Device and method for producing a concentrated reagent from a solid substance

Abstract

The invention relates to a device (1) for producing a concentrated reagent, comprising: - a solvent reservoir (3), - a container (5) containing a solid substance having a solubility in water at 20°C of greater than or equal to 340 g / l, - a pump (9), and - a production circuit (11) including a first line (13) provided with a first valve (15) and a second line (17) provided with a second valve (19). The pump (9) is fluidically connected to the reservoir (3) and to the container (5) respectively by the first line (13) and the second line (17). The pump (9) makes it possible to take solvent from the reservoir (3) and then deliver it to the container (5) such that a concentrated reagent is produced therein by dissolving at least a portion of the solid substance in the solvent.

Description

Description Title of the invention: Device and method for producing concentrated reagent from a solid substance

[0001] The field of the invention relates to the production of concentrated reagent for the purposes of analyzing a sample of biological fluid, in particular in hematology.

[0002] Medical biology is a specialty that involves analyzing biological fluids to determine the pathophysiological origin of a disease. A medical biology examination can also contribute to the prevention, screening, diagnosis, or assessment of the risk of developing pathological conditions, as well as to determining or monitoring a patient's physiological or pathophysiological state.

[0003] The biological fluid to be analyzed is, for example, blood, urine, cerebrospinal fluid, pleural fluid, synovial fluid or even bone marrow taken during a puncture.

[0004] A medical biology examination generally takes place in three phases: - a pre-analytical phase, which includes the collection of a sample of biological fluid from the patient, as well as the preparation, transport and storage of the sample; - an analytical phase, which corresponds to the technical process enabling the obtaining of a biological analysis result; and - a post-analytical phase, which corresponds to the contextual interpretation of the result.

[0005] Optimizing sample flow management is now an important aspect of the organization of a medical biology laboratory. In particular, the quality of sample flow management can be assessed using two parameters: sample processing time (often referred to by the acronym TAT for "turnaround time") and full-time equivalent (often referred to by the acronym FTE for "full-time equivalent"), which measures the workload of the personnel required for the operation of the medical biology laboratory.

[0006] These two parameters are affected by a key element inseparable from sample flow management: reagent supply.

[0007] The sample to be analyzed may contain particles of any kind (cells, proteins, biomarkers, etc.) that will need to be counted and identified. Thus, prior to biological analysis, the sample can be diluted and treated with one or more reagents. The sample can then be sent to a flow measurement machine - i.e. one that uses the principle of flow cytometry - capable of counting and identifying the particles present in the sample using electrical and / or optical measurements.

[0008] For example, in hematology, an automated system dedicated to counting and differentiating blood cells generally uses dilution, staining, lysis, and sheathing reagents. In particular, the staining reagent allows, during the preparation of the blood sample, to mix it with fluorochromes to facilitate subsequent differentiation; and the sheathing reagent - also called sleeving liquid - allows the blood sample to be stretched and guided within the system.

[0009] Also in hematology, a large portion of the total reagent volume consumed is made up of dilution and rinsing reagents. On average, a volume of 40 milliliters (mL) of reagent is consumed for a hematology analysis. On the scale of a large laboratory, the daily reagent requirement can reach 40 liters (L).

[0010] In particular, a complete blood count (CBC) - also called a blood count - is often preceded by a dilution, which reduces the concentration of blood cells in a blood sample to make counting easier.

[0011] Reagent supply for a medical biology laboratory often requires dedicated personnel, who face handling challenges. Reagents are stored in large containers—called cubitainers—which are heavy, bulky, and must be replenished frequently throughout the day.

[0012] To limit these constraints, it is known to produce reagents in situ at a so-called "working" concentration, i.e., reagents ready to be used for biological analysis. To do this, some medical biology laboratories use devices capable of producing reagents at a working concentration from a concentrated reagent and reverse osmosis water. Reverse osmosis water is often produced on site by a plant supplied with raw water and can be used directly by biochemistry analyzers.

[0013] European patent EP 3 714 252 B 1 proposes in this respect a diluent preparation module formed by a combining element ("combiner feature") connected, on the one hand, to a source of purified water and, on the other hand, to a container of concentrated reagent ("reagent concentrate"). The combining element is arranged to mix the purified water and the concentrated reagent so as to produce a diluent which is then stored pending being transported to an analyzer.

[0014] European patent EP 2 175 340 B 1 describes, on the same principle, a reagent preparation apparatus comprising a constant amount liquid quantifying unit equipped with an instrument capable of jointly maintaining a concentrated reagent ("high concentration reagent") and a diluting each to a constant quantity and transferring them into the same storage unit to produce the reagent by mixing.

[0015] Such devices use a concentrated reagent made from a liquid reagent, which has several disadvantages.

[0016] First of all, such a concentrated reagent is at best a x25 concentrated reagent, that is to say a reagent whose concentration is only 25 times higher than the working concentration. Such a concentration is notably limited by the solubility of the salt(s) present in the liquid reagent used, which solubility cannot be exceeded without risk of crystallization, which alters the physicochemical properties of the concentrated reagent obtained.

[0017] Such a low concentration results in high consumption of concentrated reagent. Generally speaking, the production of concentrated reagent from liquid reagent causes logistical problems similar to those described above and linked to the volumes involved, whether it is the liquid reagent or the concentrated reagent; the transport and storage of the concentrated reagent thus require packaging of 10 or even 20 liters (L).

[0018] Furthermore, such concentrated reagents contain chemicals marked with hazard pictograms, which complicates their transport and storage. In particular, concentrated diluents generally contain preservatives and pH buffers such as formaldehyde, imidazole, glutaraldehyde, or sodium azide, which are harmful to both the health of medical biology laboratory personnel and the environment.

[0019] The present invention improves the situation.

[0020] In this respect, the invention relates to a device for producing concentrated reagent comprising: - a solvent tank, - a container, which contains a solid substance having a solubility in water at 20°C greater than or equal to 340 g / L, - a pump, and - a production circuit including a first conduit equipped with a first valve and a second conduit equipped with a second valve.

[0021] The pump is fluidically connected to the reservoir and the container by the first pipe and the second pipe respectively.

[0022] The device is arranged to operate at least according to: a solvent sampling mode in which the first valve is open, the second valve is closed, and the pump is arranged to draw solvent from the reservoir, and a concentrated reagent production mode in which the first valve is closed, the second valve is open, and the pump is arranged to deliver solvent to the container such that a concentrated reagent is produced by dissolving at least part of the solid substance in the solvent and to draw concentrated reagent from the container.

[0023] In one or more embodiments, the device further includes a concentrated reagent storage tank, the production circuit further includes a third conduit provided with a third valve, and the pump is further fluidly connected to the storage tank by the third conduit. The third valve is closed in the solvent withdrawal mode and the concentrated reagent production mode of the device.

[0024] The device is arranged to further operate in a concentrated reagent storage mode in which the first valve is closed, the second valve is closed, the third valve is open, and the pump is arranged to deliver concentrated reagent to the storage tank.

[0025] In one or more embodiments, the device is arranged to further operate in a concentrated reagent homogenization mode in which the first valve is closed, the second valve is closed, the third valve is open, and the pump is arranged to alternately draw concentrated reagent from the storage tank and deliver concentrated reagent to the storage tank one or more times.

[0026] In one or more embodiments, the storage tank is provided with a mixer arranged to homogenize by mixing the concentrated reagent stored in the storage tank.

[0027] In one or more embodiments, the storage tank is provided with at least one level sensor arranged to detect the reaching of a volume of concentrated reagent within the storage tank.

[0028] In one or more embodiments, the concentrated reagent is a dilution, lysis, sheathing, rinsing, or staining reagent.

[0029] In one or more embodiments, the reservoir is a reservoir of one or a combination of the following solvents: reverse osmosis water, distilled water, and organic solvents such as ethanol, methanol, or ethylene glycol.

[0030] The invention also relates to a method for producing concentrated reagent implemented by the device described above and comprising the following operations - withdraw solvent from the tank by opening the first valve, closing the second valve, and sucking up the solvent with the pump, - producing concentrated reagent within the container by closing the first valve, opening the second valve, and discharging the solvent with the pump such that a concentrated reagent is produced by dissolving at least part of the solid substance in the solvent, and - withdraw concentrated reagent from the container by aspirating the concentrated reagent with the pump.

[0031] The invention also relates to a system for producing reconstituted reagent comprising: - a dilution tank, - a device as described above and arranged to supply the dilution tank with concentrated reagent, and - a solvent tank designed to supply the dilution tank with solvent.

[0032] The dilution tank is arranged to produce a reconstituted reagent by diluting the concentrated reagent in the solvent.

[0033] Finally, the invention further relates to a method for producing reconstituted reagent implemented by the system described above and comprising the following operations: - supply, via the device, the dilution tank with concentrated reagent, - supply the dilution tank with solvent via the tank, and - produce, by the dilution tank, a reagent reconstituted by diluting the concentrated reagent in the solvent.

[0034] Other characteristics, details and advantages will appear on reading the detailed description below, and on analyzing the attached drawings in which:

[0035] [Fig.l] illustrates a device for producing concentrated reagent according to the invention;

[0036] [Fig.2] illustrates a process for producing concentrated reagent according to the invention;

[0037] [Fig.3] illustrates a reconstituted reagent production system according to the invention; and

[0038] [Fig.4] illustrates a process for producing reconstituted reagent according to the invention.

[0039] Fa [Fig.l] illustrates a device 1 for producing concentrated reagent.

[0040] The term "concentrated reagent" here refers to a liquid reagent whose concentration is higher than the working concentration, i.e. the concentration at which the reagent is ready to be used for a biological analysis. The concentrated reagent is therefore intended to be diluted.

[0041] More particularly, the device 1 is arranged to produce concentrated reagent by dissolving a solid substance in a solvent. The concentrated reagent therefore corresponds to a solution whose solute is the originally solid substance. As such, the “concentration” of the concentrated reagent here designates the proportion of solute in the solution.

[0042] For example, device 1 can be used to obtain a dilution, lysis, sheathing, rinsing or even staining reagent.

[0043] The device 1 is intended to be installed in a medical biology laboratory to meet its reagent needs. The device 1 can be used in the as part of a medical biology examination, and in particular for the purposes of in vitro diagnosis (also known by the English acronym IVD for “in-vitro diagnosis”) carried out from a sample of biological fluid.

[0044] The device 1 comprises a solvent reservoir 3, a container 5, a storage tank 7 for concentrated reagent, a pump 9 and a production circuit 11.

[0045] Tank 3 is arranged to store a solvent.

[0046] Typically, tank 3 is a reverse osmosis water tank, meaning purified water without chemicals or pollutants. Such water can be obtained using a reverse osmosis filter system.

[0047] The osmosis water stored in the tank 3 is advantageously Type II purified water obtained by combining reverse osmosis with demineralization. Such water contains a very low level of inorganic, organic or colloidal contaminants and has a resistivity greater than 1 MΩ.cm, and preferably between 10 and 15 MΩ.cm. Such water quality is that generally expected for laboratory applications. Of course, the osmosis water stored in the tank 3 may be of a higher quality (Type II+, Type I, or even Type I+).

[0048] Alternatively, tank 3 is a distilled water tank, i.e. purified water obtained by distilling drinking water. Distillation makes it possible to eliminate a large part of the organisms and mineral salts present in drinking water.

[0049] Still alternatively, reservoir 3 is a reservoir of an organic solvent such as ethanol, methanol or ethylene glycol. In particular, ethanol can dissolve a large number of ionic compounds such as sodium and potassium hydroxides, magnesium, calcium and ammonium chlorides or ammonium and sodium bromides.

[0050] Tank 3 can store a mixture of several of the previously mentioned solvents. For example, tank 3 can store a mixture of water - reverse osmosis or distilled - and organic solvent.

[0051] Tank 3 can also store several different solvents in separate compartments.

[0052] The container 5 is arranged to contain a solid substance intended to be dissolved in a solvent to produce a concentrated reagent. In the context of the invention, the solid substance has a solubility in water at 20°C greater than or equal to 340 grams per liter (g / L). The solid substance may be a simple body or a chemical compound.

[0053] Examples of solid substances are potassium chloride (KCl), sodium chloride (NaCl), tris(hydroxymethyl)aminomethane (often abbreviated as "tris") or tris-HCl.

[0054] The solid substance may be contained in the container 5 in the form of powder, pellets or granules.

[0055] The container 5 may be formed from a flexible or rigid material. The container 5 may be a flask, a jar, a bottle or, more generally, any container belonging to laboratory glassware and within which a dissolution can be carried out. The container 5 is not necessarily made of glass and may be, for example, made of stainless steel or ceramic. Advantageously, the container 5 is made of plastic, preferably polyethylene and even more preferably high-density polyethylene (also known by the acronym HDPE for “high-density polyethylene”).

[0056] As detailed in the remainder of the description, the concentrated reagent is produced within the container 5 by dissolving the solid substance in solvent supplied from the reservoir 3 when the device 1 is in operation. To facilitate the sampling of concentrated reagent, the container 5 can receive a sampling rod possibly equipped with a non-return valve.

[0057] The storage tank 7 is arranged to store concentrated reagent.

[0058] More particularly, the storage tank 7 is intended to store the concentrated reagent produced by dissolving, in the solvent supplied by the reservoir 3, the solid substance contained in the container 5.

[0059] As explained above, the concentrated reagent has a concentration higher than the working concentration. The Applicant has found that the device 1 makes it possible to obtain a concentrated reagent whose concentration is at least 60 times and up to 120 times higher than the working concentration.

[0060] The capacity of the storage tank 7 may therefore be lower than that of the storage tanks of known devices, which store a concentrated reagent obtained by mixing liquid reagent and purified water. Such storage tanks in fact store a concentrated reagent whose concentration is, at most, only 25 times higher than the working concentration. These storage tanks are heavy and bulky since they are sized to contain a high volume of concentrated reagent.

[0061] As an indication, the storage tank 7 has a volume typically between 0.35 and 6 liters (L), whereas known devices require the use of cubitainers with a capacity of 10 to 20 liters (L) to store the concentrated reagent. Such a reduced volume of concentrated reagent to be stored in the storage tank 7 can be produced from a solid substance whose mass is typically between 100 and 1700 grams (g), i.e. a mass much lower than the 10 or even 20 kilograms (kg) of liquid reagent required to supply known devices.

[0062] The pump 9 is arranged to move any liquid, whether solvent or concentrated reagent, within the production circuit 11, either by suction or by discharge. The advantage of the pump 9 is that it can move the desired volume. Typically, the pump 9 has an accuracy of the order of 0.5%.

[0063] The pump 9 is for example formed of a body within which a piston is arranged to slide so as to cause the circulation, within the production circuit 11, of a liquid by pressure exerted on it.

[0064] In the example of [Fig.l], the pump 9 is a syringe, therefore an instrument made of a barrel - which forms the body of the syringe - containing a piston and ending in a tip. The functions of withdrawal and injection of the syringe correspond to the functions of suction and discharge of the pump 9.

[0065] The piston may be controlled by a stepper motor, in which case the pump 9 and the stepper motor together form a motorized syringe. The stepper motor is arranged to transform an electrical impulse into a sliding of the piston within the body.

[0066] The production circuit 11 is arranged to allow the circulation of any liquid, whether solvent or concentrated reagent, between the reservoir 3, the container 5 and the storage tank 7.

[0067] Such circulation is caused and controlled by means of pump 9.

[0068] To this end, the production circuit 11 includes a conduit 13 provided with a valve 15 and which opens onto the tank 3, a conduit 17 provided with a valve 19 and which opens onto the container 5 as well as a conduit 21 provided with a valve 23 and which opens onto the storage tank 7.

[0069] The pump 9 is fluidically connected to the reservoir 3, the container 5 and the storage tank 7 respectively by the conduit 13, the conduit 17 and the conduit 21.

[0070] In the embodiment illustrated in [Fig.l], the conduits 13, 17 and 21 communicate with each other at a branch, which makes it possible to pass a liquid directly from one conduit to another.

[0071] Each of the valves 15, 19 and 23 is arranged to be opened or closed. When open, a valve allows the flow of liquid along the pipe on which it is mounted; conversely, when closed, a valve prevents the flow of liquid along the pipe.

[0072] A method for producing concentrated reagent implemented by the device 1 will now be described with reference to [Fig.2].

[0073] In the context of the implementation of this method, the container 5 contains a solid substance having a solubility in water at 20°C greater than or equal to 340 g / L.

[0074] During an operation 200, the device 1 operates in a solvent sampling mode.

[0075] To do this, valve 15 is open, while valves 19 and 23 are closed. In such a configuration of the production circuit 11, pump 9 communicates only with tank 3.

[0076] The pump 9 draws at least part of the solvent from the reservoir 3. The solvent taken circulates along the conduit 13, at least as far as the branch of the circuit of production 11 so that it can be subsequently transferred to another conduit. The solvent can, if necessary, be sucked up until it is received in part or in full in the pump 9.

[0077] During an operation 210, the device 1 operates according to a concentrated reagent production mode.

[0078] To do this, valve 19 is open, while valve 15 is closed. Valve 23 remains closed. In such a configuration of the production circuit 11, pump 9 communicates only with container 5.

[0079] The pump 9 delivers the solvent taken to the container 5. The solvent circulates along the conduit 17 until it is distributed to the container 5. It is possible to distribute only a portion of the solvent, in particular when the volume of solvent taken is in excess. Furthermore, it is possible to distribute the solvent to the container 5 in several batches.

[0080] The solvent, once poured through the conduit 17 into the container 5, comes into contact with the solid substance. Due to its high solubility, at least part of the solid substance dissolves in the solvent, almost immediately.

[0081] Generally speaking, a dissolution results in the formation of a solution, that is to say a homogeneous mixture comprising a solvent and one or more solutes. In the present case, the dissolution carried out within the container 5 makes it possible to obtain a solution whose solvent is that taken from the reservoir 3 and whose solute is the originally solid substance. When the solvent used is purified water such as osmosis water or distilled water, such a solution can be described as an aqueous solution.

[0082] The solution obtained corresponds to the concentrated reagent that device 1 is designed to produce.

[0083] During an operation 220, pump 9 sucks up the concentrated reagent produced.

[0084] To do this, the configuration of the production circuit 11 is identical to that of operation 210: valve 17 is open, while valves 15 and 23 are closed.

[0085] In practice, the volume sucked up by the pump 9 during this operation 220 is greater than the volume sucked up during operation 200 given that the concentrated reagent comprises both the solvent taken during operation 200 and at least part of the solid substance, which is present in the concentrated reagent in the form of solute. It is however possible to take only part of the concentrated reagent from the container 5.

[0086] The concentrated reagent circulates along the conduit 17, at least as far as the branch of the production circuit 11 so that it can be subsequently transferred to another conduit. The concentrated reagent can, if necessary, be sucked up until it is received in part or in full in the pump 9.

[0087] During an operation 230, the device 1 operates according to a storage mode of concentrated reagent.

[0088] To do this, valve 23 is open, while valve 17 is closed. Valve 15 remains closed. In such a configuration of the production circuit 11, pump 9 communicates only with storage tank 7.

[0089] Pump 9 delivers the concentrated reagent taken to storage tank 7. The concentrated reagent circulates along conduit 21 until it is distributed to storage tank 7.

[0090] The sequence of operations 200, 210, 220 and 230 corresponds to a cycle of production and storage of concentrated reagent.

[0091] Each cycle makes it possible to dissolve at least part of the solid substance contained in the container 5 and to convey the concentrated reagent resulting from this dissolution to the storage tank 7. It may be necessary to carry out several cycles to dissolve all of the solid substance contained in the container 5. Advantageously, the total volume of solvent taken is substantially equal to the minimum volume of solvent necessary to completely dissolve the solid substance contained in the container 5. By "substantially equal" is meant here that, ideally, the total volume of solvent taken is equal to the minimum volume of solvent necessary; however, in practice, the total volume of solvent actually taken may differ slightly from the minimum volume of solvent necessary.

[0092] For illustration, dissolving a 200 gram (g) quantity of powder contained in container 5 may require between 30 and 300 cycles, each cycle producing between 2 and 20 milliliters (mL) of concentrated reagent.

[0093] Once the solid substance has been completely dissolved, the volume of concentrated reagent stored in the storage tank 7 is known since it comprises, on the one hand, the volume corresponding to the solid substance initially contained in the container 5 and, on the other hand, the total volume of solvent withdrawn. Consequently, the concentration of the concentrated reagent is also known.

[0094] Finally, during an optional operation 240, the device 1 operates according to a concentrated reagent homogenization mode.

[0095] To do this, the configuration of the production circuit 11 is identical to that of operation 230: valve 23 is open, while valves 15 and 19 are closed.

[0096] The pump 9 draws concentrated reagent from the storage tank 7 and then delivers the drawn concentrated reagent to the storage tank 7. The concentrated reagent thus circulates along the conduit 21 in one direction and then in the other. These alternating suction and discharge operations can be repeated several times to cause agitation within the storage tank 7, which makes it possible to homogenize the concentrated reagent.

[0097] Operation 240 can be implemented both at the end of one or more cycles of production and storage of concentrated reagent and at the end of all the cycles. production and storage of concentrated reagent, i.e. when the solid substance has been completely dissolved.

[0098] The table below summarizes the operating modes of device 1 with, each time, the corresponding configuration of the production circuit 11:

[0099] The Applicant has noted that the process for producing concentrated reagent described above and implemented by device 1 makes it possible, on average, to dissolve in one hour a mass of solid substance of between 100 and 1700 grams (g) and to produce a volume of concentrated reagent of between 0.35 and 6 liters (L).

[0100] The concentrated reagent stored in storage tank 7 has a higher concentration than the working concentration. Therefore, in order to be used to analyze a biological fluid sample, for example a blood sample in a hematology examination, the concentrated reagent must be diluted to reach the working concentration.

[0101] To do this, the device 1 can be integrated or coupled to a reconstituted reagent production system arranged to dilute the concentrated reagent until the working concentration is reached.

[0102] The term "reconstituted reagent" here refers to a liquid reagent whose concentration is lower than that of the concentrated reagent, and is as close as possible to the working concentration. Such a concentration is achieved by mixing the concentrated reagent with a solvent to reduce the proportion of solute in the diluted solution.

[0103] Those skilled in the art know that there are various systems capable of producing reconstituted reagent from concentrated reagent. Such systems for producing reconstituted reagent comprise at least one source of concentrated reagent, a solvent reservoir and a dilution tank. The source of concentrated reagent and the solvent reservoir are arranged to supply the dilution tank with concentrated reagent and solvent respectively; and the dilution tank is arranged to produce reconstituted reagent by diluting the concentrated reagent in the solvent.

[0104] In the present case, the source of concentrated reagent is device 1.

[0105] Reference is now made to [Fig. 3] in which the device 1 forms part of a system 25 for producing reconstituted reagent.

[0106] The system 25 is arranged to prepare a reconstituted reagent ready to be used for biological analysis. Such preparation comprises, firstly, the production of concentrated reagent using the device 1 described above and, secondly, the dilution of the concentrated reagent in a solvent.

[0107] It should first be noted that the device 1 illustrated in [Fig. 3] has some differences from that of [Fig. 1]. In particular, the storage tank 7 is provided with a mixer 27, a low level sensor 29 and a high level sensor 31.

[0108] The mixer 27 is arranged to mix the concentrated reagent stored in the storage tank 7 to promote homogenization of the concentrated reagent.

[0109] The mixer 27 may take the form of a blade mounted to rotate within the storage tank 7 and whose drive is controlled by a motor. Such a blade makes it possible, when driven by the motor, to stir the concentrated reagent.

[0110] Alternatively, the mixer 27 is a static mixer, for example a static plate mixer capable of generating strong turbulence in the flow of the concentrated reagent when it is crossed by the latter.

[0111] The mixer 27 can be used in addition to or instead of the concentrated reagent homogenization mode of the device 1 during operation 240 of the concentrated reagent production method of [Fig. 2].

[0112] The low level sensor 29 is arranged to detect when the concentrated reagent reaches a predetermined minimum volume. In particular, when the volume of concentrated reagent is less than this minimum volume, the low level sensor 29 makes it possible to signal that the volume of concentrated reagent is insufficient and therefore that the storage tank 7 must be replenished.

[0113] The storage tank 7 is filled in about one hour while the concentrated reagent is consumed on demand in one or more days. The low level sensor 29 therefore makes it possible to prevent a possible shortage of concentrated reagent.

[0114] The high level sensor 31 is used exceptionally, that is to say in the event of loss of information regarding the volume of concentrated reagent contained in the storage tank 7. In fact, the storage tank 7 must be filled up to the high level sensor 31 to rinse it before emptying it.

[0115] In the example of [Eig.3], the system 25 comprises, in addition to the device 1, a dilution tank 33 for concentrated reagent, an additional pump 35 and a dilution circuit 37. A configuration in which a single pump is used and fulfills the functions of the pump 9 and the additional pump 35 is also possible.

[0116] The dilution tank 33 is arranged to bring the concentrated reagent and the solvent together so as to reduce the concentration of the concentrated reagent, and this until ideally achieve the working concentration to obtain reconstituted reagent. In practice, the dilution tank 33 makes it possible to achieve a concentration as close as possible to the working concentration.

[0117] As a guide, the dilution tank 33 has a volume typically between 0.05 and 0.5 liters (L).

[0118] Furthermore, in the example of [Fig. 3], the dilution tank 33 is equipped with a mixer 39, a low level sensor 41, a high level sensor 43 and a conductivity measuring probe 45.

[0119] The mixer 39 is arranged to mix the reconstituted reagent stored in the dilution tank 33 to promote homogenization of the reconstituted reagent.

[0120] Like the mixer 27 of the storage tank 7, the mixer 39 can take the form of a blade mounted to rotate within the dilution tank 33 and whose drive is controlled by a motor, or of a static mixer such as a static plate mixer.

[0121] The low level sensor 41 is arranged, when the volume of reconstituted reagent is less than a predetermined minimum volume, to signal that the volume of reconstituted reagent is insufficient and therefore that the dilution tank 33 must be replenished.

[0122] The high level sensor 43 is arranged, when the volume of reconstituted reagent is greater than a predetermined maximum volume, to signal that the volume of reconstituted reagent is sufficient - or even that a surplus of reconstituted reagent is present - and therefore that the supply of the dilution tank 33 must cease.

[0123] The probe 45 is arranged to measure the conductivity of the reconstituted reagent within the dilution tank 33.

[0124] The conductivity of the reconstituted reagent depends on its concentration. Therefore, measuring the conductivity allows us to estimate the concentration of the reconstituted reagent and verify that it is the expected concentration.

[0125] It should be noted that physical or chemical measurements other than the conductivity measurement may be used to verify that the concentration of the reconstituted reagent is consistent with the target concentration. For example, the probe 45 may be arranged to measure the hydrogen potential (pH) of the reconstituted reagent.

[0126] The pump 35 is arranged to move any liquid, whether solvent or concentrated reagent, within the dilution circuit 37, either by suction or by discharge. The pump 35 has the advantage of being able to move the desired volume. Typically, the pump 35 has an accuracy of the order of 0.5%.

[0127] The pump 35 is for example formed of a body within which a piston is arranged to slide so as to cause the circulation, within the dilution circuit 37, of a liquid by pressure exerted on it.

[0128] In the example of [Fig.3], the pump 35 is a syringe, which can be coupled with a stepper motor to form a motorized syringe.

[0129] The dilution circuit 37 is arranged to allow the circulation of any liquid, whether solvent or concentrated reagent, between the storage tank 7, a solvent reservoir and the dilution tank 33.

[0130] Such circulation is caused and controlled by means of pump 35.

[0131] To this end, the dilution circuit 37 includes a conduit 47 provided with a valve 49 and which opens onto the storage tank 7, a conduit 51 provided with a valve 53 and which opens onto the reservoir 3 as well as a conduit 55 provided with a valve 57 and which opens onto the dilution tank 33.

[0132] The pump 35 is fluidically connected to the storage tank 7, the solvent reservoir and the dilution tank 33 respectively by the conduit 47, the conduit 51 and the conduit 55.

[0133] In the example of [Fig. 3] and in the remainder of the description, the solvent tank connected to the dilution circuit 37 is the tank 3 already connected to the production circuit 11. However, the system 25 may comprise two separate solvent tanks.

[0134] In the embodiment illustrated in [Fig. 3], the conduits 47, 51 and 55 communicate with each other at a branch, which makes it possible to pass a liquid directly from one conduit to another.

[0135] Each of the valves 49, 53 and 57 is arranged to be open or closed, and thus to selectively allow or prevent the circulation of liquid along the corresponding conduit.

[0136] The assembly formed by the solvent reservoir - here reservoir 3 -, the dilution tank 33, the pump 35 and the dilution circuit 37 can be likened to a dilution device.

[0137] A method of producing reconstituted reagent implemented by the system 25 will now be described with reference to [Fig.4].

[0138] An initial operation 400 corresponds to the production of concentrated reagent carried out by the device 1. Such production of concentrated reagent is implemented according to the method of [Fig.2] and results in the storage, in the storage tank 7, of the concentrated reagent obtained by dissolving the solid substance - contained in the container 5 - in the solvent supplied by the reservoir 3.

[0139] During an operation 410, the system 25 operates in a concentrated reagent sampling mode.

[0140] To do this, valve 49 is open, while valves 53 and 57 are closed. In such a configuration of the dilution circuit 37, the pump 35 communicates only with the storage tank 7.

[0141] The pump 35 draws at least part of the concentrated reagent from the storage tank 7. The concentrated reagent taken circulates along the conduit 47, at least until the branch of the dilution circuit 37 so that it can be subsequently transferred to another conduit. The concentrated reagent can, if necessary, be sucked up until it is received in part or in whole in the pump 35.

[0142] It is also preferable to close the valve 23 to allow the pump 35 to suck up the concentrated reagent more efficiently and to avoid sucking up residual liquids from the production circuit 11.

[0143] During an operation 420, the system 25 operates in a concentrated reagent delivery mode.

[0144] To do this, valve 57 is open, while valve 49 is closed. Valve 53 remains closed. In such a configuration of the dilution circuit 37, pump 35 communicates only with the dilution tank 33.

[0145] The pump 35 delivers the concentrated reagent taken to the dilution tank 33. The concentrated reagent circulates along the conduit 55 until it is distributed to the dilution tank 33.

[0146] The sequence of operations 410 and 420 corresponds to a cycle of transferring concentrated reagent into the dilution tank 33. Such a cycle can be repeated several times, including consecutively, to transfer the desired volume of concentrated reagent into the dilution tank 33.

[0147] During an operation 430, the system 25 operates in a solvent sampling mode.

[0148] To do this, valve 53 is open, while valve 57 is closed. Valve 49 remains closed. In such a configuration of the dilution circuit 37, pump 35 communicates only with tank 3.

[0149] The pump 35 draws at least part of the solvent from the reservoir 3. The solvent drawn off circulates along the conduit 51, at least as far as the branch of the dilution circuit 37 so that it can be subsequently transferred to another conduit. The solvent can, if necessary, be drawn up until it is received in part or in full in the pump 35.

[0150] During an operation 440, the system 25 operates in a concentrated reagent dilution mode.

[0151] To do this, valve 57 is open, while valve 53 is closed. Valve 49 remains closed. In such a configuration of the dilution circuit 37, the pump 35 communicates only with the dilution tank 33.

[0152] The pump 35 delivers the solvent taken to the dilution tank 33. The solvent circulates along the conduit 55 until it is distributed to the dilution tank 33. It is possible to distribute only a portion of the solvent, in particular when the volume of solvent taken is in excess. Furthermore, it is possible to distribute the solvent to the dilution tank 33 in several batches.

[0153] The solvent, once poured through line 55 into the dilution tank 33, mixes with the concentrated reagent, which is then diluted.

[0154] The sequence of operations 430 and 440 corresponds to a solvent transfer cycle in the dilution tank 33. Such a cycle can be repeated several times, including consecutively, to transfer the desired volume of solvent into the dilution tank 33.

[0155] In the example in [Fig.4], the concentrated reagent transfer cycle is performed before the solvent transfer cycle. However, the concentrated reagent transfer cycle can be performed after the solvent transfer cycle.

[0156] Finally, during an optional operation 450, the system 25 operates according to a reconstituted reagent homogenization mode.

[0157] To do this, the configuration of the dilution circuit 37 is identical to that of operation 420 and operation 440: valve 57 is open, while valves 49 and 53 are closed.

[0158] The pump 35 draws reconstituted reagent from the dilution tank 33 and then delivers the drawn reconstituted reagent to the dilution tank 33. The reconstituted reagent thus circulates along the conduit 55 in one direction and then in the other. These alternating suction and discharge operations can be repeated several times to cause agitation within the dilution tank 33, which makes it possible to homogenize the reconstituted reagent.

[0159] It should be noted that the mixer 39 can be used in addition to or instead of the reconstituted reagent homogenization mode of the system 25.

[0160] The table below summarizes the operating modes of the system 25 with, each time, the corresponding configuration of the dilution circuit 37:

[0161] The Applicant has found that the process for producing reconstituted reagent described above and implemented by the system 25 offers a medical biology laboratory autonomy ranging from half a day to several days, which leaves sufficient time to replace the container 5 without interrupting the routine since, as mentioned above, the dissolution of the solid substance takes on average only one hour.

[0162] Referring again to [Fig. 3], the system 25 is coupled to a distribution circuit 59.

[0163] The distribution circuit 59 is arranged to distribute the reconstituted reagent from the dilution tank 33 to one or more biological analysis devices 61.

[0164] Each biological analysis device 61 is arranged to analyze a sample of biological fluid, for example a sample of blood, urine, cerebrospinal fluid, pleural fluid, synovial fluid or bone marrow taken during a puncture. The operation of such a biological analysis device 61 is based on the use of one or more reagents such as dilution, lysis, sheathing, rinsing or coloring reagents.

[0165] To make the reconstituted reagent available to the biological analysis devices 61, the distribution circuit 59 may comprise, as illustrated in [Fig. 3], a distribution tank 63, which is fluidically connected to each biological analysis device 61.

[0166] As an indication, the distribution tank 63 has a volume typically between 3 and 10 liters (L).

[0167] The distribution tank 63 is further fluidically connected to the distribution tank 33 by a conduit 65 provided with a valve 67, a transfer pump 69 and a filter 71.

[0168] The valve 67 is arranged to be open or closed, and thus to selectively allow or prevent the circulation of reconstituted reagent along the conduit 65.

[0169] The transfer pump 69 is arranged, when the valve 67 is open, to convey the reconstituted reagent to the distribution tank 63.

[0170] The filter 71 is arranged to filter the reconstituted reagent which circulates along the conduit 65 so as to eliminate impurities likely to subsequently alter the operation of a biological analysis device 61. Typically, the filter 71 makes it possible to stop all foreign bodies of dimensions less than 0.2 micrometers (pm), and preferably less than 0.5 micrometers (pm).

[0171] In the example of [Fig. 3], the distribution tank 63 is provided with a low level sensor 73 and a high level sensor 75.

[0172] The low level sensor 73 is arranged, when the volume of reconstituted reagent to be dispensed is less than a predetermined minimum volume, to signal that the volume of reconstituted reagent to be dispensed is insufficient and therefore that the dispensing tank 63 must be replenished.

[0173] The high level sensor 75 is arranged, when the volume of reconstituted reagent to be dispensed is greater than a predetermined maximum volume, to signal that the volume of reconstituted reagent to be dispensed is sufficient - or even that a surplus of reconstituted reagent is present - and therefore that the supply of the dispensing tank 63 must stop.

[0174] In the example of [Fig. 3], the distribution circuit 59 further comprises a waste container 77 into which liquids can be discharged, whether concentrated reagent or reconstituted reagent.

[0175] To do this, the distribution tank 63 is fluidically connected to the waste tank 77 by a conduit 79 provided with a valve 81; the storage tank 7 is fluidically connected to the waste tank 77 by a conduit 83 provided with a valve 85; and the dilution tank 33 is fluidically connected to the waste tank 77 by a conduit 87 provided with a valve 89.

[0176] Each of the valves 81, 85 and 89 is arranged to be open or closed, and therefore to selectively allow or prevent the circulation of the liquid to be discharged along the corresponding conduit.

[0177] Furthermore, the transport to the waste tank 77 of the liquid to be evacuated is ensured, whatever the case, by a transfer pump 91.

[0178] [Fig. 3] and [Fig. 4] describe a configuration in which the device 1 is integrated into a reconstituted reagent production system, namely here the system 25. However, the device 1 can be used to directly produce reconstituted reagent, in which case the device 1 alone forms a reconstituted reagent production system. In such a configuration, the storage tank 7 is then also a dilution tank.

[0179] The difference between a concentrated reagent and a reconstituted reagent lies in the concentration. Therefore, the conversion of the device 1 into a reconstituted reagent production system can be achieved by increasing the total volume of solvent taken from the reservoir 3 and delivered to the container 5. In other words, the total volume of solvent used is no longer the minimum volume necessary to completely dissolve the solid substance contained in the container 5 but corresponds to the volume allowing the working concentration to be reached within the storage tank 7.

[0180] Each cycle corresponding to the sequence of operations 200, 210, 220 and 230 of [Fig. 2] is then a cycle of production and storage of reconstituted reagent, which means that the sum of the volumes of solvent withdrawn during the respective cycles, and more precisely during operation 200 of each cycle, is substantially equal to a volume such that the ratio of the total mass of solid substance to this volume is equal to the working concentration. By "substantially equal" is meant here that, ideally, the total volume of solvent withdrawn is equal to the volume making it possible to reach, in the storage tank 7, the working concentration; however, in practice, the total volume of solvent actually withdrawn may differ slightly from this desired volume.

[0181] Still on the principle of using device 1 to directly produce reconstituted reagent, it is also possible to proceed in the same way as described above with reference to [Fig.2], that is to say by implementing several cycles of production and storage of concentrated reagent until the solid substance is completely dissolved, then feeding the storage tank 7 with solvent to reach the working concentration.

[0182] To do this, the device 1 can implement the following additional operations: open the valve 15, close the valves 19 and 23, and take solvent from the tank 3 by sucking it up with the pump 9; then close the valve 15, open the valve 23 and convey the taken solvent to the storage tank 7 by discharging it with the pump 9. These additional operations can be implemented as many times as necessary to reach the working concentration and therefore to produce, within the storage tank 7, reconstituted reagent.

Claims

Claims

1. Device (1) for producing concentrated reagent comprising: - a solvent reservoir (3), - a container (5), which contains a solid substance having a solubility in water at 20°C greater than or equal to 340 g / L, - a pump (9), and - a production circuit (11) including a first conduit (13) provided with a first valve (15) and a second conduit (17) provided with a second valve (19), which pump (9) is fluidically connected to the reservoir (3) and to the container (5) respectively by the first conduit (13) and the second conduit (17), which device (1) is arranged to operate at least according to: a solvent withdrawal mode in which the first valve (15) is open, the second valve (19) is closed, and the pump (9) is arranged to suck up solvent from the reservoir (3), and a concentrated reagent production mode in which the first valve (15) is closed, the second valve (19) is open, and the pump (9) is arranged to deliver solvent to the container (5) such that a concentrated reagent is produced by dissolving at least part of the solid substance in the solvent and to suck up concentrated reagent from the container (5).

2. Device (1) according to claim 1, which device (1) further comprises a storage tank (7) for concentrated reagent, wherein the production circuit (11) further includes a third conduit (21) provided with a third valve (23), and the pump (9) is further fluidically connected to the storage tank (7) by the third conduit (21), which third valve (23) is closed in the solvent withdrawal mode and the concentrated reagent production mode of the device (1), which device (1) is arranged to operate further in a concentrated reagent storage mode in which the first valve (15) is closed, the second valve (19) is closed, the third valve (23) is open, and the pump (9) is arranged to discharge concentrated reagent to the storage tank (7).

3. Device (1) according to claim 2, which device (1) is arranged to operate further in a reagent homogenization mode. concentrate in which the first valve (15) is closed, the second valve (19) is closed, the third valve (23) is open, and the pump (9) is arranged to alternately draw concentrated reagent from the storage tank (7) and deliver said concentrated reagent to the storage tank (7) one or more times.

4. Device (1) according to claim 2 or 3, wherein the storage tank (7) is provided with a mixer (27) arranged to homogenize by mixing the concentrated reagent stored in the storage tank (7).

5. Device (1) according to one of claims 2 to 4, in which the storage tank (7) is provided with at least one level sensor (29) arranged to detect the reaching of a volume of concentrated reagent within the storage tank (7).

6. Device (1) according to one of the preceding claims in which the concentrated reagent is a dilution, lysis, sheathing, rinsing or staining reagent.

7. Device (1) according to one of the preceding claims, wherein the reservoir (3) is a reservoir of one or a combination of the following solvents: osmosis water, distilled water and organic solvents such as ethanol, methanol or ethylene glycol.

8. Method for producing concentrated reagent implemented by the device (1) according to one of the preceding claims and comprising the following operations: - withdraw (200) solvent from the tank (3) by opening the first valve (15), closing the second valve (19), and sucking up said solvent with the pump (9), - producing (210) concentrated reagent within the container (5) by closing the first valve (15), opening the second valve (19), and discharging said solvent with the pump (9) such that a concentrated reagent is produced by dissolving at least part of the solid substance in said solvent, and - withdrawing (220) concentrated reagent from the container (5) by sucking up said concentrated reagent with the pump (9).

9. System (1, 25) for producing reconstituted reagent comprising: - a dilution tank (7, 33), - a device (1) according to one of claims 1 to 7 arranged to supply the dilution tank (7, 33) with concentrated reagent, and - a solvent reservoir (3) arranged to supply the dilution tank (7, 33) with solvent, which dilution tank (7, 33) is arranged to produce a reconstituted reagent by diluting the concentrated reagent in the solvent.

10. A method of producing reconstituted reagent implemented by the system (1, 25) according to claim 9 and comprising the following operations: - supply, via the device (1), the dilution tank (7, 33) with concentrated reagent, - supply, via the tank (3), the dilution tank (7, 33) with solvent, and - produce, by the dilution tank (7, 33), a reagent reconstituted by dilution of the concentrated reagent in the solvent.

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