Analysis device and analysis method

Abstract

The analysis device comprises a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, a flow injection system for analyzing the sample water from the reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target, a first pipe through which a concentrated water in which the detection target is concentrated by the membrane filtration device flows as the sample water in the flow injection system, and a sample water pump for pressurizing the sample water in the first pipe, wherein the inner diameter of the outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe.

Description

Technology Field

[0001] The present disclosure relates to an analysis apparatus and an analysis method. Background Technology

[0002] Japanese Patent Publication No. 62-280652 describes a flow injection analysis method (hereinafter abbreviated as “FIA”) in which a liquid-liquid mixture consisting of an organic phase and an aqueous phase is introduced into the inner tube of a double tube consisting of a porous polymer membrane inner tube and an outer tube including the inner tube, or into a region enclosed by the inner tube and the outer tube, and only the organic phase is permeated to the wall of the porous polymer membrane inner tube to separate the organic phase and the aqueous phase, and the obtained organic phase is introduced into a detector to analyze the element to be tested.

[0003] The inventors, in Japanese Patent Publication No. 2022-011525 and others, perform low-concentration analysis of endotoxins, etc., using the FIA ​​method utilizing fluorescent substances. However, it was difficult to measure down to the low concentrations required for online measurement. The problem to be solved

[0004] Generally, endotoxins are pyrogenic substances that must not be included in pharmaceutical waters such as purified water and water for injection (WFI). Therefore, when manufacturing purified water or WFI, it is necessary to remove them as much as possible, and online monitoring is required. Online measurement requires the ability to quantify down to low concentrations while simultaneously ensuring high precision and stability.

[0005] When performing analysis of bacterial products containing endotoxins using an online analysis device and analysis method using the FIA ​​method, it is difficult to quantitatively analyze the bacterial products even when the concentration is low.

[0006] The object of the present disclosure is to improve the quantitative accuracy of the analysis in an online analysis apparatus and analysis method using the FIA ​​method. means of solving the problem

[0007] The analysis device of the first embodiment comprises a membrane filtration device having a microfiltration membrane or an ultrafiltration membrane, a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target, a first pipe through which a concentrated water in which the detection target is concentrated by the membrane filtration device flows as the sample water in the flow injection system, and a sample water pump for pressurizing the sample water in the first pipe, wherein the inner diameter of the outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe.

[0008] In this analysis device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, a concentrated water in which the detection target is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows to a flow injection system. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in the carrier water. In this way, by sending the concentrated water in which the detection target is concentrated by the membrane filtration device to the flow injection system as the sample water, the quantitative accuracy of the analysis of the sample water for the detection target of bacterial derivatives containing endotoxin can be increased.

[0009] In addition, in this analysis device, the inner diameter of the outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe.

[0010] Accordingly, in the first piping, the water pressure of the sample water downstream of the pump can be maintained at a higher level than the water pressure upstream of the pump. Since the flow rate of the sample water discharged from the pump can be stabilized, the concentration ratio of the detection target in the sample water can be increased.

[0011] The analysis device of the second embodiment comprises a membrane filtration device having a microfiltration membrane or an ultrafiltration membrane, a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target, a first pipe through which a concentrated water in which the detection target is concentrated by the membrane filtration device flows as the sample water to the flow injection system, a second pipe through which at least a portion of the permeate water of the membrane filtration device flows as the carrier water to the flow injection system, and a sample water pump for pressurizing the sample water in the first pipe.

[0012] In this analysis device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, a concentrated water in which the detection target is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows to a flow injection system. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in the carrier water. In this way, by sending the concentrated water in which the detection target is concentrated by the membrane filtration device to the flow injection system as the sample water, the quantitative accuracy of the analysis of the sample water for the detection target of bacterial derivatives containing endotoxin can be increased.

[0013] In addition, this analysis device is provided with a second pipe through which at least a portion of the permeate from the membrane filtration device flows as carrier water into a flow injection system.

[0014] For this reason, a device for obtaining the carrier count is unnecessary, and the configuration of the analysis device can be simplified.

[0015] The analysis device of the third embodiment comprises a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target, a first pipe through which a concentrated water in which the detection target is concentrated by the membrane filtration device flows as the sample water to the flow injection system, a second pipe through which the carrier water flows to the flow injection system, and a sample water pump for pressurizing the sample water in the first pipe, wherein the membrane filtration device has a connection port to which the second pipe is connected.

[0016] In this analysis device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, a concentrated water in which the detection target is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows to a flow injection system. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in the carrier water. In this way, by sending the concentrated water in which the detection target is concentrated by the membrane filtration device to the flow injection system as the sample water, the quantitative accuracy of the analysis of the sample water for the detection target of bacterial derivatives containing endotoxin can be increased.

[0017] In addition, this analysis device has a second pipe through which at least a portion of the permeate from the membrane filtration device flows as carrier water into the flow injection system.

[0018] For this reason, a device for obtaining the carrier count is unnecessary, and the configuration of the analysis device can be simplified.

[0019] In addition, in this analysis device, the membrane filtration device has a connection port to which a second pipe is connected.

[0020] By connecting a second pipe to the connection port of the membrane filtration device, the permeate of the membrane filtration device can be sent to the second pipe as carrier water without exposing it to the outside air, and the mixing of foreign matter into the carrier water can be suppressed.

[0021] The analysis device of the fourth embodiment comprises a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target, a first pipe through which a concentrated water in which the detection target is concentrated by the membrane filtration device flows as the sample water in the flow injection system, and a sample water pump for pressurizing the sample water in the first pipe, wherein the pressure at the inlet side of the membrane filtration device is lower than the pressure at the outlet of the sample water pump and is also 0.05 MPa or higher.

[0022] In this analysis device, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, a concentrated water in which the detection target is concentrated is obtained. The concentrated water is pressurized by a sample water pump in the first pipe and flows to a flow injection system. In the flow injection system, the sample water is analyzed through a reaction with a reagent contained in the carrier water. In this way, by sending the concentrated water in which the detection target is concentrated by the membrane filtration device to the flow injection system as the sample water, the quantitative accuracy of the analysis of the sample water for the detection target of bacterial derivatives containing endotoxin can be increased.

[0023] In addition, in this analysis device, the pressure at the inlet side of the membrane filtration device is lower than the pressure at the outlet of the sample water pump and is also 0.05 MPa or higher.

[0024] By setting the pressure on the inlet side of the membrane filtration device in this way, the quantitative accuracy of the sample number analysis can be improved.

[0025] The analysis device of the fifth embodiment, in the second or third embodiment, has a membrane filtration device that is open to the outside and has a discharge section through which permeate water passing through the microfiltration membrane or the ultrafiltration membrane is discharged, and the linear velocity of the permeate water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less.

[0026] By discharging most of the permeate that has passed through the ultrafiltration membrane of the membrane filtration device from the discharge section, the discharge volume of permeate per unit time in the membrane filtration device can be increased, and the concentration of the concentrated water can be increased.

[0027] In addition, by setting the linear velocity of the permeate in this way, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0028] The analysis device of the sixth embodiment, in the first or fourth embodiment, has a membrane filtration device that is open to the outside and has a discharge section through which permeate water passing through the microfiltration membrane or the ultrafiltration membrane is discharged, and the linear velocity of the permeate water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less, and also has a second pipe through which at least a portion of the permeate water flows as the carrier water in the flow injection system.

[0029] By discharging most of the permeate that has passed through the ultrafiltration membrane of the membrane filtration device from the discharge section, the discharge volume of permeate per unit time in the membrane filtration device can be increased, and the concentration of the concentrated water can be increased.

[0030] In addition, by setting the linear velocity of the permeate in this way, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0031] Since a second pipe is provided, a device for obtaining carrier water is unnecessary, and the configuration of the analysis device can be simplified.

[0032] The analysis method of the seventh embodiment generates a sample water in which a detection target is concentrated by a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, pressurizes the sample water by a sample water pump and sends it to a flow injection system, wherein in the flow injection system, the sample water is analyzed from the reaction between the detection target and a reagent contained in the carrier water that reacts with the detection target, and the water pressure on the downstream side of the sample water pump is higher than the water pressure on the upstream side of the sample water pump.

[0033] In this analysis method, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, a concentrated water in which the detection target is concentrated is obtained. The concentrated water is pressurized by a sample water pump and sent to a flow injection system as sample water. In the flow injection system, the detection target is analyzed through a reaction with a reagent contained in the carrier water. In this way, by sending the concentrated water in which the detection target is concentrated by the membrane filtration device to the flow injection system as sample water, the quantitative accuracy of the analysis of the detection target of bacterial derivatives containing endotoxins can be increased.

[0034] In addition, in this analysis method, the water pressure on the downstream side of the pump is higher than the water pressure on the upstream side of the pump.

[0035] By doing so, the flow rate of the sample water discharged from the pump can be stabilized, thereby increasing the concentration ratio of the detection target in the sample water.

[0036] The analysis method of the eighth embodiment generates a sample water in which a detection target is concentrated by a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, pressurizes the sample water by a sample water pump and sends it to a flow injection system, sends at least a portion of the permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device as carrier water to the flow injection system, and in the flow injection system, analyzes the sample water from the reaction between the detection target and a reagent contained in the carrier water that reacts with the detection target.

[0037] In this analysis method, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, a sample water is obtained from the concentrated water in which the detection target is concentrated. The sample water is pressurized by a sample water pump and sent to a flow injection system. At least a portion of the permeate water that has passed through the microfiltration membrane or ultrafiltration membrane in the membrane filtration device is sent to the flow injection system as carrier water. In the flow injection system, the detection target of the sample water is analyzed through a reaction with a reagent contained in the carrier water. Since the concentrated water in which the detection target is concentrated by the membrane filtration device is sent to the flow injection system as sample water, the quantitative accuracy of the analysis of the detection target of bacterial derivatives containing endotoxins can be improved.

[0038] In addition, in the membrane filtration device, at least a portion of the permeate that has passed through a microfiltration membrane or an ultrafiltration membrane is sent to a flow injection system as carrier water, so a device for obtaining carrier water is unnecessary, and the configuration of the analysis device can be simplified.

[0039] The analysis method of the ninth embodiment generates a sample water in which a detection target is concentrated by a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, pressurizes the sample water by a sample water pump and sends it to a flow injection system, and sets the pressure at the inlet side of the membrane filtration device to be lower than the pressure at the outlet of the sample water pump and also to be 0.05 MPa or higher, and in the flow injection system, analyzes the sample water from the reaction between the detection target and a reagent contained in the carrier water that reacts with the detection target.

[0040] In this analysis method, the membrane filtration device is equipped with a microfiltration membrane or an ultrafiltration membrane. By passing the water to be analyzed through the membrane filtration device, a sample water is obtained from the concentrated water in which the detection target is concentrated. The sample water is pressurized by a sample water pump and sent to a flow injection system. In the flow injection system, the detection target of the sample water is analyzed through a reaction with a reagent contained in the carrier water. Since the concentrated water in which the detection target is concentrated by the membrane filtration device is sent to the flow injection system as the sample water, the quantitative accuracy of the analysis of the detection target of bacterial derivatives containing endotoxins can be improved.

[0041] In addition, by making the pressure at the inlet side of the membrane filtration device lower than the pressure at the outlet of the sample water pump and also 0.05 MPa or higher, the quantitative accuracy of the analysis of the sample water can be improved.

[0042] The analysis method of the 10th embodiment, in the 8th embodiment, in the membrane filtration device, discharges the permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane from the discharge part of the membrane filtration device to the outside in a pressureless state and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less.

[0043] By setting the linear velocity of the permeate in this way, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0044] The analysis method of the 11th embodiment, in the 7th or 9th embodiment, in the membrane filtration device, discharges the permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane from the discharge portion of the membrane filtration device to the outside in a non-pressure state and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less, and sends at least a portion of the permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device as carrier water to the flow injection system.

[0045] By setting the linear velocity of the permeate in this way, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device.

[0046] In addition, in the membrane filtration device, at least a portion of the permeate that has passed through a microfiltration membrane or an ultrafiltration membrane is sent to a flow injection system as carrier water, so a device for obtaining carrier water is unnecessary, and the configuration of the analysis device can be simplified. Effects of the invention

[0047] In the technology of the present disclosure, in an analysis apparatus and analysis method using the FIA ​​method, it is possible to increase the quantitative accuracy of the analysis. Brief explanation of the drawing

[0048] FIG. 1 is a configuration diagram showing an analysis device of a first embodiment. FIG. 2 is a configuration diagram showing an analysis device of a modified example of the first embodiment. Figure 3 is a configuration diagram showing the analysis device of Example 8. Specific details for implementing the invention

[0049] Hereinafter, an analysis device 12 according to a first embodiment will be described with reference to the drawings. As shown in FIG. 1, this analysis device 12 is used to analyze water obtained from a water treatment system not shown, or water during treatment. In this embodiment, the analysis device 12 analyzes endotoxin contained in the analysis target. Endotoxin is an example of a bacterial product and is also an example of a detection target in the disclosed technology. That is, in the analysis device 12 and analysis method of the disclosed technology, a bacterial product containing endotoxin is used as a detection target. The detection target is not limited to endotoxin, that is, lipopolysaccharide used as a component of the cell wall of Gram-negative bacteria, but may be, for example, various types of bacteria (bacteria themselves).

[0050] In addition, water obtained by the water treatment system may include, for example, water for injection and pharmaceutical water, but is not limited to these. Specifically, the water treatment system may include, for example, facilities for producing purified water and pharmaceutical water such as water for injection (WFI).

[0051] The analysis device 12 is composed of a pre-concentration unit 12A, a reagent mixing unit 12B, and a detection unit 12C.

[0052] In the illustrated example, the pre-concentration unit 12A has a pre-concentration pump 14 and a membrane filtration device 16. The water to be analyzed is sent to the pre-concentration pump 14 from a water treatment system. The pre-concentration pump 14 pressurizes the water to be analyzed and sends it to the downstream membrane filtration device 16 through piping 18. In addition, if the analysis device 12 is directly attached to the sampling line of, for example, a purified water production device or an ultrapure water production device for online measurement, the pre-concentration pump 14 is unnecessary if the pressure of the sampling line is appropriate. In addition, if the pressure of the sampling line is excessively high compared to the appropriate pressure, a pressure reducing means such as a pressure reducing valve can be installed instead of the pre-concentration pump 14.

[0053] The membrane filtration device 16 has an outer tube 20. An inlet section 22 is provided at one end of the outer tube 20 in the longitudinal direction, and an outlet section 24 is provided at the other end. Additionally, a discharge section 26 and a water supply section 28 are provided on the outer circumference of the outer tube 20. A pipe 18 from a pre-concentration pump 14 is connected to the inlet section 22. A first pipe 32, which will be described later, is connected to the outlet section 24.

[0054] A plurality of hollow fiber ultrafiltration membranes 30 are arranged inside the outer tube 20. Sample water flowing into the outer tube 20 from the inlet section 22 is filtered by the ultrafiltration membranes 30. Specifically, since endotoxin does not pass through the ultrafiltration membranes 30, concentrated water containing concentrated endotoxin is produced and reaches the outlet section 24. The pore size of the ultrafiltration membranes 30 is approximately 0.01 to 0.001 μm. When a bacterial-derived material containing endotoxin is to be detected as described in the present disclosure, it is preferable to use an ultrafiltration membrane 30 having such a pore size in order to concentrate the detection target and obtain concentrated water, based on the relationship with the size of the bacterial-derived material. In addition, a microfiltration membrane may be used instead of an ultrafiltration membrane. As for the ultrafiltration membrane or microfiltration membrane, a membrane with a removal rate of 90% or more of the target substance is more preferable, and a membrane with a removal rate of 95% or more is even more preferable.

[0055] In this embodiment, cellulose acetate, polyacrylonitrile, polysulfone, polyethersulfone, modified polyethersulfone, polyvinylidene fluoride, etc. may be used as the material for the ultrafiltration membrane 30. In particular, since modified polyethersulfone is difficult to adsorb endotoxin, it is preferred as the material for the ultrafiltration membrane 30.

[0056] As for the membrane filtration device to be used, for example, Repligen’s KROSFLO 20CM 5K MPES, etc., can be used without limitation.

[0057] The permeate water passing through the ultrafiltration membrane 30 contains no endotoxin or only trace amounts of it. In other words, this permeate water is endotoxin-free water. Endotoxin-free water is discharged from the discharge section 26 and the water supply section 28 to the outside of the membrane filtration device 16. By the membrane filtration device 16, the sample water is concentrated by 10 to 100,000 times. A concentration ratio of 1,000 to 100,000 times is more preferable from the perspective of measurement precision.

[0058] The outlet of discharge section 26 is open. In practice, permeate is discharged from discharge section 26 in a non-pressure state. This non-pressure state means that atmospheric pressure acts on the permeate discharged from discharge section 26, but no pressure exceeding this atmospheric pressure acts on it.

[0059] One end of the first pipe 32 is connected to the outlet section 24 of the membrane filtration device 16. Concentrated water in which endotoxin is concentrated in the membrane filtration device 16 flows through the first pipe 32 as sample water.

[0060] In this embodiment, the water supply unit 24 and the pump 42 are directly connected. That is, since a reservoir is not provided between the water supply unit 24 and the pump 42, there is no risk of contamination of the sample water or evaporation of the sample water in the reservoir. Furthermore, to minimize the effects of contamination or evaporation in the reservoir, it is necessary to take measures such as increasing the flow rate to the reservoir and partially discharging the sample water in the reservoir; however, in such cases, the concentration ratio decreases, which may lead to a decrease in measurement precision. In this embodiment, there is no such risk, and accurate measurement is possible.

[0061] One end of the second pipe 34 is connected to the water supply section 28 of the membrane filtration device 16. Endotoxin-free water, from which endotoxins have been removed in the membrane filtration device 16, flows through the second pipe 34 as carrier water. The water supply section 28 is an example of a connection port to which the second pipe 34 is connected.

[0062] The flow injection system 40 has a pump 42. In this embodiment, the pump 42 is a plunger pump. In this plunger pump, the plunger reciprocates within the pump housing to pressurize the fluid and send it from the upstream side to the downstream side. In particular, in the example shown in FIG. 1, a double plunger pump having two plungers arranged in parallel is used as the pump 42 and is provided in common to the first pipe 32 and the second pipe 34. By doing so, the pump 42 can pressurize the sample number and the carrier number in synchronization and send them to the downstream side. Additionally, the pump 42 may use a peristar pump, a syringe pump, or a solenoid pump. A plunger pump is more preferred.

[0063] In the second pipe 34, a reagent injection section 44 is provided downstream of the pump 42. In the reagent injection section 44, a reagent that reacts with endotoxin is injected into the carrier water, and the carrier water is obtained.

[0064] In the reagent mixing section 12B, the first pipe 32 and the second pipe 34 extend into the interior of the flow injection system 40. Inside the flow injection system 40, the first pipe 32 and the second pipe 34 merge to form a confluence pipe 46. The confluence pipe 46 is included in the detection section 12C.

[0065] As a reagent in this invention, a fluorescent reagent in which a fluorescent site and a recognition site are coupled by a spacer as described in Japanese Patent Publication No. 2022-011525 may be used, but is not particularly limited thereto.

[0066] In the confluence pipe 46, the sample water flowing through the first pipe 32 and the carrier water flowing through the second pipe 34 are combined to form the combined water. In the combined water, a reaction occurs between the endotoxin contained in the sample water and the reagent contained in the carrier water.

[0067] Analyzer 48 is disposed in the confluence pipe 46. Analyzer 48 analyzes the concentration of endotoxin from the reaction between endotoxin and a reagent. In this embodiment, inside the analyzer 48, a pipe not shown and a quartz cell connected to the pipe are disposed. Analyzer 48 irradiates light onto the confluence water flowing through the quartz cell and detects the concentration of endotoxin from the signal intensity of the obtained fluorescence.

[0068] The analyzer 48 has an outlet pipe 50 that discharges the combined water after analysis. The inner diameter of the outlet pipe 50 is smaller than the inner diameter of the first pipe 32. By doing so, a state is realized in which the pressure P2 on the downstream side of the pump 42, for example, at the outlet, is higher than the pressure P1 on the inlet side of the pump 42, for example, on the upstream side of the membrane filter 16.

[0069] In analyzer 48, quantification is performed by irradiating with excitation light of a wavelength of, for example, 340 to 360 nm and observing the generated fluorescence of 440 to 520 nm. In analyzer 48, the flow rate of the sample is 0.01 to 4.00 mL / min, and the measurement precision is improved by having a flow rate within this range.

[0070] The materials of the first pipe 32, the second pipe 34, and the connecting pipe 46 are not limited as long as it is possible to allow the sample water, carrier water, and connecting water to flow through them, respectively. Likewise, the piping of the analyzer 48 is not particularly limited, but if, for example, a fused silica tube is used, the reaction between the connecting water flowing inside and the piping using this fused silica tube can be suppressed, and more accurate analysis becomes possible.

[0071] In this embodiment, a so-called online analysis device and online analysis method are realized, which perform analysis of endotoxin concentration by an analyzer 48 while continuously flowing the water to be analyzed.

[0072] Next, the operation and analysis method of the analysis device 12 of the present embodiment will be explained.

[0073] Water to be analyzed, sent from an unused water treatment system, is pressurized by a pre-concentration pump 14 and sent to a membrane filtration device 16. In the membrane filtration device 16, the water to be analyzed is filtered by an ultrafiltration membrane 30, and concentrated water containing endotoxin and permeate water that does not contain endotoxin (endotoxin-free water) are obtained.

[0074] The permeate is discharged to the outside of the membrane filtration device 16 from the discharge section 26 and the outlet section 24. In the analysis device 12 of this embodiment, the outlet of the discharge section 26 is open, and the permeate is discharged from the discharge section 26 in a non-pressure state. That is, most of the permeate that has passed through the ultrafiltration membrane 30 is discharged from the discharge section 26. For this reason, compared to a configuration in which a pressure exceeding atmospheric pressure is applied to the permeate discharged from the discharge section 26, the flow rate that can be discharged is increased. In terms of unit time, endotoxins can be concentrated from a larger amount of water to be treated, and the concentration of the concentrated water can be increased.

[0075] Here, it is preferable to set the inner diameter of the discharge section 26 to be 2 mm or more and 30 mm or less, or to set the linear velocity of the permeate flowing through the discharge section 26 to be 0.1 m / sec or more and 2.0 m / sec or less. In addition, it is preferable that the length of the piping of the discharge section 26 (the length from the outer tube 20 to the outlet of the discharge section 26) be 30 m or less. By setting the shape of the discharge section 26 or the linear velocity of the permeate in this way, a sufficient amount of permeate can be obtained, and endotoxin can be sufficiently concentrated in the membrane filtration device 16. In addition, the inlet pressure of the pump 42 located downstream of the water supply section 28 is maintained within an appropriate range, and the amount of reagent added in the reagent injection section 44 can be maintained appropriately, so the measurement value in the analyzer 48 becomes more stable. In addition, the inner diameter of the discharge section 26 refers to the inner diameter of the part where the cross-sectional area of ​​the flow path of the discharge section 26 is narrowest, and the above linear velocity is the linear velocity in this part.

[0076] In addition, this discharge section 26 may be arranged in a form that branches off from between the water supply section 28 and the pump 42, as shown in FIG. 2 as a first modified example. In that case, the pipe diameter from the water supply section 28 to the discharge section 26 is set to the above range, and the inner diameter of the second pipe 34 between the discharge section 26 and the pump 42 is preferably, for example, 0.5 mm or more and 2.0 mm or less.

[0077] At least a portion of the permeate water that has passed through the ultrafiltration membrane 30 is sent as carrier water from the water supply unit 28 to the reagent injection unit 44 of the flow injection system 40 via the second pipe 34. Since there is no need to use another device to obtain carrier water, it is possible to simplify the configuration of the analysis device 12 and the procedure of the analysis method.

[0078] If the membrane filtration device 16 is of the internal pressure type, either of the methods of FIG. 1 or FIG. 2 can be applied, but if it is of the external pressure type, the method of FIG. 2 can be suitably used.

[0079] In addition, the second pipe 34 is connected to the discharge section 26, so the permeate water is not exposed to the outside air. By doing so, it is possible to suppress the mixing of foreign substances into the permeate water (carrier water) as endotoxin-free water.

[0080] The carrier water is pressurized by pump 42 and sent downstream. Downstream of pump 42, the reagent is injected by the reagent injection part 44.

[0081] The concentrated water obtained from the membrane filtration device 16 is sent as sample water from the outlet section 24 to the reagent injection section 44 of the flow injection system 40 via the first pipe 32. Then, it is pressurized by the pump 42 and sent downstream. In the analysis device 12 of the present embodiment, the concentration of endotoxin can be analyzed by the flow injection system 40 by using the concentrated water, in which endotoxin is concentrated to a high concentration by the membrane filtration device 16, as sample water. Compared to the case where the membrane filtration device 16 is not used and sample water with a low endotoxin concentration is used, it is possible to increase the quantitative accuracy of the endotoxin analysis.

[0082] The first pipe 32 is connected to the outlet section 24, so that the concentrated water is not exposed to the outside air. By doing so, the mixing of foreign matter into the concentrated water (sample water) can be suppressed.

[0083] The sample water of the first pipe 32 and the carrier water of the second pipe 34 are combined in the confluence pipe 46 to form the combined water. Then, a reaction occurs between the endotoxin contained in the sample water and the reagent contained in the carrier water. Additionally, the combined water is sent to analyzer 48. In analyzer 48, the concentration of endotoxin is obtained from the reaction between the endotoxin and the reagent, and the sample water is analyzed.

[0084] In the analysis device 12 of the present embodiment, the inner diameter of the outlet pipe 50 of the analyzer 48 is smaller than the inner diameter of the first pipe 32. As a result, a state is realized in which the pressure P2 at the outlet side downstream of the pump 42 is higher than the pressure P1 at the upstream side of the membrane filtration device 16 upstream of the pump 42. Since the discharge pressure at the outlet side of the pump 42 is higher than the water pressure at the inlet side of the pump 42, the operation of the pump 42 is less affected by the water pressure at the inlet side. In other words, the water pressure at the outlet side becomes dominant regarding the influence on the flow rate of the sample water discharged from the pump 42. Since the discharge flow rate of the sample water from the pump 42 is not affected by pressure fluctuations at the inlet side, the flow rate at the outlet side can be stabilized and maintained within a certain range. As a result, compared to the case where the discharge pressure at the outlet side of pump 42 is lower than the water pressure at the inlet side of pump 42, the concentration ratio of endotoxin in the sample volume is increased. And as the concentration ratio of endotoxin increases, the signal intensity at analyzer 48 also becomes stronger. That is, in the flow injection system 40, it is possible to increase the quantitative accuracy of endotoxin analysis.

[0085] (Example)

[0086] Next, the technology of the present disclosure will be explained in more detail through examples and comparative examples. However, the technology of the present disclosure is not limited to the contents of the examples shown below.

[0087] In the examples and comparative examples, the endotoxin concentration of sample water was analyzed by injecting endotoxin into the carrier water to achieve an endotoxin concentration of 10 nM using the analysis device 12 of the first embodiment. Specifically, the range of measured values ​​for the endotoxin concentration of sample water by the analyzer 48 was verified.

[0088] In the examples and comparative examples, the measurement conditions were set as follows: excitation wavelength 350 nm, detection fluorescence wavelength 500 nm, fluorescent reagent Zn-dpa-C2OPy (see chemical formula (1) below), and fluorescent reagent concentration 10 μM at the reagent injection site.

[0089]

[0090] In the examples and comparative examples, the measurement conditions were set to an excitation wavelength of 350 nm and a detection fluorescence wavelength of 500 nm.

[0091] Table 1 shows the pressure P1 at the inlet side of the membrane filtration device 16, the pressure P2 at the outlet of the pump 42, and the measurement range at the analyzer 48 for each of the examples and comparative examples. This measurement range is the range of values ​​actually measured as the concentration of endotoxin at the analyzer 48, and specifically, five measurements were performed, and the maximum and minimum values ​​obtained are shown.

[0092] The pressure P1 at the inlet side of the membrane filter 16 can be adjusted to a desired pressure value by an unillustrated water treatment system and a pre-concentration pump 14 placed upstream of the analysis device 12.

[0093] Examples 1 to 7 and Comparative Examples 1 to 3 shown in Table 1 are an analysis device 12 shown in FIG. 1 in which the settings of pressure P1 and pressure P2 were changed and the range of measured values ​​was verified.

[0094] In addition, Example 8 shown in Table 1 is an example using the analysis device 52 shown in FIG. 3. In this analysis device 52, a small tank 54 is additionally installed between the outlet section 24 and the pump 42, in addition to the analysis device 12 shown in FIG. 1. In this case, the sample water concentrated in the membrane filtration device 16 is initially stored in the tank 54, and this stored sample water is sucked by the pump 42. In addition, the capacity of the tank 54 is 10 ml.

[0095]

[0096] As can be seen from Table 1, in Examples 1 to 7, the relationship P1 < P2 is satisfied, and a measurement value almost equivalent to the endotoxin concentration of the feed water is obtained as a measurement value range. That is, in Examples 1 to 7, quantitative measurement of the endotoxin concentration in the sample water is possible. This is because, in the case of Examples 1 to 7, the flow rate of the sample water flowing through the first pipe 32 is appropriately controlled, and the flow rate ratio between this sample water and the carrier water flowing through the second pipe 34 is an appropriate value. Also, since the endotoxin concentration of the concentrated water is high, the analyzer 48 functions properly.

[0097] In the case of Example 8, the pressures of P1 and P2 are set to specified values, and the relationship P1 < P2 is satisfied. In Example 8, the numerical range of the measured value tends to increase compared to other examples. This is because contamination occurs in Tank 54 when a sample is received from Tank 54. As such, since it is known in advance that the numerical range of the measured value in Example 8 is measured to be larger than the actual value, a predetermined correction factor can be obtained to address this, for example, and the measured value can be multiplied by the correction factor.

[0098] This embodiment 8 has the advantage that, by means of tank 54, the pressure at the front end of tank 54 does not affect the rear end of tank 54, so the pressure P1 can be freely set.

[0099] In particular, regarding the value of pressure P1, it is preferable that the above condition of P1 < P2 is satisfied, and that P1 ≥ 0.03 MPa, and more preferable that P1 ≥ 0.05 MPa. By setting the lower limit of the pressure P1 value in this way, sufficient concentration can be performed on the ultrafiltration membrane 30, so the measurement precision is higher. In addition, in each example shown in Table 1, the smallest value of pressure P1 is 0.03 MPa and the next smallest value is 0.06 MPa, but substantially, if the pressure P1 satisfies P1 ≥ 0.05 MPa, sufficient concentration can be performed on the ultrafiltration membrane 30.

[0100] In contrast, in Comparative Examples 1 to 3, the relationship P1 ≥ P2 is maintained, and the range of measured values ​​is smaller than the endotoxin concentration of the supply water. This is because, in the case of Comparative Examples 1 to 3, a large amount of sample water flows through the first pipe 32, and the flow rate ratio between this sample water and the carrier water flowing through the second pipe 34 is not appropriate, so the reagent concentration in the confluence pipe 46 becomes diluted or the concentration does not stabilize. Furthermore, because the amount of sample water flowing through the first pipe 32 is not stable and the endotoxin concentration cannot be maintained at a high level, the measured value does not reach the appropriate range of measured values ​​of the analyzer 48.

[0101] In addition, in the analysis device 52 shown in Fig. 3, it is conceivable to install a pressure regulating valve instead of the tank 54. However, since there are no commercially available valves capable of regulating the pressure of this flow rate, this method cannot be implemented.

[0102] In addition, the following bookkeeping is initiated.

[0103] (Appendix 1)

[0104] A membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane, and

[0105] A flow injection system that analyzes the number of samples from the reaction between a detection target included in the number of samples and a reagent included in the number of carriers that reacts with the detection target, and

[0106] A first pipe through which the concentrated water, in which the detection target is concentrated by the above membrane filtration device, flows as the sample water in the flow injection system, and

[0107] A pump that pressurizes the sample water in the first pipe above

[0108] The branch analysis device.

[0109] (Appendix 2)

[0110] The analysis device described in Appendix 1, wherein the inner diameter of the outlet pipe in the above-described flow injection system is smaller than the inner diameter of the first pipe.

[0111] (Appendix 3)

[0112] The above membrane filtration device is,

[0113] An analysis device described in Appendix 1 or Appendix 2, having a discharge portion that is open to the outside and through which permeate water passing through the ultrafiltration membrane is discharged.

[0114] (Appendix 4)

[0115] An analysis device described in Appendix 3 having a second pipe through which at least a portion of the permeate of the membrane filtration device flows as the carrier water in the flow injection system.

[0116] (Appendix 5)

[0117] The above membrane filtration device is an analysis device described in Appendix 4, having a connection port to which the second pipe is connected.

[0118] (Appendix 6)

[0119] An analysis device described in Appendix 1, wherein the pressure at the inlet side of the membrane filtration device is lower than the pressure at the outlet of the pump and is also 0.05 MPa or higher.

[0120] (Appendix 7)

[0121] A membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane generates a sample water in which the detection target is concentrated, and

[0122] The above sample volume is pressurized by a pump and sent to a flow injection system,

[0123] In the above-described flow injection system, the number of samples is analyzed from the reaction between the detection target and a reagent included in the carrier number and reacting with the detection target.

[0124] Analysis method.

[0125] (Appendix 8)

[0126] The analysis method described in Appendix 7, wherein the water pressure on the downstream side of the pump is higher than the water pressure on the upstream side of the pump.

[0127] (Appendix 9)

[0128] The analysis method described in Appendix 7 or Appendix 8, wherein the permeate water that has passed through the ultrafiltration membrane is discharged to the outside of the membrane filtration device under no-pressure conditions in the above membrane filtration device.

[0129] (Appendix 10)

[0130] The analysis method described in Appendix 9, which sends at least a portion of the permeate of the above membrane filtration device as the carrier water to the flow injection system.

[0131] (Appendix 11)

[0132] The analysis method described in Appendix 7, wherein the pressure at the inlet side of the above membrane filtration device is lower than the pressure at the outlet of the above pump and is also 0.05 MPa or higher.

[0133] The disclosure of Japanese Patent Application No. 2023-210477, filed on December 13, 2023, is incorporated herein by reference in its entirety.

[0134] All documents, patent applications, and technical specifications described in this specification are incorporated by reference in this specification to the same extent as where individual documents, patent applications, and technical specifications are incorporated by reference in a specific and individual manner.

Claims

Claim 1 A membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target; a first pipe through which a concentrated water, in which the detection target is concentrated by the membrane filtration device, flows as the sample water in the flow injection system; and a sample water pump for pressurizing the sample water in the first pipe; wherein the inner diameter of the outlet pipe in the flow injection system is smaller than the inner diameter of the first pipe. Claim 2 An analysis device comprising: a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target; a first pipe through which a concentrated water, in which the detection target is concentrated by the membrane filtration device, flows as the sample water to the flow injection system; a second pipe through which at least a portion of the permeate water of the membrane filtration device flows as the carrier water to the flow injection system; and a sample water pump for pressurizing the sample water in the first pipe. Claim 3 A membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target; a first pipe through which a concentrated water, in which the detection target is concentrated by the membrane filtration device, flows as the sample water in the flow injection system; a second pipe through which the carrier water flows in the flow injection system; and a sample water pump for pressurizing the sample water in the first pipe; wherein the membrane filtration device has a connection port to which the second pipe is connected. Claim 4 An analysis device comprising: a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a flow injection system for analyzing the sample water from a reaction between a detection target included in the sample water and a reagent included in the carrier water that reacts with the detection target; a first pipe through which a concentrated water, in which the detection target is concentrated by the membrane filtration device, flows as the sample water through the flow injection system; and a sample water pump for pressurizing the sample water in the first pipe; wherein the pressure at the inlet side of the membrane filtration device is lower than the pressure at the outlet of the sample water pump and is also 0.05 MPa or higher. Claim 5 An analysis device according to claim 2 or claim 3, wherein the membrane filtration device comprises a discharge section that is open to the outside and discharges permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane, and the linear velocity of the permeate water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less. Claim 6 The analysis device according to claim 1 or claim 4, wherein the membrane filtration device comprises a discharge section that is open to the outside and discharges permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane, and the linear velocity of the permeate water discharged from the discharge section is 0.1 m / sec or more and 2.0 m / sec or less, and the analysis device further comprises a second pipe through which at least a portion of the permeate water flows as the carrier water in the flow injection system. Claim 7 A method of analysis comprising: a step of generating a sample water in which a detection target is concentrated by a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a step of pressurizing the sample water by a sample water pump and sending it to a flow injection system; and a step of analyzing the sample water from the reaction between a reagent contained in a carrier water and reacting with the detection target in the flow injection system, wherein the water pressure on the downstream side of the sample water pump is higher than the water pressure on the upstream side of the sample water pump. Claim 8 A method of analysis comprising: a step of generating a sample water in which a detection target is concentrated by a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a step of pressurizing the sample water by a sample water pump and sending it to a flow injection system; a step of sending at least a portion of the permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device as carrier water to the flow injection system; and a step of analyzing the sample water from the reaction between a reagent contained in the carrier water and reacting with the detection target and the detection target in the flow injection system. Claim 9 A method of analysis comprising: a step of generating a sample water in which a detection target is concentrated by a membrane filtration device equipped with a microfiltration membrane or an ultrafiltration membrane; a step of pressurizing the sample water by a sample water pump and sending it to a flow injection system; a step of making the pressure at the inlet side of the membrane filtration device lower than the pressure at the outlet of the sample water pump and also 0.05 MPa or higher; and a step of analyzing the sample water from the reaction between a reagent contained in the carrier water and reacting with the detection target and the detection target in the flow injection system. Claim 10 The analysis method according to claim 8 further comprises the step of discharging permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane from the discharge portion of the membrane filtration device to the outside in a pressureless state and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less. Claim 11 The method of claim 7 or claim 9 further comprises: a step of discharging permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane from a discharge portion of the membrane filtration device to the outside in a non-pressure state and at a linear velocity of 0.1 m / sec or more and 2.0 m / sec or less; and a step of sending at least a portion of the permeate water that has passed through the microfiltration membrane or the ultrafiltration membrane in the membrane filtration device as carrier water to the flow injection system.

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