invention is applied. [Figure 11] This is a schematic diagram illustrating a second embodiment (measurement mode 2-1) of the present invention. [Figure 12] This is a schematic diagram illustrating a second embodiment (measurement mode 2-2) of the present invention. [Figure 13] This is a schematic diagram illustrating a second embodiment (measurement mode 2-3) of the present invention. [Figure 14] This is a schematic diagram illustrating a second embodiment (measurement mode 2-4) of the present invention. [Modes for carrying out the invention]

[0011] The chromatographic apparatus of the present invention and a method for inspecting the valves of the chromatographic apparatus will be described below with reference to the drawings. Figure 1 shows an exemplary schematic configuration of a pseudo-mobile bed chromatographic apparatus 1 to which the present invention is applied. In this embodiment, the stock solution supplied to the chromatographic apparatus contains two components that are separated by an eluent. The eluent may be, for example, water.

[0012] The chromatograph device 1 has a liquid circulation mechanism 2, a plurality of valves provided in the liquid circulation mechanism 2, an eluent storage tank TD for storing an eluent, and a stock solution storage tank TF for storing a stock solution. The liquid circulation mechanism 2 has a plurality of columns (first to fourth columns 11 to 14), a circulation line LR for sequentially connecting the plurality of columns 11 to 14, and a plurality of liquid lines connected to the circulation line LR. The plurality of columns 11 to 14 are filled with an adsorbent (for example, a specific ion exchange resin). The adsorbent has a high adsorbability for the strongly adsorbed components contained in the stock solution and shows a lower adsorbability for the weakly adsorbed components contained in the stock solution than for the strongly adsorbed components. The circulation line LR is composed of a plurality of connection sections LR1 to LR4 that connect adjacent columns 11 to 14 to each other. The number of columns is not limited, and at least two columns are sufficient.

[0013] The plurality of liquid lines are provided for the liquid (stock solution and eluent) supplied to the plurality of columns 11 to 14 to flow in and the treated liquid (fraction) to flow out. The plurality of liquid lines include the following lines. In the following description, each line may be identified by a symbol name (for example, the main eluent supply line LD is referred to as line LD). - A main eluent supply line LD connected to the eluent storage tank TD for supplying an eluent (only a part is shown in FIG. 1) - A plurality of (four in this embodiment) eluent sub-supply lines LD1 to LD4 that connect the main eluent supply line LD and the connection sections LR1 to LR4, respectively - A main stock solution supply line LF connected to the stock solution storage tank TF for supplying a stock solution (only a part is shown in FIG. 1) - A plurality of (four in this embodiment) stock solution sub-supply lines LF1 to LF4 that connect the main stock solution supply line LF and the connection sections LR1 to LR4, respectively - A plurality of (four in this embodiment) strongly adsorbed component extraction sub-lines LC1 to LC4 that branch from each of the connection sections LR1 to LR4 and extract strongly adsorbed components - A main strongly adsorbed component extraction line LC formed by the confluence of the plurality of strongly adsorbed component extraction sub-lines LC1 to LC4 (only a part is shown in FIG. 1) - A plurality of (four in this embodiment) weak adsorption component extraction sub-lines LA1 to LA4 that branch off from each connection section LR1 to LR4 and extract weak adsorption components - A weak adsorption component extraction main line LA formed by the confluence of a plurality of weak adsorption component extraction sub-lines LA1 to LA4 (only a part is shown in FIG. 1)

[0014] On the lines LD and LF, recirculation lines LD0 and LF0 equipped with safety valves D0 and F0 are provided respectively (see FIGS. 3 and 10).

[0015] The plurality of valves provided in the liquid circulation mechanism 2 include the following valves. In the following description, each valve may be identified by a symbol name (for example, the eluent supply switching valve D1 is referred to as valve D1). - Eluent supply switching valves D1 to D4 provided on the eluent sub-supply lines LD1 to LD4 respectively - Stock solution supply switching valves F1 to F4 provided on the stock solution sub-supply lines LF1 to LF4 respectively - Strong adsorption component extraction switching valves C1 to C4 provided on the strong adsorption component extraction sub-lines LC1 to LC4 respectively - Weak adsorption component extraction switching valves A1 to A4 provided on the weak adsorption component extraction sub-lines LA1 to LA4 respectively - Isolation valves R1 to R4 provided on the connection sections LR1 to LR4 respectively

[0016] The chromatography device 1 operates as follows. The stock solution stored in the stock solution storage tank TF is supplied by the stock solution pump PF provided on the stock solution main supply line LF through the line LF and one of the lines LF1 to LF4 to one of the connection sections LR1 to LR4 connected to any of the LF1 to LF4. The eluent stored in the eluent storage tank TD is supplied by the eluent pump PD provided on the line LD through the line LD and one of the lines LD1 to LD4 to one of the connection sections LR1 to LR4 connected to any of the lines LD1 to LD4.

[0017] The liquid in circulation line LR is circulated in a constant direction (for example, counterclockwise in Figure 1) by the circulation pump PR (see Figures 3 and 10) installed in circulation line LR, so the stock solution and eluent flow in the same direction. During operation, isolation valves R1 to R4 are open. Due to the difference in adsorption properties between the strongly adsorbed and weakly adsorbed components in the stock solution, the strongly adsorbed and weakly adsorbed components are gradually separated. The strongly adsorbed components are withdrawn as fraction C along with the solvent and eluent in the stock solution from one of the sublines LC1 to LC4. The weakly adsorbed components are withdrawn as fraction A along with the solvent and eluent in the stock solution from one of the sublines LA1 to LA4.

[0018] Lines LD1-LD4, lines LF1-LF4, sub-lines LC1-LC4, and sub-lines LA1-LA4 are switched by valves D1-D4, F1-F4, C1-C4, and A1-A4, respectively. Liquid flows through one of lines LD1-LD4, one of lines LF1-LF4, one of sub-lines LC1-LC4, and one of sub-lines LA1-LA4, for a total of four lines. The four lines through which the liquid flows are always connected to different connection sections LR1-LR4. No more than two valves of the same type (e.g., valves F1-F4) are open at the same time, and open valves of the same type move along the circulation line LR over time. The switching of these valves is controlled by a control device called a sequencer, although this is not shown in the diagram. This allows for the separate extraction of strongly adsorbed and weakly adsorbed components while supplying the stock solution and eluent.

[0019] Next, the inspection method for the valve of the chromatography apparatus 1 will be described based on an embodiment. The valve inspection method described below checks for the presence or absence of valve leakage. Valve leakage refers to the phenomenon of fluid flowing between the upstream and downstream sides of a closed valve, and is distinguished from the phenomenon of fluid leaking to the outside of the valve. In the chromatography apparatus 1, it is important to prevent the remixing of the separated strongly adsorbed and weakly adsorbed components, so the presence or absence of the former leakage is the subject of inspection. In contrast, the latter leakage is not a direct cause of the remixing of strongly adsorbed and weakly adsorbed components, and can be detected relatively easily by visual inspection from the outside, so in this embodiment it is not subject to inspection.

[0020] (First embodiment) Figure 2 is a schematic diagram illustrating the principle of the valve inspection method according to the first embodiment. For the sake of explanation, valves V1 to V4 are provided on parallel lines L1 to L4, and a pump P is provided on the upstream line L5. In this embodiment, valve V5 is provided on line L5 between the branching point BR of lines L1 to L4 and the pump P, and a branch line L6 is provided that branches off from line L5 between the branching point BR and valve V5. The tip of the branch line L6 is an atmospheric outlet end 16. A back pressure valve BV1 is provided between the atmospheric outlet end 16 of the branch line L6 and the branch section 17, and valve V6 is provided between the back pressure valve BV1 and the branch section 17.

[0021] First, as shown in Figure 2(a), a pre-pressurized region S0 is formed in a part of the liquid flow mechanism 2. The pre-pressurized region S0 is the region that encompasses the first region S1, which will be described later. Specifically, valves V1 to V4 are closed, valves V5 and V6 are opened, and the liquid is supplied to lines L1 to L6 by pump P. Due to the action of the back pressure valve BV1, the area shown by the thick line in Figure 2(a) is pressurized to a predetermined pressure (test pressure P1).

[0022] Next, as shown in Figure 2(b), the pump P is stopped and valves V5 and V6 are closed. This forms a first region S1 in a part of the liquid flow mechanism 2, which is closed by valves V1 to V6. Valves V1 to V6 are among the multiple valves provided in the liquid flow mechanism 2 that are capable of forming the first region S1, and are also the valves to be inspected. In the following description, these valves V1 to V6 will be referred to as the first region-forming valves VS1. Therefore, the first region S1 is a closed region defined by the multiple first region-forming valves VS1, with a higher pressure than the multiple regions S3 adjacent to the first region S1. The multiple regions S3 are multiple regions adjacent to the first region S1 via the multiple first region-forming valves VS1. During inspection, valve V6 is closed, so the back pressure valve BV1 is located outside the first region S1.

[0023] At least one of the back pressure valve BV1 and valve V6 can be made detachable. In this case, although not shown in the diagram, piping is installed where the back pressure valve BV and valve V6 were installed. Since the back pressure valve BV1 and valve V6 are installed in the branch line L6 which is unrelated to the operation of the chromatograph 1, removing them during the operation of the chromatograph 1 can reduce the impact on the chromatograph 1 due to malfunctions of the back pressure valve BV1 or valve V6. Instead of making the back pressure valve BV1 and valve V6 individually detachable, the entire branch line L6 may be made detachable and a cap may be installed at the branch section.

[0024] Next, the pressure gauge PR1 detects whether the pressure in the first region S1 has decreased. If the pressure in the first region S1 falls below a predetermined pressure (hereinafter referred to as the judgment pressure P2), it is determined that at least one of the multiple first region forming valves VS1 may be leaking. A decrease in pressure in the first region S1 can occur due to causes other than valve leakage, but in most cases, it is thought to be caused by valve leakage. Therefore, by disassembling and inspecting the first region forming valves VS1 as necessary, the leaking valve can be further narrowed down. If the pressure in the first region S1 does not fall below the judgment pressure P2, it can be determined that none of the inspected valves are leaking. In general, valve leakage does not occur very frequently, so there is a high probability that all valves are normal when inspected. The first embodiment can inspect multiple valves simultaneously, so the inspection efficiency is particularly high when there is no valve leakage.

[0025] The back pressure valve BV1 closes when the back pressure (back pressure is the pressure on the upstream side of the valve, in this case the pressure on the valve V6 side) is below the set pressure, and opens when the back pressure exceeds the set pressure. The back pressure valve BV1 also functions as a safety valve, but more importantly, it maintains a constant pressure in the first region S1. Together with the pump P, the back pressure valve BV1 constitutes a pressure regulating means that increases the pressure in the first region S1 for multiple regions S3 adjacent to the first region S1. Since the back pressure valve BV1 is closed when the back pressure is below the set pressure, the first region S1 is efficiently pressurized. When the back pressure exceeds the set pressure, the back pressure valve BV1 opens. As a result, the pressure in the first region S1 decreases, and the back pressure valve BV1 closes again, pressurizing the first region S1. When the back pressure exceeds the set pressure again, the back pressure valve BV1 opens again. Therefore, once the pressure in the first region S1 reaches the set pressure of the back pressure valve BV1, the state in the first region S1 being pressurized to approximately the set pressure will be maintained. Since the set pressure of the back pressure valve BV1 is equal to the inspection pressure P1 of the first region S1, the inspection pressure P1 of the first region S1 can be adjusted by adjusting the set pressure of the back pressure valve BV1.

[0026] Figure 3 shows the configuration of the chromatography apparatus 1 of this embodiment in more detail. This embodiment is divided into multiple measurement modes depending on the valve to be inspected or the first region S1. The valve inspection method will be described below for each measurement mode based on the apparatus configuration shown in Figure 3.

[0027] (Measurement Mode 1-1) Table 1 shows the measurement procedure. In measurement mode 1-1, in order to form the first region S1, a pre-pressurized region S0 encompassing the first region S1 is formed (steps S1-4 to S1-6), and a part of it is closed off to form the first region S1 (step S1-8). The pre-pressurized region S0 is shown as a thick line in Figure 4(a), and the first region S1 is shown as a thick line in Figure 4(b). The first region S1 includes a part of line LD and a part of each line LD1 to LD4.

[0028] [Table 1]

[0029] As can be seen from Figure 4(b), the valves to be inspected, i.e., the first area-forming valve VS1, are valves D1 to D4 and valves DR and DS provided in line LD. Valve DS may be provided anywhere on line LD, as long as it is between the eluent pump PD and each of lines LD1 to LD4. In other words, valve DS may be provided anywhere in the branching section of lines LD1 to LD4 between the upstream branching section with respect to the direction of eluent supply and the eluent pump PD.

[0030] The pressure in the first region S1 may change depending on the fluid temperature, etc. Therefore, in order to ensure the accuracy of leak detection and prevent false detections, it is preferable to maintain a certain difference between the inspection pressure P1 and the judgment pressure P2. To achieve this, it is preferable that the pressure drop in the first region S1 when any of the first region forming valves VS1 leaks be as large as possible. For example, if valve D1 is leaking, and the fluid leaking from valve D1 flows into the adjacent region, the pressure difference between the first region S1 and the adjacent region decreases, the amount of leakage from valve D1 decreases, and the pressure drop in the first region S1 is suppressed. Therefore, in this embodiment, valves A1 to A4 are opened in step S1-8. The adjacent region enclosed by valves D1 to D4, A1 to A4, and C1 to C4 is at atmospheric pressure in step S1-2, so valves A1 to A4 could remain closed, but by opening valves A1 to A4, the adjacent region can be reliably maintained at atmospheric pressure. Since the adjacent region is prevented from being pressurized by the fluid leaking from valve D1, the fluid leaking from valve D1 can easily flow into the adjacent region, thereby promoting a pressure drop in the first region S1.

[0031] The boundary of the pre-pressurized area S0 includes a part that ceases to function as a pressure boundary after operation stops (eluent pump PD) and a part that may open due to pressure fluctuations (back pressure valve BRD). Since the liquid-flowable part of the first area S1 consists only of shut-off valves, the sealing performance of the first area S1 is improved. Therefore, leakage of the valve under inspection can be detected more reliably.

[0032] (Measurement Mode 1-2) Table 2 shows the measurement procedure. Figure 5(a) shows the pre-pressurized region S0, and Figure 5(b) shows the first region S1, both shown with thick lines. The first region S1 includes a part of line LF and a part of each line LF1 to LF4. As can be seen from Figure 5(b), the valves to be inspected, i.e., the first region-forming valves VS1, are valves F1 to F4 and valves FR and FS provided on line LF. Valve FS may be provided anywhere on line LF, as long as it is between the stock pump PF and each of lines LF1 to LF4. This measurement mode is the same as measurement mode 1-1 except that valves D1 to D4, DR, and DS, which are the first region-forming valves VS1 (valves to be inspected) in measurement mode 1-1, are replaced with valves F1 to F4, FR, and FS, respectively.

[0033] [Table 2]

[0034] (Measurement modes 1-3) Table 3 shows the measurement procedure. The pre-pressurized region S0 is shown in thick lines in Figure 6(a), and the first region S1 is shown in thick lines in Figure 6(b). As can be seen from Figure 6(b), the valves to be inspected, i.e., the valves forming the first region VS1, are valves C1-C4, valves A1-A4, valves DR and DS located on line LD, and valves FR and FS located on line LF. Valves D1-D4 and valves F1-F4 are open. In this measurement mode, valves C1-C4 and valves A1-A4 can be inspected together, so if there is no leakage in these valves, the valve inspection can be performed efficiently. Here, the pre-pressurized region S0 is formed using the eluent pump PD, but the pre-pressurized region S0 may also be formed using the stock pump PF. In this case, valves FR and FS are opened instead of valves DR and DS in Figure 6(a).

[0035] [Table 3]

[0036] (Measurement modes 1-4) In this measurement mode, the second column 12 is removed in advance, and the connection between the second column 12 and the connection section LR1 is sealed with a cap 18. Valve D2 is open. As a result, valve D2, which defined the first region S1 in measurement mode 1-1, is changed to isolation valve R1 and valve F2. Table 4 shows the measurement procedure. The pre-pressurized region S0 is shown in thick lines in Figure 7(a), and the first region S1 is shown in thick lines in Figure 7(b). As can be seen from Figure 7(b), the valves to be inspected, i.e., the valves that form the first region VS1, are valves D1, F2, D3, D4, isolation valve R1, and valves DR and DS provided in line LD.

[0037] In measurement mode 1-1 and measurement mode 1-4, most of the first region-forming valves VS1 are common. However, in measurement mode 1-1, valve D2 is the first region-forming valve VS1, whereas in measurement mode 1-4, isolation valves R1 and F2 are the first region-forming valves VS1. Therefore, by comparing the results of measurement mode 1-1 and measurement mode 1-4, it is possible to evaluate whether there is leakage in valves D2, valve F2, and isolation valve R1. That is, if leakage is detected in measurement mode 1-1 but not in measurement mode 1-4, it can be evaluated that there is a high possibility that valve D2, which is identified as the first region-forming valve VS1 only in measurement mode 1-1, is leaking. Conversely, if leakage is not detected in measurement mode 1-1 but is detected in measurement mode 1-4, it can be evaluated that there is a high possibility that isolation valve R1 or valve F2, which is identified as the first region-forming valve VS1 only in measurement mode 1-4, is leaking. However, it is not possible to distinguish whether isolation valve R1 or valve F2 is leaking.

[0038] Although not shown in the diagram, by removing the first, third, and fourth columns 11, 13, and 14 in place of the second column 12, isolation valve R1 / valve F3, isolation valve R3 / valve F4, and isolation valve R4 / valve F1 become the first region-forming valves VS1, respectively. In this embodiment as well, as in measurement mode 1-2, valves F1 to F4 can be made into the first region-forming valves VS1. Therefore, by combining measurement modes 1-1 to 1-3, it is possible to narrow down the valves that may be leaking from among isolation valves R1 to R4, valves D1 to D4, and valves F1 to F4. As shown in Figure 7(b), since each column 11 to 14 is outside the first region S1, it is also possible to remove not only the second column 12 but also some or all of the other columns and attach the caps 18. Removing columns 11 to 14 is also preferable from the viewpoint of protecting columns 11 to 14 during inspection.

[0039] [Table 4]

[0040] (Measurement modes 1-5) In this measurement mode, the first and second columns 11 and 12 are removed in advance, and the connections between the first and second columns 11 and 12 in connection sections LR1 and LR2 are sealed with caps 18. As a result, valve D2, which defined the first region S1 in measurement mode 1-1, is changed to valves F2, C1, and A1. Table 5 shows the measurement procedure. The pre-pressurized region S0 is shown in Figure 8(a) and the first region S1 is shown in Figure 8(b) with thick lines.

[0041] [Table 5]

[0042] As can be seen from Figure 8(b), the valves to be inspected, i.e., the first region-forming valve VS1, are valves D1, F2, D3, D4, valve C1, valve A1, and valves DR and DS located in line LD. Valve D2 and isolation valve R1 are open. This measurement mode is the same as measurement mode 1-4 except that valves C1, A1, and F2 are designated as the first region-forming valve VS1, instead of isolation valve R1 and valve F2 as the first region-forming valve VS1 in measurement mode 1-4. Therefore, by combining this measurement mode with measurement modes 1-1, 1-2, and 1-5, it is possible to narrow down the valves that may be leaking from each of the valves C1-C4, each of the valves A1-A4, each of the valves D1-D4, and each of the valves F1-F4. However, since valves F2 / C1 / A1, F3 / C2 / A2, F4 / C3 / A3, and F1 / C4 / A4 are treated as a set, it is not possible to distinguish which one is leaking.

[0043] In each of the measurement modes described above, valve DS can also be installed in line LD at a position between the branch point of recirculation line LD0 from line LD and the eluent pump PD (for example, part A in Figure 3). In this case, since safety valve D0 is included in the first region S1, safety valve D0 can be the object of inspection. Similarly, valve FS can also be installed in line LF at a position between the branch point of recirculation line LF0 from line FD and the raw material pump FD (for example, part B in Figure 3). In this case, since safety valve F0 is included in the first region S1, safety valve F0 can be the object of inspection.

[0044] (Second embodiment) Figure 9 is a schematic diagram illustrating the principle of the valve inspection method according to the second embodiment. Similar to Figure 2, valves V1 to V4 are provided on parallel lines L1 to L4, and a pump P is provided on the upstream line L5. In this embodiment, valve V7 is provided downstream of valve V1 on line L1, and a branch line L7 is provided between valve V1 and valve V7, branching off from line L1. The tip of the branch line L7 is an atmospheric outlet end 19. A back pressure valve BV2 is provided between the atmospheric outlet end 19 of the branch line L7 and the branch section 20, and a valve V8 is provided between the back pressure valve BV2 and the branch section 20.

[0045] First, as shown in Figure 9(a), a pre-pressurized region S0 is formed in a part of the liquid flow mechanism 2. The pre-pressurized region S0 is the region that encompasses the first region S1, which will be described later. Specifically, valves V2~V4 and V7 are closed, valves V1, V5 and V8 are opened, and the liquid is supplied to lines L1, L5 and L7 by pump P. Due to the action of the back pressure valve BV2, the area shown by the thick line in Figure 9(a) is pressurized to a predetermined pressure. Next, as shown in Figure 9(b), pump P is stopped and valves V1, V5 and V8 are closed. This forms a closed first region S1 in a part of the liquid flow mechanism 2. After that, as shown in Figure 9(c), valve V7 is opened and the section downstream of valve 1 is depressurized to atmospheric pressure. Next, as shown in Figure 9(d), valve V7 is closed. This forms a closed second region S2 in a part of the liquid flow mechanism 2. The inspection pressure P1 of the second region S2 is atmospheric pressure.

[0046] The first region S1 is a region defined and closed by a plurality of first region-forming valves VS1. The second region is a region defined and closed by a plurality of second region-forming valves VS2. The first region-forming valves VS1 are valves V1 to V5, and the second region-forming valves VS2 are valves V1, V7, and V8. The second region is adjacent to the first region S1 via a connecting valve VS3. The connecting valve VS3 is one of the plurality of first region-forming valves VS1 and one of the plurality of second region-forming valves VS2, i.e., a single valve V1 common to the first region-forming valves VS1 and the second region-forming valves VS2. The valve to be inspected is the connecting valve VS3. The back pressure valve BV2, pump P, and valves V1 and V7 constitute a pressure adjustment means that raises the pressure in the first region S1 relative to the second region S2 adjacent to the first region S1. During inspection, valve V8 is closed, so back pressure valve BV2 is located outside the first region S1.

[0047] Next, the pressure gauge PR2 detects whether the pressure in the second region S2 is increasing. Since leakage from the second region forming valve VS2 other than the connecting valve VS3 does not cause an increase in the pressure in the second region S2, if the pressure in the second region S2 exceeds a predetermined pressure (hereinafter referred to as the judgment pressure P2), it is determined that there is a possibility that the connecting valve VS3 is leaking. Since there is only one connecting valve VS3, in this embodiment it is possible to detect whether or not a specific valve (connecting valve VS3) is leaking. Similar to the first embodiment, the back pressure valve BV2 and valve V8 can be detachable.

[0048] Figure 10 shows the configuration of the chromatograph 1 of this embodiment in more detail. Pressure gauges PRA and PRC correspond to the pressure gauge PR2, valves CS and AS correspond to valve V7, valves CR and AR correspond to valve V8, and back pressure valves BRC and BRA correspond to back pressure valve BV2. In this embodiment, at least one of the pressure gauges PRA, valves AS and AR, back pressure valve BRA, and pressure gauges PRC, valves CS and CR, back pressure valve BRC, which are not necessarily required for normal operation, can be made detachable. That is, these devices can be disconnected from the upstream of pressure gauge PRA and the upstream of pressure gauge PRC. In this embodiment as well, there are multiple measurement modes depending on the valve to be inspected or the first and second regions S1 and S2. The measurement modes will be described below.

[0049] (Measurement Mode 2-1) Table 6 shows the measurement procedure. To form the first and second regions S1 and S2, a pre-pressurized region S0 encompassing the first and second regions S1 and S2 is formed (steps S6-4 to S6-6), and a portion of it is closed off to form the first region S1 (step S6-8). Subsequently, the remaining portion of the pre-pressurized region S0 (the pre-pressurized region S0 excluding the first region S1) is temporarily opened to the atmosphere to reduce the pressure, and a portion of the remaining portion is closed off again to form a closed second region S2 with a lower pressure than the first region S1 (steps S6-9 to S6-11).

[0050] [Table 6]

[0051] Figure 11(a) shows the pre-pressurized region S0, and Figure 11(b) shows the first region S1, both indicated by thick lines. Figure 11(c) also shows the first region S1 with a thick line and the second region S2 with a dashed line. As can be seen from Figure 11(c), the valve to be inspected is valve D1. Since the liquid-flowable parts of the first and second regions S1 and S2 consist only of shut-off valves, the sealing performance of the first and second regions S1 and S2 is improved. Therefore, leakage from the valve to be inspected can be detected more reliably. Valves D2 to D4 can be inspected using the same process.

[0052] (Measurement mode 2-2) Table 7 shows the measurement procedure. Figure 12(a) shows the pre-pressurization region S0, and Figure 12(b) shows the first region S1, both with thick lines. Also, in Figure 12(c), the first region S1 is shown with a thick line, and the second region S2 is shown with a dashed line. As can be seen from Figure 12(c), the valve to be inspected is valve F1. This measurement mode is the same as measurement mode 2-1 except that valve D1 is replaced with valve F1.

[0053] [Table 7]

[0054] (Measurement Mode 2-3) In this measurement mode, the first and second columns 11 and 12 are removed beforehand, and the connections between the first and second columns 11 and 12 in connection sections LR1 and LR2 are sealed with caps 18. The measurement procedure is shown in Table 8. The pre-pressurized area S0 is shown in Figure 13(a) and the first area S1 is shown in Figure 13(b) with thick lines. In Figure 13(c), the first area S1 is shown with a thick line and the second area S2 is shown with a dashed line. As can be seen from Figure 13(c), the valve to be inspected is the isolation valve R1. Isolation valves R2 to R4 can be inspected using the same procedure.

[0055] [Table 8]

[0056] (Measurement modes 2-4) Table 9 shows the measurement procedure. Figure 14(a) shows the pre-pressurization area S0, and Figure 14(b) shows the first area S1, both with thick lines. In Figure 14(c), the first area S1 is shown with a thick line, and the second area S2 is shown with a dashed line. As can be seen from Figure 14(c), the valve to be inspected is valve A1. Valves A2-A4 and valves C1-C4 can be inspected using the same procedure.

[0057] [Table 9]

[0058] Although several embodiments of the present invention have been described above, the present invention is not limited to these embodiments. Each embodiment describes the case where there is one stock solution, one eluent, and two fractions. However, in some fields, one stock solution, two or more eluents, and three or more fractions may be required. This embodiment can be extended to such cases. The present invention includes a configuration in which one stock solution and (M-1) types of eluents are supplied to a chromatograph, and N types of components (fractions) are separated and extracted (M and N are integers of 2 or more). Specifically, the chromatograph of the present invention may include at least one eluent storage tank and at least one main eluent supply line. The liquid flow mechanism has, for each of the two or more fractions, a plurality of extraction sublines that branch off from each connection section and extract the fraction, and a main extraction line formed by the confluence of the plurality of extraction sublines.

[0059] The present invention can also be applied to chromatographic apparatus equipped with a rotary valve. A rotary valve is formed by combining multiple valves D1-D4, multiple valves F1-F4, multiple valves C1-C4, and multiple valves A1-A4 into a single rotary valve. In such a chromatographic apparatus, one of the aforementioned valves corresponds to one port of the rotary valve. Therefore, by configuring the first region S1 (and the second region S2) in the manner described above, leakage at each port can be checked.

[0060] Furthermore, the present invention can also be applied to chromatographic apparatus equipped with valve block type valves. For example, the valves used in the pseudo-mobile layer type chromatographic apparatus disclosed in Japanese Patent Publication No. 2017-538083 are of a valve block type, which is a combination of multiple valves, but by configuring the first region S1 (and the second region S2) in the manner described above, leakage at each port can be checked. In addition, the chromatographic apparatus disclosed in Japanese Patent Publication No. 4945364 has the isolation valves R1 to R4 of the present invention as an essential component, but the present invention can be applied in the same manner. [Explanation of Symbols]

[0061] 1. Chromatography apparatus 2 Liquid distribution mechanism Columns 11-14 BRD,BRF Back pressure valve LA,LC Main Line LA1~LA4, LC1~LC4 Subline LR circulation line LR1~LR4 Connection Section LD, LD1~LD4, LF, LF1~LF4 line PRD, PRF pressure gauge S1 First Domain S2 Second area TD Eluent Storage Tank TF concentrate storage tank VS1 First region forming valve VS2 Second region forming valve VS3 connecting valve

Claims

1. A method for inspecting the valves in a chromatography apparatus having a liquid flow mechanism and a plurality of valves provided in the liquid flow mechanism, the plurality of valves including a plurality of first region forming valves, wherein the liquid flow mechanism has a plurality of columns, a circulation line sequentially connecting the plurality of columns, and a plurality of liquid lines connected to the circulation line through which liquid supplied to the plurality of columns flows in and liquid processed by the plurality of columns flows out, The plurality of first region-forming valves and pressure regulating means form a closed first region in a part of the liquid flow mechanism, where the pressure is higher than that of the plurality of adjacent regions defined by the plurality of first region-forming valves. By detecting whether the pressure in the first region is decreasing using a pressure gauge, it is possible to detect whether at least one of the plurality of first region forming valves is leaking. A method for inspecting the valves of a chromatograph.

2. The circulation line has a plurality of connection sections that connect adjacent columns to each other. The liquid line comprises a main stock supply line for supplying stock solution, a plurality of sub-stock supply lines connecting the main stock supply line to each connection section, at least one main eluent supply line for supplying at least one eluent, and a plurality of sub-eluent supply lines connecting the at least one main eluent supply line to each connection section. The method for inspecting a valve in a chromatography apparatus according to claim 1, wherein the first region includes a portion of the main stock solution supply line and a portion of each sub-stock solution supply line, or a portion of at least one main eluent supply line and a portion of each sub-eluent supply line.

3. A stock solution storage tank for storing the stock solution and connected to the main stock solution supply line, The eluent is stored in at least one eluent storage tank connected to the at least one main eluent supply line, The main supply line of the concentrate includes a concentrate pump located downstream of the concentrate storage tank, The eluent main supply line includes at least one eluent pump located downstream of the at least one eluent storage tank, A method for inspecting a valve in a chromatography apparatus according to claim 2, wherein one of the plurality of region-forming valves is provided between the stock solution pump and each stock solution sub-supply line, or between at least one eluent pump and each eluent sub-supply line.

4. A method for inspecting the valves in a chromatography apparatus having a liquid flow mechanism and a plurality of valves provided in the liquid flow mechanism, the plurality of valves including a plurality of first region forming valves, wherein the liquid flow mechanism has a plurality of columns, a circulation line sequentially connecting the plurality of columns, and a plurality of liquid lines connected to the circulation line through which liquid supplied to the plurality of columns flows in and liquid processed by the plurality of columns flows out, The plurality of first region-forming valves and pressure regulating means form a first region defined and closed by the plurality of first region-forming valves in a part of the liquid flow mechanism, and a second region adjacent to the first region and with a lower pressure than the first region is formed via a connecting valve, which is one of the plurality of first region-forming valves. By detecting whether the pressure in the second region is increasing using a pressure gauge, it is possible to detect whether the connecting valve is leaking or not. A method for inspecting the valves of a chromatograph.

5. The system further comprises a stock solution storage tank for storing the stock solution, and at least one eluent storage tank for storing at least one eluent, The circulation line has a plurality of connection sections that connect adjacent columns to each other. The liquid line comprises a main stock supply line connected to the stock storage tank, a plurality of sub-stock supply lines branching from the main stock supply line and connected to each connection section, at least one main eluent supply line connected to at least one eluent storage tank, and a plurality of sub-eluent supply lines branching from the at least one main eluent supply line and connected to each connection section. The method for inspecting a chromatography apparatus according to claim 4, wherein the first region includes a portion of the main stock solution supply line and a portion of each sub-stock solution supply line, or a portion of at least one main eluent supply line and a portion of each sub-eluent supply line.

6. The second region is defined and has a plurality of second region-forming valves including the connecting valve, The liquid flow mechanism has, for each of the two or more fractions, a plurality of extraction sublines that branch off from the respective connection sections and extract the fraction, and a main extraction line formed by the confluence of the plurality of extraction sublines. A method for inspecting valves in a chromatograph according to claim 5, wherein at least one of the plurality of second region-forming valves, excluding the connecting valve, is provided in the main line of at least one of the fractions.

7. The inspection method for a chromatographic apparatus according to claim 6, wherein one of the valves is detachable.

8. The method for inspecting a chromatograph according to any one of claims 1 to 7, wherein the liquid flow mechanism has a back pressure valve for adjusting the pressure in the first region.

9. A liquid flow mechanism comprising: multiple columns; a circulation line sequentially connecting the multiple columns; and multiple liquid lines connected to the circulation line through which liquid supplied to the multiple columns and processed liquid enter and exit; A plurality of valves provided in the liquid flow mechanism, including a plurality of first region-forming valves capable of forming a closed first region, Pressure adjustment means for increasing the pressure in the first region with respect to a plurality of regions adjacent to the first region via the plurality of first region forming valves, A pressure gauge for measuring the pressure in the first region, A chromatography apparatus having the following features.

10. A liquid flow mechanism comprising: multiple columns; a circulation line sequentially connecting the multiple columns; and multiple liquid lines connected to the circulation line through which liquid supplied to the multiple columns and processed liquid enter and exit; A plurality of valves provided in the liquid flow mechanism, including a plurality of first region-forming valves capable of forming a closed first region, and a plurality of valves that form a second region adjacent to the first region via a connecting valve which is one of the plurality of first region-forming valves, A pressure adjustment means for lowering the pressure in the second region to the pressure in the first region, A pressure gauge for measuring the pressure in the second region, A chromatography apparatus having the following features.

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