Device and method for producing concentrated reagent from a solid substance

Abstract

The invention relates to a device (1) for producing concentrated reagent comprising: - a solvent reservoir (3), - a container (5) containing 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) equipped with a first valve (15) and a second conduit (17) equipped with a second valve (19). The pump (9) is fluidically connected to the reservoir (3) and the container (5) respectively by the first conduit (13) and the second conduit (17). The pump (9) draws solvent from the reservoir (3) and then pumps 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. [Fig. 1]

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 purpose of analyzing a sample of biological fluid, particularly in hematology.

[0002] Medical biology is a specialty that consists of analyzing biological fluids in order to determine the pathophysiological origin of a disease. A medical biology examination can also contribute to the prevention, screening, diagnosis, or risk assessment of pathological conditions, as well as to the determination or monitoring of 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 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 biological fluid sample from the patient, as well as the preparation, transport and storage of the sample; - an analytical phase, which corresponds to the technical process for obtaining 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 evaluated with two parameters: sample processing time (often referred to by the English acronym TAT for "tumaround time") and full-time equivalent (often referred to by the English acronym FTE for "full-time equivalent"), which measures the workload of the staff required for the operation of the medical biology laboratory.

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

[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 may be diluted and treated with one or more reagents. The sample may then be sent to an automated flow cytometer—that is, one that uses the principle of flow cytometry—capable of counting and identifying the particles present in the sample by electrical and / or optical measurements.

[0008] For example, in hematology, an automated analyzer dedicated to counting and differentiating blood cells typically uses dilution, staining, lysis, and sheathing reagents. In particular, the staining reagent allows the blood sample to be mixed with fluorochromes during preparation to facilitate subsequent differentiation; and the sheathing reagent—also called sleeving fluid—allows the blood sample to be stretched and guided within the analyzer.

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

[0010] In particular, a complete blood count (often referred to by the English acronym CBC for "complete blood count") - also called a hemogram - is often preceded by a dilution, which reduces the concentration of blood cells in a blood sample to facilitate counting.

[0011] Supplying a medical biology laboratory with reagents often requires dedicated staff, who face handling challenges. The reagents are stored in large containers – called cubitainers – which are heavy, bulky, and must be replenished frequently throughout the day.

[0012] To mitigate these constraints, it is known to produce reagents in situ at a so-called "working" concentration, that is, reagents ready for use in biological analysis. To achieve this, some medical biology laboratories use devices capable of producing reagent at a working concentration from a concentrated reagent and reverse osmosis water. The 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 B1 provides for this purpose a diluent preparation module consisting of a combining element ("combinerfeature") connected, on the one hand, to a purified water source and, on the other hand, to a reagent concentrate container ("reagent concentrate"). The combining element is arranged to mix the purified water and the reagent concentrate so as to produce a diluent which is then stored pending delivery to an analyzer.

[0014] European patent EP 2 175 340 B1 describes, on the same principle, a reagent preparation apparatus comprising a constant amount liquid quantifying unit equipped with an instrument capable of simultaneously maintaining a 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, such a concentrated reagent is at best a reagent concentrated to x25, that is, a reagent whose concentration is only 25 times greater 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 resulting concentrated reagent.

[0017] Such a low concentration results in a high consumption of concentrated reagent. In general, the manufacture of concentrated reagent from liquid reagent causes logistical problems similar to those described above and related 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 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 reservoir, - 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 connected in a fluidic manner to the reservoir and the container respectively by the first conduit and the second conduit.

[0022] The device is arranged to operate at least according to: a solvent withdrawal method 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 method of producing concentrated reagent in which the first valve is closed, the second valve is opened, and the pump is arranged to pump solvent back to the container in such a way 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 comprises a concentrated reagent storage tank, the production circuit further comprises a third conduit equipped with a third valve, and the pump is fluidically connected to the storage tank via the third conduit. The third valve is closed in both the solvent withdrawal and concentrated reagent production modes of the device.

[0024] The device is arranged to operate further 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 pump concentrated reagent to the storage tank.

[0025] In one or more embodiments, the device is arranged to operate further according to 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 pump the concentrated reagent back to the storage tank one or more times.

[0026] In one or more embodiments, the storage tank is equipped 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 equipped with at least one level sensor arranged to detect when a certain volume of concentrated reagent has been reached within the storage tank.

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

[0029] In one or more embodiments, the reservoir 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.

[0030] The invention also relates to a method for producing concentrated reagent implemented by the device described above and comprising the following operations - to draw solvent from the reservoir by opening the first valve, closing the second valve, and drawing the solvent with the pump, - produce concentrated reagent within the container by closing the first valve, opening the second valve, and expelling the solvent with the pump in such a way that 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 reconstituted reagent production system comprising: - a dilution tank, - a device such as described above, arranged to supply the dilution tank with concentrated reagent, and - a solvent reservoir arranged 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 process for producing reconstituted reagent implemented by the system described above and comprising the following operations: - to supply the dilution tank with concentrated reagent via the device, - to supply the solvent dilution tank via the reservoir, and - to produce, via the dilution tank, a reagent reconstituted by dilution of the concentrated reagent in the solvent.

[0034] Other features, details and advantages will become apparent upon reading the detailed description below, and upon analysis of the accompanying drawings on which:

[0035] [Fig.1] illustrates a concentrated reagent production device according to the invention;

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

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

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

[0039] Fig. 1 illustrates a device 1 for the production of concentrated reagent.

[0040] The term "concentrated reagent" here refers to a liquid reagent whose concentration is higher than the working concentration, that is, 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 specifically, device 1 is arranged to produce concentrated reagent by dissolving a solid substance in a solvent. The concentrated reagent therefore corresponds to a solution in which the solute is the originally solid substance. As such, the "concentration" of the concentrated reagent here refers to the proportion of solute in the solution.

[0042] By way of example, device 1 can be used to obtain a reagent for dilution, lysis, sheathing, rinsing or coloring.

[0043] Device 1 is intended to be installed in a medical biology laboratory to meet its reagent requirements. Device 1 can be used in the within the framework 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 diagnostic") carried out from a sample of biological fluid.

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

[0045] The reservoir 3 is arranged to store a solvent.

[0046] Typically, tank 3 is a tank of reverse osmosis water, that is, purified water free of chemicals and pollutants. Such water can be obtained using a reverse osmosis filter system.

[0047] The reverse osmosis water stored in 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. This water quality is generally expected for laboratory applications. Of course, the reverse osmosis water stored in tank 3 can be of a higher quality (Type II+, Type I, or even Type I+).

[0048] Alternatively, reservoir 3 is a distilled water reservoir, that is, 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] 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] The reservoir 3 can store a mixture of several of the solvents mentioned above. For example, the reservoir 3 can store a mixture of water – either reverse osmosis or distilled – and an organic solvent.

[0051] The reservoir 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 an element or a chemical compound.

[0053] The solid substance is for example potassium chloride (KCl), sodium chloride (NaCl), tris(hydroxymethyl)aminomethane (often abbreviated "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 made of a flexible or rigid material. The container 5 may be a flask, jar, bottle, or, more generally, any container belonging to laboratory glassware in which a dissolution can be carried out. The container 5 is not necessarily made of glass and may, for example, be 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 as HDPE).

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

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

[0058] More specifically, 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 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 can 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 store a concentrated reagent whose concentration is, at most, only 25 times greater than the working concentration. These storage tanks are heavy and bulky since they are designed to contain a large volume of concentrated reagent.

[0061] By way of example, the storage tank 7 typically has a volume of 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 small volume of concentrated reagent to be stored in the storage tank 7 can be produced from a solid substance with a mass typically between 100 and 1700 grams (g), a mass much smaller 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 on the order of 0.5%.

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

[0064] In the example of [Fig. 1], 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 nozzle. The syringe's sampling and injection functions correspond to the suction and delivery functions of the pump 9.

[0065] The piston can 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 motion 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 equipped with a valve 15 and which leads to reservoir 3, a conduit 17 equipped with a valve 19 and which leads to container 5, and a conduit 21 equipped with a valve 23 and which leads to storage tank 7.

[0069] The pump 9 is connected in a fluidic manner 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.1], conduits 13, 17 and 21 communicate with each other at a branch, which allows a liquid to pass directly from one conduit to another.

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

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

[0073] In the context of implementing this process, 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 according to a solvent sampling mode.

[0075] To achieve this, valve 15 is opened, 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 some of the solvent from the reservoir 3. The extracted solvent flows along the conduit 13, at least as far as the branch of the circuit of production 11 in such a way that it can be subsequently transferred to another conduit. The solvent can, if necessary, be drawn up until it is partially or completely received in pump 9.

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

[0078] To achieve this, valve 19 is opened, while valve 15 is closed. Valve 23 remains closed. In this configuration of the production circuit 11, the pump 9 communicates only with the vessel 5.

[0079] Pump 9 delivers the extracted solvent to container 5. The solvent flows along conduit 17 until it is dispensed into container 5. It is possible to dispense only a portion of the solvent, particularly when there is an excess of solvent extracted. Furthermore, it is possible to dispense the solvent into container 5 in several stages.

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

[0081] Generally speaking, dissolution results in the formation of a solution, that is, a homogeneous mixture comprising a solvent and one or more solutes. In the present case, the dissolution carried out in container 5 yields a solution in which the solvent is that taken from reservoir 3 and the solute is the originally solid substance. When the solvent used is purified water such as reverse 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 arranged to produce.

[0083] During an operation 220, the pump 9 draws in 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 aspirated by pump 9 during this operation 220 is greater than the volume aspirated during operation 200, since the concentrated reagent comprises both the solvent withdrawn during operation 200 and at least part of the solid substance, which is present in the concentrated reagent as a solute. However, it is possible to withdraw only a portion of the concentrated reagent from container 5.

[0086] The concentrated reagent flows along the conduit 17, at least as far as the branch of the production circuit 11, so that it can subsequently be transferred to another conduit. The concentrated reagent can, if necessary, be drawn off until it is partially or completely received in the pump 9.

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

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

[0089] Pump 9 pumps the concentrated reagent taken from the storage tank 7. The concentrated reagent flows along the conduit 21 until it is distributed to the 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 withdrawn is substantially equal to the minimum volume of solvent required to completely dissolve the solid substance contained in the container 5. By "substantially equal" is meant here that, ideally, the total volume of solvent withdrawn is equal to the minimum volume of solvent required; however, in practice, the total volume of solvent actually withdrawn may differ slightly from the minimum volume of solvent required.

[0092] By way of illustration, the dissolution of a quantity of 200 grams (g) of powder contained in container 5 may require between 30 and 300 cycles, each cycle producing between 2 and 20 millilitres (mL) of concentrated reagent.

[0093] Once the solid substance has 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 mode of homogenization of concentrated reagent.

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

[0096] Pump 9 draws concentrated reagent from storage tank 7 and then discharges the drawn-in concentrated reagent back into storage tank 7. The concentrated reagent thus flows along conduit 21 in one direction and then the other. These alternating suction and discharge cycles can be repeated several times to create agitation within storage tank 7, thereby homogenizing the concentrated reagent.

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

[0098] The table below summarizes the operating modes of device 1 with, in each case, the corresponding configuration of the production circuit 11: Valve 15 Valve 19 Valve 23 Solvent sampling method open closed closed Concentrated reagent production method closed open closed Concentrated reagent storage method closed closed open Concentrated reagent homogenization method closed closed open

[0099] The Applicant has observed that the concentrated reagent production process 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 the storage tank 7 has a higher concentration than the working concentration. Therefore, in order to be used to analyze a sample of biological fluid, 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 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 resulting 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 device 1 forms part of a System 25 for the production of reconstituted reagent.

[0106] The system 25 is arranged to prepare a reconstituted reagent ready for use in biological analysis. Such preparation includes, 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 compared to that of [Fig.1]. In particular, the storage tank 7 is equipped 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 can take the form of a rotating blade mounted within the storage tank 7 and driven by a motor. Such a blade, when driven by the motor, stirs 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 traversed by the latter.

[0111] The mixer 27 can be used in addition to or instead of the concentrated reagent homogenization mode of device 1 during operation 240 of the concentrated reagent production process 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 signals 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 approximately one hour, while the concentrated reagent is consumed on demand over one or more days. The low-level sensor 29 therefore prevents a potential shortage of concentrated reagent.

[0114] The high level sensor 31 is used on an exceptional basis, i.e. in case of loss of information regarding the volume of concentrated reagent contained in the storage tank 7. It is necessary to fill the storage tank 7 up to the high level sensor 31 to rinse it before emptying it.

[0115] In the example of [Fig.3], the system 25 includes, 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 performs 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 into contact in such a way as to reduce the concentration of the concentrated reagent, down to Ideally, the working concentration must be reached to obtain reconstituted reagent. In practice, dilution tank 33 allows a concentration to be reached as close as possible to the working concentration.

[0117] As an indication, the dilution tank 33 typically has a volume between 0.05 and 0.5 litres (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 tank dilution 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 rotating blade mounted within the dilution tank 33 and driven by a motor, or 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 makes it possible to estimate the concentration of the reconstituted reagent and to verify that it is indeed the expected concentration.

[0125] It should be noted that physical or chemical measurements other than conductivity measurements can be used to verify that the concentration of the reconstituted reagent conforms to the target concentration. For example, probe 45 can 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 advantage of the pump 35 is that it allows the desired volume to be moved. Typically, the pump 35 has an accuracy on the order of 0.5%.

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

[0128] In the example of [Fig. 3], the pump 35 is a syringe, which can be coupled to 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 equipped with a valve 49 and which opens onto the storage tank 7, a conduit 51 fitted with a valve 53 which opens onto the reservoir 3, and a conduit 55 fitted with a valve 57 which opens onto the dilution tank 33.

[0132] The pump 35 is connected in a fluidic manner 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 following description, the solvent reservoir connected to the dilution circuit 37 is the reservoir 3 already connected to the production circuit 11. However, the system 25 may include two separate solvent reservoirs.

[0134] In the embodiment illustrated in [Fig.3], conduits 47, 51 and 55 communicate with each other at a branch, which allows a liquid to pass 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 flow 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 considered as a dilution device.

[0137] A process for producing reconstituted reagent implemented by 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 device 1. Such production of concentrated reagent is implemented according to the process 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 according to a concentrated reagent sampling mode.

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

[0141] The pump 35 draws at least some of the concentrated reagent from the storage tank 7. The drawn-off concentrated reagent flows along the conduit 47, at least as far as The branch of the dilution circuit 37 is positioned so that it can be subsequently transferred to another conduit. The concentrated reagent can, if necessary, be drawn up until it is partially or completely received in the pump 35.

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

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

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

[0145] Pump 35 pumps the concentrated reagent taken from the dilution tank 33. The concentrated reagent flows 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 transfer of 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 according to a solvent sampling mode.

[0148] To achieve this, valve 53 is opened, while valve 57 is closed. Valve 49 remains closed. In this configuration of the dilution circuit 37, pump 35 communicates only with reservoir 3.

[0149] The pump 35 draws at least some of the solvent from the reservoir 3. The drawn-off solvent flows 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 until it is partially or completely received in the pump 35.

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

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

[0152] Pump 35 delivers the extracted solvent to the dilution tank 33. The solvent flows along the conduit 55 until it is distributed to the dilution tank 33. It is possible to distribute only a portion of the solvent, particularly when there is an excess of extracted solvent. Furthermore, it is possible to distribute the solvent to the dilution tank 33 in several stages.

[0153] The solvent, once poured through conduit 55 into 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 carried out before the solvent transfer cycle. However, the concentrated reagent transfer cycle can be carried out 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 pumps the aspirated reconstituted reagent back into the dilution tank 33. The reconstituted reagent thus flows along the conduit 55 in one direction and then the other. These alternating suction and pumping operations can be repeated several times to create agitation within the dilution tank 33, thereby homogenizing 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 system 25.

[0160] The table below summarizes the operating modes of system 25 with, in each case, the corresponding configuration of the dilution circuit 37: Valve 49 Valve 53 Valve 57 Concentrated reagent sampling method open closed closed Concentrated reagent delivery method closed closed open Solvent sampling method closed open closed Concentrated reagent dilution method closed closed open Reconstituted reagent homogenization method closed closed open

[0161] The Applicant has observed that the reconstituted reagent production process described above and implemented by the system 25 offers a medical biology laboratory autonomy ranging from half a day to several days, which leaves enough 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] With further reference 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 obtained by puncture. The operation of such a biological analysis device 61 relies on the use of one or more reagents such as dilution, lysis, sheathing, rinsing, or staining reagents.

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

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

[0167] The distribution tank 63 is further connected in a fluidic manner to the distribution tank 33 by a conduit 65 equipped 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 flow 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 flowing along the conduit 65 so as to remove impurities that could subsequently impair the operation of a biological analysis device 61. Typically, the filter 71 makes it possible to stop all foreign bodies with a size less than 0.2 micrometers (qm), and preferably less than 0.5 micrometers (qm).

[0171] In the example of [Fig.3], the distribution tank 63 is equipped 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 exceeds 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 to the dispensing tank 63 must stop.

[0174] In the example of [Fig.3], the distribution circuit 59 further includes 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 connected in a fluidic manner to the waste bin 77 by a conduit 79 equipped with a valve 81; the storage tank 7 is connected in a fluidic manner to the waste bin 77 by a conduit 83 equipped with a valve 85; and the dilution tank 33 is connected in a fluidic manner to the waste bin 77 by a conduit 87 equipped with a valve 89.

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

[0177] Furthermore, the conveyance to the waste container 77 of the liquid to be evacuated is ensured, in all cases, by a transfer pump 91.

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

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

[0180] Each cycle corresponding to the sequence of operations 200, 210, 220, and 230 in [Fig. 2] is then a cycle for the 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," it is meant here that, ideally, the total volume of solvent withdrawn is equal to the volume required to reach the working concentration in the storage tank 7; however, in practice, the total volume of solvent actually withdrawn may differ slightly from this desired volume.

[0181] Still based 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, by implementing several cycles of production and storage of concentrated reagent until the solid substance is completely dissolved, then supplying the storage tank 7 with solvent to reach the working concentration.

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

Claims

Demands

1. A device (1) for producing concentrated reagent comprising: - a solvent reservoir (3), - a container (5) containing 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 the container (5) respectively by the first conduit (13) and the second conduit (17), which device (1) is arranged to operate at least in: 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 draw solvent from the reservoir (3), and a concentrated reagent production mode in which the first valve (15) is closed, the second valve (19) is closed. (19) is open,and the pump (9) is arranged to pump solvent towards the container (5) in such a way 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 (5).

2. Device (1) according to claim 1, wherein device (1) further comprises a storage tank (7) for concentrated reagent, in which 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 device (1), which device (1) is arranged to further operate 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 pump concentrated reagent back to the storage tank (7).

3. Device (1) according to claim 2, wherein device (1) is arranged to further operate in a reagent homogenization mode concentrated 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 pump said concentrated reagent back to the storage tank (7) once or more.

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 any one of claims 2 to 4, wherein the storage tank (7) is provided with at least one level sensor (29) arranged to detect when a volume of concentrated reagent has been reached within the storage tank (7).

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

7. Device (1) according to any one of the preceding claims, wherein the reservoir (3) 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.

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

9. System (1, 25) for the production of reconstituted reagent comprising: - a dilution tank (7, 33), - a device (1) according to any 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 dilution of the concentrated reagent in the solvent.

10. A process for producing reconstituted reagent implemented by the system (1, 25) according to claim 9 and comprising the following operations: - supplying, by the device (1), the dilution tank (7, 33) with concentrated reagent, - supplying, by the reservoir (3), the dilution tank (7, 33) with solvent, and - producing, by the dilution tank (7, 33), a reconstituted reagent by diluting the concentrated reagent in the solvent.

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