A method for flushing an apparatus configured to generate a medical fluid

Abstract

A method and an apparatus (10) usable in the context of online generation of a medical fluid, such as a dialysis fluid. A flushing method is set out in the apparatus, which is configured to generate the medical fluid by continually mixing a base fluid with at least one soluble substance in a fluid line (11) extending from an inlet (12) to an outlet (13). The method comprises: detecting conductivity of a fluid at a sensing point (171) in the fluid line, wherein said conductivity is indicative of a concentration level of a first substance introduced at a supply point (15) in the fluid line upstream of the sensing point; flushing the fluid line with the base fluid from said inlet to decrease concentration of at least a second substance in the fluid; determining a concentration level of the second substance based on monitoring the detected conductivity during the flushing and on a known relation between amounts of the first and second substances included in the fluid.

Description

[0001] A METHOD FOR FLUSHING AN APPARATUS CONFIGURED TO GENERATE A MEDICAL FLUID

[0002] Technical Field

[0003] The present disclosure generally relates to the field of medical fluid generation. The proposed solution may be set out in an apparatus configured for online generation of the medical fluid, during which a continually supplied base fluid is mixed with at least one soluble substance to obtain and subsequently deliver the medical fluid. Specifically, the proposed solution relates to controlling flushing of such an apparatus to ensure proper substance removal from the apparatus.

[0004] Background

[0005] Fluids which are obtained from mixing a base fluid with at least one substance which is soluble in the base fluid may be generated for various purposes. Notably, mixed fluids in the form of medical fluids may be generated for use in therapeutic treatment of a patient. In various apparatus types, a session of medical fluid generation may be followed by a session of cleansing of fluid systems of the apparatus, e.g., for reasons of functionality of the apparatus or due to regulatory requirements. This may, inter alia, be carried out to ensure that at least one solute is removed from or at least diluted to a reasonable degree in the fluid systems of the apparatus.

[0006] On example of medical fluids generated for use in therapeutic treatment of a patient relates to fluids used in dialysis treatment, which may be required or beneficial when a person’s renal system has failed, such that it is no longer possible to balance water and minerals or to excrete daily metabolic load. Toxic end products of metabolism, such as, urea, creatinine, uric acid and others, may accumulate in a patient’s blood and tissue. Dialysis removes waste, toxins, and excess water from the body that normal functioning kidneys would otherwise remove and is typically applied when kidney function is reduced and, above all, upon kidney failure.

[0007] One type of kidney failure therapy is peritoneal dialysis (“PD”), which infuses a medical fluid known as a dialysis solution, also called dialysis fluid, into a patient’ s peritoneal cavity via a catheter. The dialysis fluid is in contact with the peritoneal membrane in the patient’s peritoneal cavity. Waste, toxins, and excess water pass from the patient’ s bloodstream, through the capillaries in the peritoneal membrane, and into the dialysis fluid due to diffusion and osmosis, i.e., an osmotic gradient occurs across the membrane. An osmotic agent in the PD dialysis fluid provides the osmotic gradient. Used or spent dialysis fluid is drained from the patient, removing waste, toxins, and excess water from the patient. This cycle is repeated, e.g., multiple times, at one therapy occasion. Traditionally, PD fluids are prepared in a factory and shipped to the patient’s home in ready-to-use bags, which may e.g., hold 5 or 8 liters of medical fluid.

[0008] As indicated, the dialysis machines, either for hemodialysis or for peritoneal dialysis, usually require a fair amount of fresh dialysis fluid to be used during the respective therapies. Handling a huge number of relatively heavy bags storing ready to use dialysis fluid is sometimes problematic and requires both physical effort and storing capability. This is particularly, but not exclusively, relevant in the case of home dialysis, wherein it is the patient or his / her family members who has to handle the fluid reservoirs.

[0009] As an alternative, various apparatus types have been suggested, which are capable of producing the medical fluid using a base fluid, typically pre-treated water, and substances comprising proper concentrates. In this context, the medical fluid is generated by, inter alia, mixing the concentrates with the base fluid in the apparatus. Between different occasions of using the apparatus, the apparatus will normally be properly cleaned, which may involve flushing fluid paths in the apparatus with a cleaning agent, such as purified water. The cleaning may further involve heat disinfection, wherein purified water heated above a predetermined temperature is led through the fluid paths. Flushing and disinfecting are process steps that require time and which may involve extensive use of water.

[0010] Summary

[0011] It is an objective to provide a solution for proper flushing of fluid paths of an apparatus configured to generate a medical fluid, such as a dialysis fluid. One objective is to provide a technical solution for minimizing time consumption and waste of fluid associated with the flushing. One object is to provide a solution which for controlling the flushing to ensure durability and function of the apparatus over time. One or more of these objectives, as well as further objectives that may appear from the description below, are at least partly achieved by a flushing method carried out in an apparatus configured to generate a medical fluid by continually mixing a base fluid with at least one soluble substance in a fluid line extending from an inlet to an outlet, said method comprising: detecting, at a sensing point, conductivity of a fluid in the fluid line, wherein said conductivity is indicative of a concentration level of a first substance introduced at a supply point in the fluid line upstream of the sensing point; flushing the fluid line with the base fluid from said inlet to decrease concentration of at least a second substance in the fluid; determining a concentration level of the second substance based on monitoring the detected conductivity during the flushing and on a known relation between amounts of the first and second substances included in the fluid.

[0012] According to another aspect, these objectives are targeted by an apparatus configured to generate a medical fluid by continually mixing a base fluid with at least one soluble substance, said apparatus comprising: a fluid line extending from an inlet for receiving the base fluid to an outlet for delivering the medical fluid, said fluid line comprising a pump and a hold-up volume; a supply arrangement fluidly connected at a supply point in the fluid line, upstream of the hold-up volume, to add the substance into the fluid line; a sensor configured to detect conductivity of a fluid in the fluid line at a sensing point downstream of the hold-up volume; and a control system connected to control substance addition from the supply arrangement, and connected to receive detected conductivity from the sensor, wherein said conductivity is indicative of a concentration level of a first substance added by the supply arrangement, wherein the control system is configured to perform flushing of the fluid line with the base fluid from said inlet to decrease concentration of at least a second substance in the fluid; and determine a concentration level of the second substance based on monitoring the detected conductivity during the flushing and on a known relation between amounts of the first and second substances included in the fluid.

[0013] As a result of the proposed solution, indirect detection of the flush status of the apparatus with respect to the second substance is obtained, which may be useful where direct determination of concentration of the second substance in the fluid is challenging. The method is particularly beneficial for indirectly determining the concentration of a solute, i.e., of the second substance, having low conductivity response, by using a marker solute, i.e., the first substance, with high conductivity response and knowledge of the known relation, e.g., concentration or amount ratio, of the two solutes.

[0014] According to some embodiments, the method further comprises: terminating the flushing upon the detected conductivity being indicative of the concentration level of the second substance meeting a target value. This way, undue further flushing may be avoided.

[0015] According to some embodiments, the fluid line comprises a hold-up volume between the supply point and the sensing point.

[0016] According to some embodiments, said hold-up volume is formed in an ultrafilter, wherein said target value is associated with the ultrafilter. This way, deterioration of the ultrafilter caused by heating of the fluid while holding remaining amounts of the second substance may be avoided

[0017] According to some embodiments, the method further comprises: providing heat to the fluid in the fluid line after terminating the flushing, to obtain heat disinfection.

[0018] According to some embodiments, the method is initiated in a state wherein concentrations of the first substance and the second substance in the fluid are homogeneous throughout the fluid line prior to the flushing.

[0019] According to some embodiments, the method further comprises: adding an additional amount of the first substance into the fluid line. This may be beneficial to reach a range of conductivity of the fluid which is more easily detected or detected with higher accuracy, to more correctly detect concentration of the second substance.

[0020] According to some embodiments, adding an additional amount comprises adding an initial amount of the first substance at start of the flushing.

[0021] According to some embodiments, adding an additional amount comprises adding an extra amount of the first substance after start of the flushing.

[0022] According to some embodiments, the extra amount is added upon the detected conductivity falling to reach a trigger level. According to some embodiments, the extra amount is added at a point in time such that, during the flushing, the detected conductivity increases, on account of the added extra amount of the first substance, prior to the detected conductivity falling below a predetermined conductivity threshold.

[0023] According to some embodiments, adding an additional amount comprises repeatedly adding extra amounts of the first substance after start of the flushing.

[0024] According to some embodiments, a magnitude of the additional amount is determined based on a system volume of fluid between the supply point and the sensing point in the fluid line.

[0025] According to some embodiments, the apparatus is configured to generate a dialysis fluid, said first substance comprising an electrolyte and said second substance comprising an osmotic agent.

[0026] According to some embodiments, the method further comprises: introducing the second substance at said supply point in the fluid line, prior to the flushing.

[0027] According to some embodiments, the flushing is carried out without addition of the second substance.

[0028] According to some embodiments, the method is initiated at a state of holding a fluid in the fluid line, prior to the flushing, wherein said fluid comprises the medical fluid having a predetermined concentration of the at least one soluble substance.

[0029] Brief Description of the Drawings

[0030] Fig. 1 is a schematic view of a fluid circuit associated with an apparatus for generating a medical fluid in an online generation phase, wherein a base fluid is continually obtained from an inlet and mixed with at least one substance to form the medical fluid which is passed to an outlet.

[0031] Fig. 2 schematically illustrates a control system for use in an apparatus according to various examples of the proposed solution.

[0032] Fig. 3 schematically illustrates an example of a substance supply arrangement, for use in an apparatus according to various examples of the proposed solution. Fig. 4 schematically illustrates a filter setup in an apparatus for carrying out the method according to various examples of the proposed solution, wherein the filter setup comprises two ultrafilters with respective filter chambers.

[0033] Fig. 5 schematically shows various parts of an apparatus in which the proposed solution may be set out.

[0034] Fig. 6 is a flow chart showing various steps included in different examples of a method according to the proposed solution.

[0035] Fig. 7A shows a diagram which indicates flow rate of a substance and conductivity of the fluid during flushing according to a first example.

[0036] Fig. 7B shows a diagram which indicates substance concentration during flush and at a conductivity detection limit in the first example.

[0037] Fig. 8A shows a diagram which indicates flow rate of a substance and conductivity of the fluid during flushing according to a second example, with addition of the first substance at start of flushing.

[0038] Fig. 8B shows a diagram which indicates substance concentration during flush and at a conductivity detection limit in the second example.

[0039] Fig. 9A shows a diagram which indicates flow rate of a substance and conductivity of the fluid during flushing according to a third example, with addition of the first substance after start of flushing.

[0040] Fig. 9B shows a diagram which indicates substance concentration during flush and at a conductivity detection limit in the third example.

[0041] Detailed Description

[0042] Embodiments will be described more fully hereinafter with reference to the accompanying drawings, in which some embodiments are shown. Indeed, the subject of the present disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure may satisfy applicable legal requirements.

[0043] Also, it will be understood that, where possible, any of the advantages, features, functions, devices, and / or operational aspects of any of the embodiments described and / or contemplated herein may be included in any of the other embodiments described and / or contemplated herein, and / or vice versa. In addition, where possible, any terms expressed in the singular form herein are meant to also include the plural form and / or vice versa, unless explicitly stated otherwise. As used herein, "at least one" shall mean "one or more" and these phrases are intended to be interchangeable. Accordingly, the terms "a" and / or "an" shall mean "at least one" or "one or more", even though the phrase "one or more" or "at least one" is also used herein. As used herein, except where the context requires otherwise owing to express language or necessary implication, the word "comprise" or variations such as "comprises" or "comprising" is used in an inclusive sense, that is, to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments.

[0044] As used herein, the terms "multiple", "plural" and "plurality" are intended to imply provision of two or more elements. The term "and / or" includes any and all combinations of one or more of the associated listed elements.

[0045] It will furthermore be understood that although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first element could be termed a second element, and, similarly, a second element could be termed a first element, without departing the scope of the present disclosure.

[0046] For brevity and / or clarity, well-known functions or constructions may not be described in detail. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0047] The present disclosure generally relates to processes used in an apparatus configured to generate a medical fluid by continually mixing a base fluid with at least one soluble substance. In this context, the fluid generated in the apparatus may be referred to as a medical fluid. The proposed solution is associated with flushing of the apparatus, for the purpose of removing or diluting at least one substance solved in the fluid held in a fluid system of the apparatus, as a part of a cleaning or replenishing process. The cleaning process may further comprise, or be followed by, a heat disinfection stage. When a hold-up volume is included in the fluid system between substance introduction and a medical fluid outlet, the hold-up volume will act as a buffer volume. This means that the fluid content in the hold-up volume may need to be replaced every time the apparatus is reconfigured to change target fluid composition of the medical fluid to be generated, which may cause waste of medical fluid and time consumption. Furthermore, a change of the amount of substance injected into the fluid system will be subjected to internal mixing in the hold-up volume. This will cause a delay and uncertainty of the completion of a transition of a concentration setting obtained at the medical fluid outlet.

[0048] Specifically, various aspects of the proposed solution will be described herein with references to a method set out in an apparatus configured to generate a medical fluid usable in dialysis treatment. Different medical fluids may be used depending on the type of dialysis treatment.

[0049] As already noted, one type of dialysis treatment is peritoneal dialysis (PD) therapy, wherein diffusion in a patient’ s own peritoneal membrane is used for removing waste products from the patient’ s blood.

[0050] Another type of kidney failure therapy is Hemodialysis (“HD”), which in general uses diffusion in a dialyzer membrane to remove waste products from a patient’ s blood. A diffusive gradient occurs along the semi-permeable dialyzer between the blood and a medical fluid often referred to as an HD fluid, which comprises an electrolyte solution called dialysate or dialysis fluid to cause diffusion. HD fluids are typically created by the dialysis machines by mixing concentrates and clean water.

[0051] Hemofiltration (“HF”) is an alternative renal replacement therapy that relies on a convective transport of toxins from the patient’ s blood. HF is accomplished by adding a medical fluid referred to as substitution or replacement fluid to the extracorporeal circuit during treatment. The substitution fluid and the fluid accumulated by the patient in between treatments is ultrafiltered over the course of the HF treatment, providing a convective transport mechanism that is particularly beneficial in removing middle and large molecules.

[0052] Hemodiafiltration (“HDF”) is a treatment modality that combines convective and diffusive clearances. HDF uses dialysis fluid as the medical fluid, flowing through a dialyzer, similar to standard hemodialysis, to provide diffusive clearance. In addition, substitution solution is delivered directly to the extracorporeal circuit, providing convective clearance. Here, more fluid than the patient’s excess fluid is removed from the patient, causing the increased convective transport of waste products from the patient. The additional fluid removed is replaced via the substitution or replacement fluid. As used herein, dialysis refers to any therapy / treatment that replaces or supplements the renal function of a patient by use of a medical fluid. Dialysis includes, without limitation, extracorporeal (EC) blood therapy and PD therapy. Various aspects of the present disclosure relate to apparatuses for online preparation of medical fluid such as dialysis fluid for peritoneal dialysis or hemodialysis. In a specific aspect, the present disclosure relates to online preparation of PD fluid to be directed to, e.g., a cycler for peritoneal dialysis treatments. While the present disclosure focuses more on apparatuses for PD fluid generation, the teachings discussed herein is also applicable to other treatment and injectable fluids, such as continuous renal replacement treatment (“CRRT”) fluids including HD fluids, substitution or replacement fluids for HF and HDF, lactated ringers and the like.

[0053] For context, it may be noted that there are various types of peritoneal dialysis therapies, including continuous ambulatory peritoneal dialysis (“CAPD”), automated peritoneal dialysis (“APD”), tidal flow dialysis, and continuous flow peritoneal dialysis (“CFPD”). CAPD is a manual dialysis treatment, where fluid transport is driven by gravity. If initially full of used dialysis fluid, the patient manually connects an implanted catheter to a drain to allow the used or spent dialysis fluid to drain from the patient’s peritoneal cavity. The patient then switches fluid communication so that the patient catheter communicates with a bag of fresh dialysis fluid to infuse the fresh dialysis fluid through the catheter and into the patient. The patient disconnects the catheter from the fresh dialysis fluid bag and allows the dialysis fluid to dwell within the peritoneal cavity, wherein the transfer of waste, toxins, and excess water takes place. After a dwell period, the patient repeats the manual dialysis procedure, for example, four times per day. If the peritoneal cavity is not initially full of used dialysis fluid, the sequence is instead fill, dwell, and drain. Manual peritoneal dialysis requires a significant amount of time and effort from the patient, leaving ample room for improvement.

[0054] Automated peritoneal dialysis (“APD”) is similar to CAPD in that the dialysis treatment includes drain, fill, and dwell cycles. APD machines, however, perform the cycles automatically, typically while the patient sleeps. APD machines free patients from having to manually perform the treatment cycles and from having to transport supplies during the day. APD machines are fluidly connected to an implanted catheter, to a source or bag of fresh dialysis fluid and to a fluid drain. APD machines pump fresh dialysis fluid from a dialysis fluid source, through the catheter and into the patient’ s peritoneal cavity. APD machines also allow for the dialysis fluid to dwell within the chamber and for the transfer of waste, toxins, and excess water to take place. The source may include multiple liters of dialysis fluid including several solution bags. APD machines pump used or spent dialysate from the peritoneal cavity, through the catheter, and to the drain. As with the manual process, several drain, fill and dwell cycles occur during dialysis. A “last fill” may occur at the end of the APD treatment. The last fill fluid may remain in the peritoneal cavity of the patient until the start of the next treatment, or it may be manually emptied at some point during the day.

[0055] Shipping of ready-made medical fluid in bags or other containers brings about various drawbacks. For one thing, transportation of a fluid which predominantly comprises water, which normally is available at the location of use of the medical fluid, may cause undue consumption of resources in terms of fuel and associated pollution. It also brings about a need for handling storage onsite, such as at a patient’s home e.g., in the case of PD treatment, besides the burden of handling the bags, such as changing bags and disposing of the empty bags.

[0056] A solution is thus to prepare the medical fluid at or near the point of use. This may e.g., include configuring an apparatus for generating (producing) PD fluid locally in the patient’ s home by mixing PD fluid concentrates (concentrates for short) with purified water. Instead of having to ship the final medical fluid, of an intended composition, only the concentrates need to be supplied to the point of use (e.g., in bags), whereas the pure water needed for mixing is sourced from e.g. a water purification device that purifies tap water. This may be referred to as an apparatus capable of online production of medical fluid.

[0057] Fig. 1 schematically illustrates an example of such an apparatus 10, where at least some of the relevant elements and functions employed in online production of medical fluid are shown. These elements and functions will be broadly described with reference to Fig. 1, whereas certain elements and functions will additionally be described in more detail further below.

[0058] The apparatus 10 has a fluid circuit which comprises a fluid line 11, indicated by the thicker line in the drawing. The fluid circuit, including the fluid line 11, may be defined by hoses, pipes, tubes, ducts, or other hollow conduits which serve to lead fluid (liquid, in particular) in the apparatus 10. The fluid line 11 extends from an inlet 12 for receiving a base fluid to an outlet 13 for delivering a medical fluid which may serve as a medical fluid. The inlet 12 thus acts as an interface configured to receive a base fluid from a base fluid source. For this purpose, the inlet 12 may comprise a connector or port for a hose, tube, or the like.

[0059] By way of example, where the base fluid comprises tap water, a water faucet 1 may serve as the base fluid source located at the point of use of the apparatus 10. A water purifier 2 may be arranged between the base fluid source and the inlet 12 to provide purified water. In some examples, the water purifier 2 may be included in the apparatus 10, whereas Fig. 1 shows an embodiment in which the water purifier 2 is a standalone unit, separate from the apparatus 10 and connected to provide purified water to the inlet 12. Purified water may be obtained in the water purifier 2 by distillation, deionization, reverse osmosis, or other suitable processes and that meets the definition of pure water in the relevant Pharmacopeia. For example, the purified water has a purity level as of “water for dialysis”.

[0060] The apparatus 10 comprises various elements and functions for producing or generating medical fluid of a target composition, from the base fluid obtained from the inlet 12. In the context of the proposed solution, the target composition relates to at least a certain concentration of one or more solutes in the base fluid, which solutes are obtained based on one or more supplied substance, whereas the exact nature and definition of the target composition is not crucial. The substance(s) may be a concentrate which is solved in the base fluid to provide a solute of the respective substance(s). For this reason, the terms substance and concentrate are interchangeably used herein. In some examples, a composition is defined by a set of concentrations of different solutes. Examples of such solutes include an osmotic agent such as glucose or icodextrin, or a salt such as NaCl. The concentrate is a highly concentrated solute solution intended for dilution. The target composition may be a desired or predetermined composition, for example determined by a prescription.

[0061] The outlet 13 provides an interface configured to deliver generated medical fluid to a receiving entity 3. For this purpose, the outlet 13 may comprise a connector or port for a hose, tube, or the like. In various examples, the receiving entity may comprise a patient, or a cycler configured to further deliver the medical fluid to a patient, or a device for containing the produced medical fluid, such as a medical fluid bag, or an HD machine. The apparatus 10 comprises a fluid pump 14, also referred to herein as a main pump 14, configured to pump fluid in the fluid line 11. The main pump 14 is predominately operated to pump fluid forward, or downstream, in the fluid line 11, i.e. from the inlet 12 to the outlet 13, but may in some examples additionally be operated in the opposite direction, so as to pump or drag fluid from the outlet 13. In some examples, the main pump 14 is a volumetric pump. If the main pump 14 is not a volumetric pump, at least one sensor, such as a flow meter, may be added in the fluid line 11 to provide feedback in a control circuit to ensure a desired flow rate.

[0062] The apparatus further comprises a concentrate supply arrangement 20, fluidly connected at a supply point 15 on the fluid line 11. The concentrate supply arrangement 20 has an inlet connected to receive at least one type of concentrate, or substance, from a concentrate source 4 connected to the apparatus 10, such as a bag or other container. The concentrate may be received in the concentrate supply arrangement 20 in liquid form, as a gel, or other. In other examples, the concentrate may be provided as a powder, pellets, or other solid state form, wherein the concentrate may be dissolved in the base fluid in the supply arrangement 20 before being injected into the fluid line 11. The concentrate supply arrangement 20 is further configured to add the concentrate to the base fluid, for the purpose of generating the medical fluid, by injection of the concentrate at the supply point 15. In order to obtain controlled injection of concentrate, the concentrate supply arrangement 20 may comprise at least one concentrate pump.

[0063] The apparatus 10 may further comprise a mixer including a mixing chamber 16, which may comprise a motorized or flow-driven mechanism for mixing the concentrate with the base fluid. The mixing chamber 16 is arranged for mixing fluids in the fluid line 11.

[0064] The apparatus may further comprise at least one sensor 17, such as a conductivity sensor, configured to measure a property of the fluid flowing in the main line 11, which property is indicative of the composition of the fluid in the fluid line 11.

[0065] The apparatus may further comprise at least one filter 18, such as an ultrafilter, which is intended to reduce or remove microbials and endotoxins from the finally mixed medical fluid prior to fluid delivery at the outlet 13. The filter 18 may comprise at least one chamber, capable of holding a volume of fluid. The drawing indicates placement of the conductivity sensor 17 between the mixer 16 and the filter 18, which may be used for controlling concentrate injection by the supply arrangement 20 upon generating the medical fluid.

[0066] Additionally, or alternatively, the apparatus 10 may comprise a conductivity sensor 171 positioned to sense fluid conductivity in the fluid line 11 between the filter

[0067] 18 and the outlet 13. Use of the conductivity sensor 171 in a method according to the proposed solution will be described in further detail below.

[0068] The apparatus may further comprise a valve arrangement 19, four valves being indicated in the drawing by way of example. The valve arrangement may be controlled to, inter alia, selectively connect or disconnect fluid communication to the outlet 13, and to selectively purge fluid from the fluid line 11, e.g., to drain 5. The valve arrangement

[0069] 19 may comprise a plurality of valves configured to operate on the fluid circuit to set different fluid paths, in particular according to different processes and operations to be executed by the apparatus 10. In general, a valve has an open state allowing fluid passage and a closed state preventing fluid passage. Any type of valve suitable for the task may be used, such as an on / off valve, a pinch valve, a cassette valve, a proportional valve, etc.

[0070] The apparatus further comprises a control system 30, configured to operate the apparatus 10 in at least an online generation phase. In the drawing, the control system is represented by a control unit. In an online generation phase of medical fluid, the medical fluid is continuously produced from concentrates and base fluid in the fluid line 11 to be continuously delivered at the outlet 13. The medical fluid is thus produced “inline”. The control system 30 controls the concentrate supply arrangement 20 to continuously or continually deliver at least one concentrate at the supply point 15 for mixing with the base fluid in the fluid line 11 to form the medical fluid with a target composition to be delivered at the outlet 13. The control system 30 may further be configured to control the main pump 14, optionally the mixer, and the valve arrangement 19, in the process of medical fluid generation. In this process, the control system 30 may further be configured to take input from the sensor 17 and to adapt control of the elements and functions in the apparatus 10 based on said input.

[0071] The apparatus 10 may further comprise a heater unit 40, connected to heat fluid in the fluid line 11. The heater unit 40 may, inter alia, be used for heat disinfection of the fluid line 11. Fig. 2 schematically illustrates an example of the control system 30. The control system 30 comprises all necessary components, hardware, and software, to interact with, monitor and control all necessary aspects of the apparatus 10 and its use.

[0072] The control system 30 comprises logic circuitry 31 configured to control the apparatus 10. The logic circuitry 31 may include a processing device 32, including one or multiple processors, microprocessors, data processors, co-processors, and / or some other type of component that interprets and / or executes instructions and / or data. Processing device 32 may be implemented as hardware (e.g., a microprocessor, etc.) or a combination of hardware and software (e.g., a system-on-chip (SoC), an applicationspecific integrated circuit (ASIC), etc.). The processing device 32 may be configured to perform one or multiple operations based on an operating system and / or various applications or programs. The logic circuitry 31 may further include memory storage 33, which may include one or multiple memories and / or one or multiple other types of storage mediums. For example, memory storage 33 may include a random access memory (RAM), a dynamic random access memory (DRAM), a cache, a read only memory (ROM), a programmable read only memory (PROM), flash memory, and / or some other type of memory. Memory storage 33 may include a hard disk (e.g., a magnetic disk, an optical disk, a magneto-optic disk, a solid state disk, etc.). The memory storage 33 is configured for holding computer program code, which may be executed by the processing device 32, wherein the logic circuitry 31 is configured to control the apparatus 10 to carry out any of the method steps as provided herein. Software defined by said computer program code may include an application or a program that provides a function and / or a process. The software may include device firmware, an operating system (OS), or a variety of applications that may execute in the processor 32.

[0073] The control system 30 may further comprise an interface 34, configured for communication with various entities in or associated with the apparatus 10. As indicated, this may, inter alia, include communicating with a user interface 36 and taking input from one or more sensors 37, such as conductivity sensors 17 and 171, and possibly additional sensors for sensing pressure, temperature, flow, or other properties of the fluid in the fluid line 11. The interface 34 may further be configured for providing control output to, inter alia, the concentrate supply arrangement 30, the main pump 14, the valves of the valve arrangement, etc. Additionally, the control system 30 will further comprise an input of electric power (not shown in the drawing). Connectivity between the control system 30 and further entities of or associated with the apparatus 10, as indicated by arrows in the drawing, may comprise electrical and / or electronic connections. Alternatively, connectivity may be accomplished by wireless connection.

[0074] Fig. 3 schematically illustrates an embodiment of the concentrate supply arrangement 20, which may be useful in e.g., an apparatus 10 configured for generation of a PD fluid. In this embodiment, the concentrate supply arrangement 20 comprises, at least, two subunits 210 and 220.

[0075] A first subunit 210 is configured to supply a first substance, which may be an electrolyte concentrate (EC) including an electrolyte. For this purpose, the first subunit 210 may comprise a pump 211, connected with an outlet at the supply point 15 to deliver EC to the fluid line 11. The pump 211 has an inlet 212 which is connectable to an EC source, such as a bag comprising liquid EC. The pump 211 is in some embodiments a volumetric pump. The connections typically include fluid lines.

[0076] A second subunit 220 is configured to supply a second substrate, which may be an Osmotic Agent Concentrate (OAC) including an osmotic agent, such as glucose, icodextrin, or other. For this purpose, the second subunit 220 may comprise a pump 221, connected with an outlet at the supply point 15 to deliver OAC to the fluid line 11. The pump 221 has an inlet 222 which is connectable to an OAC source, such as a bag comprising liquid OAC. In some embodiments, the pump 221 is a volumetric pump. The connections typically include fluid lines.

[0077] The concentrate supply arrangement 20 is in some embodiments configured to independently set delivery flows of EC and OAC, respectively, under control of the control system 30. This may include, at least, controlling an injection flow rate of the subunits 210, 220 to obtain a known relation between amounts of the first and second substances provided into the fluid line. This may include controlling injection flow rate of one of the subunits 210, 220 while maintaining the other of the subunits 210, 220 at a constant injection flow, such as zero injection. Control of injection flow rate may be based on sensor feedback to the control system 30 from the sensor 17.

[0078] Fig. 4 schematically illustrates an embodiment of a setup of the filter 18 arranged in the fluid line 11. The filter 18 comprises at least one chamber, which will be substantially or completely filled with fluid upon operation of the apparatus 10. Specifically, in online generation of medical fluid of a target composition, the produced medical fluid will fill up and pass through the filter chamber(s), prior to delivery at the outlet 13. The filter 18 may, as such, comprise one or more individual filters, which may be serially arranged in the fluid line 11, as shown. Specifically, Fig. 4 shows an example wherein the filter 18 comprises two successive filters 181, 183 connected in the fluid line 11. The two filters 181, 183 may be differently or substantially identically configured. It should be noted that more than two filters may alternatively be included in the filter 18. In some examples, at least one filter (i.e., the only filter or one or more of a plurality of filters 181, 183) is an ultrafilter, which is intended to reduce any microbial contamination prior to fluid delivery to the external unit 3.

[0079] Using filter 181 as reference by way of example, it may comprise a semipermeable membrane separating a filter volume into an inlet chamber and an outlet chamber, which together form a filter chamber 182. An inlet is connected to the main fluid line 11 for receiving fluid in the filter 181, and an outlet is connected to deliver filtered fluid to the main fluid line 11. In this context, it may be noted that the connection between two successive serially connected filters 181, 183, as in Fig. 4, also forms part of the main fluid line 11. The medical fluid entering the filter through the inlet leaves the filter through the outlet after passing through the semipermeable membrane. The function and characteristics of an ultrafilter is, as such, well-known in the field of dialysis, and is therefore not described in further detail herein. However, it may be noted that filter chamber(s) 182, 184 may comprise a considerable hold-up volume of fluid in the apparatus 10, in particular compared to other entities along the fluid line 11.

[0080] Referring back to Fig. 1, and with reference to the foregoing, a preferred location of the filter 18 may be downstream of the supply point 15 and the mixing chamber 16, in order to remove contaminants and endotoxins from the finally produced medical fluid. Specifically, it is beneficial that the filter 18 is located downstream of the supply point 15, to remove any contaminants originating from the concentrate supply arrangement 20. However, this configuration, wherein a large hold-up volume (compared to the other components on the fluid line 11) is introduced at a far downstream position, also presents certain challenges. An intended action of the apparatus 10 is to change the composition of the incoming base fluid and deliver as an output a medical fluid that is different from the base fluid. As a hold-up volume (i.e., provided by the filter 18) is introduced between the concentrate input and mixing, and a receiving device 3 (e.g., a PD cycler) which requires the medical fluid, e.g. PD fluid, to be of correct composition for storing or further administration to a patient, the hold-up volume will act as a buffer volume. For one thing, this means that the fluid content in the hold-up volume would need to be replaced (flushed) more or less completely every time the apparatus is reconfigured to generate and deliver a different target fluid composition. This means increased medical fluid waste and time consumption. Moreover, whereas fluid flow in the fluid line 11, specifically in tubes, pipes or ducts, can be characterized as a plug flow, a change of the amount (concentration) of substance injected at the supply point will be subjected to a degree of internal mixing and dilution in the hold-up volume on the filter 18. This will cause a delay and uncertainty of the completion of a transition from one concentration setting to another concentration setting, applied by the concentrate supply arrangement 20, at the outlet 13.

[0081] Heat disinfection of the fluid line 11 of the apparatus 10 will normally be performed regularly, such as daily. This will include the entire fluid path of fluid line 11 including the ultrafilters 18. There is a concern that heat in combination with OAC (e.g., glucose) presence in the chambers 182, 184 may lead to performance deterioration of the ultrafilters 18, for example by glucose polymerization followed by membrane fouling. The ultrafilters 18 therefore need to be flushed with the base fluid, typically purified water, before the heat disinfection to decrease the OAC (e.g., glucose) amount / concentration below a certain threshold limit. This may be referred to as a predisinfection flush. The actual value of such a threshold limit may be different for different filter types and use cases and is, as such, not essential to the proposed solution. It may nevertheless be noted that in certain examples, the threshold limit of glucose concentration may be in the range of 0.01-10 %o.

[0082] Fig. 5 shows a drawing of the apparatus 10 in which elements that are directly relevant for understanding of the proposed solution are shown, which elements form a subset of the elements shown in Fig. 1. The drawing shows a schematic system setup usable for generating, or producing, dialysis fluid using online mixing. While the proposed solution may be applied in other context, the following description will provide details and aspects related to flushing of the apparatus 10 after generation of a dialysis fluid based on mixing (purified) water with a first substance comprising an electrolyte concentrate (EC) and a second substance comprising a glucose concentrate (GC). The fluid system of the apparatus 10 comprises a hold-up volume 18 which may be an ultrafilter (UF), incorporated to minimize the biological burden in the produced dialysis fluid. Various aspects related to the apparatus of Fig. 1 will briefly be repeated or elaborated here. It may be noted, though, that various elements and functions described with reference to Fig. 1 are left out of Fig. 5, such as the mixing chamber 16 and the control system 30, for the sake of clear presentation of the relevant functions.

[0083] The drawing shows the fluid line 11, extending from the inlet 12 for receiving the base fluid, such as purified water, to the outlet 13 for delivering fluid to a receiving entity. In this context, dependent on operational state, the fluid may be delivered for the purpose of using the fluid, such as to a cycler, a patient, or a storage container. Alternatively, the fluid may be delivered for disposal, e.g., to drain. This may be controlled by operating valves, such as valves of the valve arrangement 19 indicated in Fig. 1. A main pump 14, such as a volumetric pump, is included for pumping fluid in the fluid line, at least in the direction from the inlet 12 towards the outlet 13. The supply point 15 is indicated by a dashed contour and comprises at least a supply point 151 for a first substance, such as EC. Injection into the fluid line 11 of the EC is controlled by an EC pump 211, which may be a volumetric pump. The supply point 15 may further comprise a supply point 152 for a second substance, such as an osmotic agent GC. The term dosing point is interchangeably used with the term supply point herein, as the point of substance injection into the fluid line 11. Injection into the fluid line 11 of the GC is then controlled by a GC pump 221, which also may be a volumetric pump. It should be noted, though, that the proposed solution as outlined herein may additionally be used when the second substance is already present in the received base fluid, i.e., when the second substance is not separately added to the fluid line 11. Going forward, the description will nevertheless be focused on embodiments including the GC pump 221. A filter setup of one or more UF(s) 18, which comprises one or more separate filters with filter chambers, form a hold-up volume in the fluid line 11. At a sensing point downstream of the UF 18, a conductivity sensor 171 is arranged to sense fluid conductivity in the fluid line, i.e., electrical conductivity of the fluid.

[0084] Fig. 6 provides a flowchart of various steps which may be included in different embodiments of the proposed solution. These steps are briefly discussed below, after which more detailed examples associated with those steps will be described. The process may be controlled by control system 30, indicated in and described with reference to Fig. 1.

[0085] Step 600 indicates a state of the apparatus upon starting the method according to the proposed solution. At this starting state, the fluid line 11 of the apparatus 10 holds fluid with homogeneous concentrations of the first substance and the second substance. Based on the example of Fig. 5, after a completed online production phase for generating and delivering the dialysis fluid, the fluid line 11 including the UF 18 is filled with dialysis fluid. Concentrations CE of the first substance E and CG of the second substance G in the fluid are then typically homogeneous throughout the fluid line 11. Moreover, these concentrations are known, as the preceding stage of generating the fluid has been carried out to obtain a specific target composition, comprising given concentrations CE and CG within a certain tolerance level. The medical fluid held in the fluid line 11 needs to be flushed with water prior heat disinfection. More specifically, the glucose concentration CG in the UF needs to be below a certain threshold to avoid negative impact on the membrane when heat is applied.

[0086] Step 610 comprises detecting conductivity of the fluid at a sensing point in the fluid line, wherein said conductivity is indicative of a concentration level of a first substance introduced at a supply point in the fluid line upstream of the sensing point. With reference to the example of Fig. 5, the sensing point is the location of the conductivity sensor 171 in the fluid line 11. Detecting conductivity may be carried out repeatedly, such as with a certain measurement frequency. The measurement frequency may be in the range of 0.1-100Hz, such as 5-20Hz., e.g. about 10Hz. Step 610 may thus be seen as a start of monitoring the conductivity throughout the flushing process. With reference to detecting conductivity, it shall be noted that the electrolyte has a large conductivity-increasing effect while the glucose (or other OAC) has a weak conductivity-decreasing effect. In fact, it can be assumed, at least for the purpose of flushing according to the proposed solution, that the conductivity effect of glucose in relation to that of electrolytes is negligible.

[0087] Step 620 comprises flushing the fluid line with the base fluid from said inlet to decrease concentration of at least a second substance in the fluid. With reference to the example of Fig. 5 this may comprise supplying purified water from the inlet 12 while allowing fluid output from the fluid line 11 to drain at the outlet 13 and using the pump 14 to drive the fluid in the fluid line 11. With reference to Fig. 1, allowing fluid output to drain may be accomplished by closing valve 191 and opening valve 192. Step 620 may thus comprise initiating the flushing and maintaining a certain flow rate in the main line using the pump 14. An objective with flushing is to clean the fluid line 11, e.g., for reducing residual amounts of the second substance. The flushing is thus carried out without addition of the second substance. In this context, the concentrate supply arrangement 20 is controlled to inhibit addition of the second substance in the fluid line 11 during the flushing.

[0088] Step 630 comprises the optional step of adding an additional amount of the first substance into the fluid line. In this context, it may be noted that the purpose of flushing is to expel all amounts of both substances from the fluid line 11, at least down to allowable concentration levels. However, by adding an additional amount of the first substance, the relation of the amounts of the first and second substances in the fluid line 11 is changed to increase the concentration of the first substance in relation to the second substance. With reference to Fig. 5, this may entail adding additional EC into the fluid line, using the EC pump 211. This may be accomplished by operating the EC pump for a short period to volumetrically inject a pulse of EC into the fluid line during the flushing. As will be described in greater detail and with different examples, this means that an increased conductivity will be measured when the fluid comprising increased EC concentration reaches the conductivity sensor 171. Where the conductivity sensor has a certain accuracy or detection limit for detecting low conductivity levels, the added additional amount allows for determining lower levels of GC. The proposed method may thus comprise adding 630 an additional amount of the first substance into the fluid line for a period of time and otherwise flushing 620 without adding the first substance into the fluid line.

[0089] 631 indicates a certain character of step 630, wherein adding an additional amount comprises adding an initial additional amount of the first substance at start of the flushing.

[0090] 632 also indicates a certain character of step 630, wherein adding an additional amount comprises adding an extra amount of the first substance after start of the flushing. This may further comprise repeatedly adding extra amounts of the first substance after start of the flushing. In some examples, the extra amount may be added at a point in time such that, during the flushing, the detected conductivity increases, on account of the added extra amount of the first substance, prior to the detected conductivity falling below a predetermined conductivity threshold. This will be described in further detail with reference to examples below and is helpful for determining low GC levels.

[0091] Step 630, if included, may be carried out according to the character of step 631, step 632, or both.

[0092] Step 640 comprises determining a concentration level of the second substance based on monitoring the detected conductivity during the flushing and on a known relation between amounts of the first and second substances included in the fluid. In other words, the first substance is used as a marker substance for determining the concentration of the second substance. Specifically, based on knowledge of the relation, such as CG / CE at the conductivity sensor 171, CE as measured by conductivity sensor 171 is an indirect measure of CG. With reference to the example of Fig. 5, the electrolytes of EC are hence used as a marker for the glucose of GC, so that CG can be indirectly measured by the conductivity sensor 171. During the flushing, the medical fluid originally held in the fluid line 11 will be replaced with the base fluid, upon which the detected conductivity will fall. Due to the internal mixing in the hold-up volume, the fluid in the fluid line will gradually decrease at the sensing point, as the concentration CE decreases. This step may therefore comprise monitoring the detected conductivity during the flushing, wherein the medical fluid is gradually replaced with the base fluid at the sensing point.

[0093] Step 650 indicates an optional step of terminating the flushing upon the detected conductivity being indicative of the concentration level of the second substance meeting a target value. This implies that once a certain acceptable CG has been determined to be present in the fluid at the conductivity sensor 171, i.e., at the outlet 13, the flushing can be terminated. This saves undue time consumption and water waste that may result from continued flushing.

[0094] Step 660 indicates the optional step of providing heat to the fluid in the fluid line after terminating the flushing, to obtain heat disinfection. With reference to Fig. 1, this step may be obtained using the heater unit 40.

[0095] Various examples of the method outlined with reference to Fig. 6 will now be described, in association with a process for online production of a dialysis fluid by mixing purified water with EC and GC to obtain a certain target composition of the dialysis fluid. The proposed solution aims at obtaining a measure of the concentration of glucose present in the fluid line 11, specifically for the purpose of ensuring that proper removal or dilution of glucose is obtained in the UF 18.

[0096] As has been noted, the proposed solution involves determining level of concentration CG of glucose based on monitoring detected conductivity after the UF 18 during the flushing and on a known relation between amounts of electrolytes and glucose included in the fluid.

[0097] Electric conductivity (Cond) may be measured in the unit mScm1. Whereas the glucose concentration CG can be measured in ppm, expressed as ppmG. For convenience, the co / Cond ratio (GCR) can be introduced. GCR may thus, for example, be expressed in the unit ppmG / mScm1. By way of example, a 1.36% glucose concentration Dianeal solution with a conductivity of 12mS / cm has a GCR of 1.36*10 000 / 12 ppmG / mScm1= 1133 ppmG / mScm1.

[0098] During the production phase the volumetric flow rates IT. of pump 211, TG of pump 221, and r\i of main pump 14 [ml / min] were kept constant for a time sufficient to achieve a uniform (homogeneous) solution throughout the fluid line 11 downstream of the supply point 152. GCR as well as CG and CE themselves are hence stable and known at the conductivity sensor 171. This represents the state indicated by 600 in Fig. 6.

[0099] Cond detection 610 is initiated for obtaining of conductivity measurements during flushing. As noted, Cond is assumed to be determined by CE. In Fig. 6, it is indicated that conductivity detection and monitoring is a step which is separate from initiating flushing. This shall not be seen as defining time of occurrence of these steps. Start of detecting 610 may thus occur before start of flushing 620, simultaneously with start of flushing 620, or even slightly after start of flushing.

[0100] As flushing 620 with water starts, I . and I'G become zero and the concentrations start to decrease with a dependency on time as well as the fluidic distance from the concentrate dosing points 151 and 152. It can be assumed that the electrolyte concentration CE and the glucose concentration CG follow the same dependency on time and fluidic distance from the concentrate dosing points and hence that GCR is constant in all parts of the system downstream the concentrate dosing point, including at the conductivity sensor 171. In this context, the known relation between amounts of the first and second substances included in the fluid is a constant concentration ratio held in the fluid line at start 600. Consider the example above with a GCR of 1133 ppm / mScm1. GCR can be used to convert Cond to CG during the flushing. If for example Cond is 2mS / cm after some time of flushing, then CG = GCR*Cond = 1133*2ppm =2266ppm. Hence, the concentration level CG is obtained based on monitoring the detected conductivity, which is dependent on CE, during the flushing 620 and on the known relation between the concentrations. The known relation between the concentrations CG and CE then furthermore translates directly to the (same) known relation between the amounts of G and E in the fluid in the fluid in the fluid line 11.

[0101] At some point during the flushing, Cond will fall below a measurement range of the sensor 171, and the method can thereafter not determine CG accurately. If for example the lower Cond measurement limit is 0.5mS / cm, then the lowest possible CG that can be determined is 566ppm (0.5*GCR). This measurement sensitivity limit may be higher than the required CG threshold, or target value, that the flush should achieve.

[0102] As has been stated, GCR can be used to calculate CG via Cond instantaneously since GCR is constant throughout the system, i.e., in every point of the fluid line 11 at least between the dosing point 15 (specifically point 152) and the outlet 13. A way to increase the sensitivity of the method, e.g., to improve capability of measuring even lower CG, is to decrease GCR by increasing the conductivity via increased electrolyte dosing rate. This is feasible if the increased electrolyte dosing rate is active for a time sufficient to achieve a uniform solution throughout the system, since GCR would otherwise have different values at different points of the fluid line 11 between the dosing point 15 and the outlet 13, which would disable the Cond-to-CG conversion via GCR. The time required with increased electrolyte dosing would be quite long and hence lead to a large amount of wasted concentrate.

[0103] However, by monitoring detected conductivity, determined by on CE, by integrating the conductivity (Cond), the requirement of uniform solution throughout the system may be avoided. Compared to requiring uniform electrolyte solution, this means that lower CG can be determined and with less waste of EC.

[0104] Initially, this example of the proposed solution will be described based on the notion of uniform solution existing throughout the system. The system may be defined as the fluid line 11 between the dosing point 15 and the outlet 13. The dosing point 15 may specifically be defined as the most downstream dosing point 152. The conductivity sensor 171 is positioned at a sensing point in the fluid line 11, at or near the outlet 13. The following parameters may be considered:

[0105] • Go and Eo are the amounts of glucose and electrolytes initially present in the system at the start of flushing. They are known provided that the system volume is known.

[0106] • G and E are the amounts of glucose and electrolyte present in the system during flushing. They will both decrease during the flush and the ratio between them will be constant provided that no concentrate is added.

[0107] • Eo can be translated into a volume integrated Cond value EICo (Electrolyte Integrated Cond).

[0108] By way of example, if Eo = 50ml of 20x electrolyte concentrate is present in a 1000ml volume to be flushed (nominal dilution) and it is known that Cond is 12mS / cm at nominal dilution, then EICo = 1000*12ml*mS / cm = 12000ml*mS / cm.

[0109] • E can be translated into a volume integrated Cond value EIC similarly as was done with Eo to EICo.

[0110] • IC is the volume integrated Cond (post UF 18) since the flush start.

[0111] EIC can be calculated as:

[0112] EIC = EICo - IC (eq. 1)

[0113] The ratio between G and E is constant and hence is the ratio between G and EIC constant. Where flushing is carried out with the aim to obtain or go below a certain concentration CG, that concentration may be determined or assessed based on determining the amount G as the parameter of interest. Moreover, G may be obtained based on the known relation between amounts of G and E, wherein G may be calculated as:

[0114] G = Go*EIC / EICo (eq. 2)

[0115] Figs 7 A and 7B show diagrams which illustrate flushing without additional E concentrate dosing, meaning that the G / E ratio is constant, as in the foregoing example. Fig. 7A shows the Cond curve, i.e., conductivity measured using the sensor 171 at the sensing point post the UF 18 as a function of time since start of flushing 620. Here, the flow rate of E is zero throughout the flushing. EICo is the area under the entire Cond curve, i.e., the integrated value of the Cond curve.

[0116] Fig. 7B shows the glucose concentration CG curve. Go is the area under the entire concentration curve. Similarly, as for the GCR method, the measured Cond will eventually be too low to enable accurate measurement as indicated by the Cond detection limit (horizontal line in Fig. 7A, pertaining to left y axis). This will limit the method’s G determination sensitivity. The vertical line in Figs 7A and 7B thus indicates when the Cond detection limit is reached. The determined G is then equal to Gi (the area enclosed by the glucose concentration curve and the black line). The outlet glucose concentration detection limit was 3.6%o in this case.

[0117] Dependent on the sensitivity of the conductivity sensor 171, and the target value of the concentration level that needs to be obtained, e.g., based on requirements associated with the UF 18, the process above may be further refined by adding 630 an additional amount of electrolytes E (by additional injection of EC) into the fluid line 11 during the flush, without adding further glucose G. This will increase the sensitivity for measuring lower glucose concentration CG-

[0118] If additional E (Eadd) is added during the flush, corresponding to the addition of ElCadd, eq. 1 can be modified to:

[0119] EIC = EICo - IC + ElCadd (eq. 3)

[0120] EIC will still represent the volume integrated Cond present in the system. If EIC is recalculated during the flush because of an E addition, it needs to be related to the glucose amount present in the system at the time of the E addition (Gadd). Eq. 2 therefore modifies to:

[0121] G = Gadd*EIC / EICo (eq. 4)

[0122] Here, EIC is calculated by eq. 3 and Gadd is the glucose amount in the system at the time of the E addition. As mentioned in correlation with the flowchart of Fig. 6, adding the additional amount may in one example comprise adding 631 an initial amount Eadd at start of the flushing 620.

[0123] Figs 8A and 8B show diagrams of such an example. As in Figs 7A and 7B, Fig. 8A indicates the Cond detection limit by a horizontal line, pertaining to the left y axis, whereas the vertical line in Figs 8A and 8B indicates when this Cond detection limit is reached (dependent on flow rate in the fluid line 11). Since no G is added, the concentration curve of Fig. 8B looks the same as in Fig. 7B.

[0124] Since the E addition occurs at the flush start, EIC is calculated per eq. 3 during the flush. G is then calculated during the flush per eq. 4. Since the E addition (Eadd) is performed before any glucose has been flushed out, Gadd will equal Go.

[0125] As can be seen from Fig. 8A, this example provides an injection of Eadd which takes the shape of a pulse of a flowrate IT. (using pump 211) for a brief period of time. In the example shown in Fig. 8A, the flow rate is 40ml / min for 10s, but other configurations of the injection of Eadd are possible. The flushing 620 may otherwise be carried out without adding E into the fluid line, i.e., outside said period of time. This is also indicated in Fig. 8A. Due to the flow distance between the E dosing point 15 (151) and the sensing point of conductivity sensor 171, and the internal mixing caused by the hold-up volume of the UF 18, this pulse results in a later bump increase in the measured Cond. In turn, this results in the Cond detection limit being reached later than in the example of Figs 7A and 7b. The glucose detection limit, related to the remaining glucose Gi in the system at the Cond detection limit, was 0.9%o in this example.

[0126] As mentioned in correlation with the flowchart of Fig. 6, adding the additional amount may in some examples comprise adding 632 an extra amount Eadd after start of the flushing 620.

[0127] Figs 9A and 9B show diagrams of such an example. As in the previous graphs, Fig. 9A indicates the Cond detection limit by a horizontal line, pertaining to the left y axis, whereas the vertical line in Figs 9A and 9B indicates when this Cond detection limit is reached. Since no G is added, the concentration curve of Fig. 8B looks the same as in Figs. 7B and 8B.

[0128] As can be seen from Fig. 9A, this example provides an injection of Eadd which takes the shape of a pulse of a flowrate I . (using pump 211) for a brief period of time. As in the previous embodiment, Fig. 9A shows an example where the flow rate is 40ml / min for 10s, but other configurations of the injection of Eadd are possible. Rather than taking place at the start of flushing, the pulse of Eadd is injected at a point in time when the detected conductivity has declined, due to flushing.

[0129] In some examples, the extra amount Eadd is added upon the detected conductivity falling to reach a trigger level. The trigger level may be the detection limit, or higher. In the shown example, if this functionality is implemented, the trigger level would be about 2 mS / cm.

[0130] In some examples, the extra amount Eadd is added at a point in time such that, during the flushing, the detected conductivity increases, on account of the added extra amount Eadd, prior to the detected conductivity falling below a predetermined conductivity threshold, such as the detection limit of the sensor 171. This is also the case shown in Fig. 9A. This can be ensured by proper timing of the injection of the extra amount Eadd, based on pre-characterization of the system in a calibration stage and / or based on historical conductivity measurements upon flushing the apparatus, i.e., to obtain knowledge of how the conductivity is expected to change based on timing of the injection. This will thus be based on the actual system setup of the fluid line 11.

[0131] Injection of the extra amount Eadd may thus be executed based on the detected conductivity and / or based on time (corresponding to a flow of a certain even flow rate of the main pump 14).

[0132] In the examples of Figs 9A and 9B, Eadd may thus be injected during the flush as the conductivity approaches the lower measurement limit of the conductivity sensor 171, i.e., the dosing of Eadd is timed as to not have the conductivity at the sensing point of the sensor 171 undercut its measurement limit. The flushing 620 may otherwise be carried out without adding E into the fluid line, i.e., outside said period of time. This is also indicated in Figs 9 A and 9B.

[0133] As Eadd is injected during the flush, ElCadd needs to be added to the current EIC value, per eq. 3.

[0134] Eq. 2 can be used to calculate G during the flush before the E addition but from the E addition and onwards, eq. 4 needs to be used (since some of the glucose has been flushed out of the system at the time of the E addition, Gadd needs to replace Go).

[0135] Due to the flow distance between the E dosing point 15 (151) and the sensing point of conductivity sensor 171, and the internal mixing caused by the hold-up volume of the UF 18, the pulse of Eadd injection results in a later bump increase in the measured Cond, and specifically later than in the example of Figs 8 A and 8B. In turn, this results in the Cond detection limit being reached later than in both the example of Figs 7 A and 7b and Figs 8A and 8B. The outlet glucose concentration detection limit was 0.5%o in this case.

[0136] Based on the example described with reference to Figs 9A and 9B, it shall be noted that adding an additional amount may in some examples comprise repeatedly adding extra amounts Eadd after start of the flushing, optionally in combination with adding an initial amount at the start of flushing as described with reference to Figs 8A and 8B. Repeatedly adding extra amounts Eadd may thus be carried out at different occasions of said period of time, which occasions are distributed in time during the flushing. The flushing may otherwise be carried out without adding E into the fluid line, i.e., outside said occasions of said period of time. The amount of E injected on each occasion of adding an additional amount Eadd may also differ. As noted, this may be configured based on pre-characterization or historic use of the system at hand. Specific configuration of the method may be designed to ensure that the glucose concentration detection limit does not exceed the target value at hand for the glucose level which, as noted, may be associated with requirements on fluid held in the UF 18 upon subsequent heat disinfection.

[0137] Various aspects of the proposed solution have been outlined in the foregoing, both related to the apparatus 10 and the method. In this context, it may be noted that the proposed solution is not limited to hold-up volumes caused by ultrafilter priming volumes but could be used to mitigate the negative effects of hold-up volumes caused by any component used for whatever reason. It may further be mentioned that where various examples of the proposed solution have been described as including calculations (including integration), these may be carried out by the control system 30.

[0138] The proposed solution is defined by the terms of the appended claims.

Claims

29CLAIMS1. A flushing method carried out in an apparatus configured to generate a medical fluid by continually mixing a base fluid with at least one soluble substance in a fluid line extending from an inlet to an outlet, said method comprising: detecting (610) conductivity of a fluid at a sensing point in the fluid line, wherein said conductivity is indicative of a concentration level of a first substance introduced at a supply point in the fluid line upstream of the sensing point; flushing (620) the fluid line with the base fluid from said inlet to decrease concentration of at least a second substance in the fluid, wherein the flushing is carried out without addition of the second substance; determining (640) a concentration level of the second substance based on monitoring the detected conductivity during the flushing and on a known relation between amounts of the first and second substances included in the fluid.

2. The method of claim 1, further comprising: terminating (650) the flushing upon the detected conductivity being indicative of the concentration level of the second substance meeting a target value.

3. The method of claim 1 or 2, wherein said fluid line comprises a hold-up volume between the supply point and the sensing point.

4. The method of claim 2 and 3, wherein said hold-up volume is formed in an ultrafilter, wherein said target value is associated with the ultrafilter.

5. The method of any preceding claim, further comprising: providing (660) heat to the fluid in the fluid line after terminating the flushing, to obtain heat disinfection.

6. The method of any preceding claim, wherein, prior to the flushing, concentrations of the first substance and the second substance in the fluid are homogeneous throughout the fluid line.

307. The method of claim 6, wherein the flushing comprises: adding (630) an additional amount of the first substance into the fluid line.

8. The method of claim 7, wherein adding an additional amount comprises adding (631) an initial amount of the first substance at start of the flushing.

9. The method of claim 7 or 8, wherein adding an additional amount comprises adding (632) an extra amount of the first substance after start of the flushing.

10. The method of claim 9, wherein the extra amount is added upon the detected conductivity falling to reach a trigger level.

11. The method of claim 9 or 10, wherein the extra amount is added at a point in time such that, during the flushing, the detected conductivity increases, on account of the added extra amount of the first substance, prior to the detected conductivity falling below a predetermined conductivity threshold.

12. The method of any of claims 9-11, wherein adding an additional amount comprises repeatedly adding extra amounts of the first substance after start of the flushing.

13. The method of any of claims 7-12, wherein a magnitude of the additional amount is determined based on a system volume of fluid between the supply point and the sensing point in the fluid line.

14. The method of any preceding claim, wherein the apparatus is configured to generate a dialysis fluid, said first substance comprising an electrolyte and said second substance comprising an osmotic agent.

15. The method of any preceding claim, comprising introducing the second substance at said supply point in the fluid line, prior to the flushing.

16. The method of any preceding claim, comprising:holding (600), prior to the flushing, a fluid in the fluid line, wherein said fluid comprises the medical fluid having a predetermined concentration of the at least one soluble substance.

17. An apparatus (10) configured to generate a medical fluid by continually mixing a base fluid with at least one soluble substance, said apparatus comprising: a fluid line (11) extending from an inlet (12) for receiving the base fluid to an outlet (13) for delivering the medical fluid, said fluid line comprising a pump (14) and a hold-up volume (18); a supply arrangement (20) fluidly connected at a supply point (15) in the fluid line, upstream of the hold-up volume, to add the substance into the fluid line; a sensor (171) configured to detect conductivity of a fluid in the fluid line at a sensing point downstream of the hold-up volume; and a control system (30) connected to control substance addition from the supply arrangement, and connected to receive detected conductivity from the sensor, wherein said conductivity is indicative of a concentration level of a first substance added by the supply arrangement, wherein the control system is configured to: perform, while inhibiting addition of a second substance to the fluid line, flushing of the fluid line with the base fluid from said inlet to decrease concentration of at least the second substance in the fluid; and determine a concentration level of the second substance based on monitoring the detected conductivity during the flushing and on a known relation between amounts of the first and second substances included in the fluid.

18. The apparatus of claim 17, further configured to operate under control of the control system in accordance with any of claims 2-16.

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