Method for operating a heat exchanger unit for changing the physical state of a substance in an aqueous formulation

Abstract

A method for operating a heat exchanger unit for freezing or thawing an aqueous formulation comprises segmenting a target temperature profile into two separate stages, at least one stage being a step indicating a change in the physical state of the aqueous formulation, determining control parameter variables based on which operation of the heat exchanger unit is to be controlled during an operating cycle, operating the heat exchange unit based on the determined control parameter variables and performing a commissioning operating cycle by measuring the temperature profile of the aqueous formulation, segmenting the measured temperature profile into two separate stages, at least one stage being a step indicating a change in the physical state of the substance, adapting the determined control parameter variables based on a comparison between the segmented measured temperature profile of the substance and the segmented target temperature profile, and operating the heat exchanger unit based on the adapted control parameter variables.

Description

Technical Field

[0001] The present invention relates to a method and a system for operating a heat exchanger unit for changing the physical state of substances in an aqueous formulation, in particular for freezing and / or thawing an aqueous formulation. Further, the present invention relates to a computer program comprising instructions for causing a computer to execute such a method when executed by the computer.

Background Art

[0002] For the proper and effective treatment of pharmaceuticals, for example in pharmaceutical manufacturing procedures, it may be necessary to strictly comply with predefined storage, transportation, and handling requirements. This may be due to the unstable nature of pharmaceuticals and may particularly apply to aqueous formulations containing proteins.

[0003] Depending on the storage temperature, aqueous formulations of proteins may undergo various changes, particularly chemical or biochemical changes such as withstanding microbial growth, foaming during transportation, forming aggregates, and decomposing over time. When such aqueous protein solutions are used in pharmaceutical manufacturing, these changes can affect the properties of the manufactured pharmaceuticals, such as the stability of the pharmaceuticals. Therefore, in order to prevent unwanted and unintended changes, the process of freezing and then thawing protein solutions or other aqueous formulations is commonly used in the pharmaceutical industry.

[0004] However, the process steps of freezing and thawing aqueous formulations, particularly those containing proteins, must follow a tightly controlled process because both of these steps can affect the final properties of the pharmaceuticals. For example, in both of these steps, denaturation can occur for various reasons including freeze concentration and co-solutes, cryoprotectant crystallization, low-temperature denaturation and unfolding / misfolding, immunogenicity, loss of potency, or aggregation which can also cause other changes in important quality characteristics required.

[0005] Therefore, the specification, implementation, and verification of the process of freezing and thawing aqueous formulations used in pharmaceutical manufacturing require long-term experiments and design, and usually take a great deal of time and cost. To carry out these process steps in pharmaceutical manufacturing, it is known to use a heat exchanger system. However, it can be particularly time-consuming and costly to operate and configure such a heat exchanger system so that the predefined freezing and thawing processes and requirements are met during operation.

[0006] Further technical background is known from PARVIZ A SHAMLOU ET AL: "A new scaleable freeze-thaw technology for bulk protein solutions", BIOTECHNOLOGY AND APPLIED BIOCHEMISTRY, ACADEMIC PRESS, US, vol.46, no.1, 23 December 2010 (2010-12-23), pages 13-26. SUMMARY OF THE INVENTION

[0007] Accordingly, an object of the present invention is to provide an improved method and system for operating a heat exchanger unit for changing the physical state of an aqueous formulation by freezing or thawing, and in particular for reliably and efficiently operating the heat exchanger unit according to predefined process requirements. A further object of the present invention is to provide a computer program comprising instructions for causing a computer to execute such an improved method when executed by the computer.

[0008] These objects are solved by the subject matter of the independent claims. Preferred embodiments are described in the present specification, the drawings, and the dependent claims.

[0009] Accordingly, a method is provided for operating a heat exchanger unit for changing the physical state of a substance of an aqueous formulation by freezing or thawing, wherein the aqueous formulation is contained in a container and the heat exchanger unit acts on the aqueous formulation in the container such that the temperature of the pharmaceutical during the operating cycle is regulated based on, or in accordance with, a target temperature profile. The method comprises - segmenting the target temperature profile into at least two distinct stages, wherein at least one stage indicates a change in the physical state of the aqueous formulation, and - determining at least one control parameter variable for controlling the operation of the heat exchanger unit during the operating cycle based on the target temperature profile, and - -- operating the heat exchange unit during a commissioning operating cycle based on the determined control parameter variable, and -- measuring a temperature profile indicative of the course of the temperature of the aqueous formulation during the commissioning operating cycle, including performing a commissioning operating cycle comprising these sub-steps.

[0010] The method further comprises - segmenting the measured temperature profile into at least two distinct stages, wherein at least one stage indicates a change in the physical state of the aqueous formulation, and - adapting the determined control parameter variable based on a comparison between the segmented measured temperature profile and the segmented target temperature profile, and - operating the heat exchanger unit based on the adapted control parameter variable to freeze and / or thaw the aqueous formulation.

[0011] By providing a method of segmenting the temperature profile into distinct stages, with at least one stage indicating a change in the physical state of the substance of the aqueous formulation, the proposed method can enable the efficient and effective determination and / or adaptation of control parameter variables in order to reliably operate the heat exchanger in accordance with a target temperature profile that constitutes predefined process requirements.

[0012] The proposed method may be a computer-implemented method. That is, the method steps described below can include at least in part a computer, a computer network, or other programmable devices. In other words, at least one method step is realized by a program.

[0013] In particular, the method of the present invention can be implemented by using a computer, that is, by storing the method steps of the present invention in a memory (for example, a non-transitory memory) and executing the stored method steps by using a central processing unit (CPU). As used herein, the term "computer program" or "program" is intended to refer to a series of method steps stored in a memory configured to be executed by a CPU.

[0014] Furthermore, the proposed method can be used in pharmaceutical manufacturing where an aqueous formulation can undergo a predetermined and strictly controlled freezing and / or thawing treatment step. However, the proposed method is not limited to this application and can be applied to any suitable application where the change in the physical state of the substance of the aqueous formulation is carried out according to strict specifications and regulations. Therefore, the proposed method can be applied to set or readjust the proper operation of any heat exchanger unit aimed at changing the physical state of the substance of the aqueous formulation.

[0015] As used herein, the term "physical state of a substance" (which may also be called the state of aggregation) means the physical state such as the solid, liquid, or gaseous state of the substance, and the method of the present invention focuses on the change in the physical state between solid and liquid (by freezing or thawing).

[0016] Preferably, the aqueous formulation to be frozen and / or thawed during the execution of the method contains water as the main (or even sole) component and may further contain a buffer solution, a cell culture medium, and / or one or more active pharmaceutical ingredients. The change in the physical state of the substance in the sense of the present invention essentially includes the freezing or thawing of water in the aqueous formulation.

[0017] In the context of the present disclosure, the term "aqueous formulation of an active pharmaceutical ingredient" (often also referred to as "formulation") refers to any aqueous formulation containing an active pharmaceutical ingredient in an aqueous medium such as a buffer solution, cell culture medium, etc. The active pharmaceutical ingredient is a pharmaceutically active substance (often referred to as the "API", active pharmaceutical ingredient).

[0018] Various types of active pharmaceutical ingredients are known to those skilled in the art, ranging from large molecules such as proteins or peptides to small organic molecules. In particular, in the case of large molecules, changes in the physical state of aqueous formulations containing such active pharmaceutical ingredients can be particularly significant as described herein.

[0019] The term "protein" means a macromolecule composed of an amino acid sequence. The protein may be, for example, a therapeutic protein used for the diagnosis, treatment, and / or prevention of a disease or disorder. The protein may be a natural protein, i.e., a protein produced by naturally occurring non-recombinant cells, or may be produced by genetically engineered cells or recombinant cells, and includes molecules having the amino acid sequence of a natural protein, or molecules having a deletion, addition, and / or substitution of one or more amino acids of the natural sequence, or molecules having the amino acid sequence of a protein not related to the natural protein. This term also includes amino acid polymers in which one or more amino acids are chemical analogs of the corresponding naturally occurring amino acid polymers.

[0020] Preferred protein active pharmaceutical ingredients are antibodies, and the antibodies may include monoclonal antibodies and polyclonal antibodies, whole antibodies, antibody-drug conjugates, chimeric antibodies, humanized antibodies, human antibodies, or hybrid antibodies having dual or multiple antigen or epitope specificities, antibody fragments, and antibody sub-fragments such as Fab, Fab’, F(ab’)2, fragments, and include any immunoglobulin that acts like an antibody by binding to a specific antigen to form a complex, or any hybrid fragment of a natural, synthetic, or genetically engineered protein.

[0021] Suitable aqueous media are known to those skilled in the art. Preferred aqueous media are water or aqueous buffers.

[0022] At least one pharmaceutically acceptable excipient may also be included in the aqueous formulation. Suitable excipients such as stabilizers, pH adjusters, etc. are known to those skilled in the art. In some embodiments, polysorbates such as polysorbate 20, 40, 60, or 80 can be used as stabilizers that can improve the stability of protein drugs in aqueous formulations.

[0023] A preferred embodiment of the aqueous formulation used in the proposed method is an aqueous formulation containing the active pharmaceutical ingredient. According to this embodiment, the change in the physical state of the substance of the aqueous formulation can refer to the change in the physical state of the substance of the water contained in the aqueous formulation containing the active pharmaceutical ingredient, i.e., the freezing and / or thawing of the water in the aqueous composition containing the active pharmaceutical ingredient.

[0024] As described above, this method is intended and applied to control the operation of the heat exchanger unit. The heat exchanger unit is configured to change the physical state of the substance of the aqueous formulation, particularly by freezing and / or thawing the aqueous formulation during the operation cycle. In the context of the present disclosure, the term "operation cycle" refers to a period of a predetermined length during which the heat exchanger unit is operated to control heat transfer to and / or from the aqueous formulation, and at least one change in the physical state of the aqueous formulation occurs. In other words, the heat exchanger unit can be configured to freeze and / or thaw the aqueous formulation during the operation cycle. For example, the heat exchanger unit can be operated to first freeze and then thaw the aqueous formulation during the operation cycle, or vice versa. Therefore, the heat exchanger unit may also be referred to as a cooling unit, a freezing unit, a thawing unit, or a freeze-thaw unit.

[0025] Generally, a heat exchanger unit can be configured to transfer heat to or from an aqueous formulation, particularly to control or manipulate the heat flow. To do so, the heat exchanger unit can comprise a controllable heat transfer component, which can also be referred to as a cooling component. Accordingly, the heat exchanger unit can be configured to control the heat transfer between the heat transfer component and the aqueous formulation during an operating cycle based on determined control parameter variables. The heat transfer component can be configured to manipulate the amount and direction of the heat flow to or from the aqueous formulation. Specifically, the heat transfer component can be configured to transfer heat to or from the aqueous formulation by at least one of heat conduction, heat convection, and heat radiation. For example, the heat transfer component can comprise a heat transfer plate through which a heat transfer medium (also referred to as a "cooling medium") can pass, the flow rate and / or temperature of which can be controlled by the heat exchanger unit during the operating cycle.

[0026] The heat exchanger unit can be configured to receive or contain the aqueous formulation to be processed. To do so, the heat exchanger unit can comprise a receiving space for containing the aqueous formulation during the operating cycle. The heat transfer component can at least partially delimit the receiving space. In a receiving state in which the aqueous formulation is received within the receiving space of the heat exchanger unit, a heat conduction connection may be provided between the heat transfer component and the aqueous formulation. Specifically, the surface of the heat transfer component can form the surface of the receiving space, particularly the inner surface of the receiving space. The receiving space can form a reservoir for the aqueous formulation. According to one configuration, in the receiving state of the aqueous formulation, the aqueous formulation may be in direct contact with or in thermal contact with the surface of the receiving space.

[0027] Alternatively, the heat exchanger unit may be configured to receive or store an aqueous formulation within a container such as a bag or a bottle. In the context of the present disclosure, the term "container" refers to any component configured to contain or store an aqueous formulation. The container may be removably received within the heat exchanger unit, particularly within the receiving space. That is, the container received within the heat exchanger unit may be replaced with another container that may be structurally the same or different, particularly having a different size or volume. For example, the container may have a volume in the range of 10 l to 0.25 l, but may have a volume greater than 10 l or less than 0.25 l. For example, the container may have a volume of 9 l, or 5 l, or 0.4 l. The container may be made of plastic such as polyethylene and / or copolymers, particularly ethylene-vinyl alcohol copolymer. Further, the container may be intended for single use only, such as for only a single operating cycle of the heat exchanger unit, for example. Furthermore, the container may be intended to be used over multiple unit operations and multiple actions or cycles within a given unit operation. The container can be at least partially in direct or thermal contact with the surface of the receiving space, particularly the surface of the heat transfer component, thereby allowing heat to be transferred via heat conduction and / or heat convection. To enable proper placement of the container within the receiving space, at least one insertion component may be disposed within the receiving space together with the container. In this way, containers of various sizes and volumes can be reliably and properly placed within the receiving space.

[0028] As described above, in order to change the physical state of a substance, the heat exchanger unit is configured to control or manipulate the heat flow to or from an aqueous formulation, particularly to or from a container. To do so, the heat exchanger unit may comprise a control unit configured to control the operation of the heat exchanger unit, particularly the heat transfer components, based on at least one control parameter. In the context of the present disclosure, the term "control parameter" refers to a parameter that is controlled based on the operation of the heat exchanger unit, particularly the heat transfer components, particularly a process variable. Thus, changing the control parameter affects the operation of the heat exchanger unit or the process variable. In other words, changing the control parameter during operation of the heat exchanger unit enables the manipulation of heat transfer to or from the aqueous formulation. The control parameter can indicate the process variable of the heat exchanger unit that is set. For example, the control parameter may indicate or refer to the temperature of the heat transfer component that is set during operation of the heat exchanger unit. More specifically, the control parameter may indicate or refer to the temperature of the cooling medium flowing through the heat transfer component. Preferably, the control parameter may indicate a predetermined temperature of the heat transfer medium or a temperature setpoint of the cooling medium. Alternatively or additionally, the control parameter may indicate or refer to the flow rate of the cooling medium flowing through the heat transfer component. In other words, the control parameter variable, i.e., the variable of the control parameter, affects the desired change of the control variable of the heat exchanger unit, particularly the change in the temperature and / or flow rate of the heat transfer medium flowing through the heat transfer component. In other words, the control parameter variable, i.e., the variable of the control parameter, affects the desired change of the control variable of the heat exchanger unit, particularly the change in the temperature and / or flow rate of the heat transfer medium flowing through the heat transfer component.

[0029] In this context, the term "control parameter variable" refers to a variable or process of at least one control parameter of the heat exchanger unit during an operating cycle. Thus, the control parameter variable indicates how at least one process variable of the heat exchanger unit is set and changed over time, i.e., during the operating cycle. Accordingly, the control parameter variable associates one value of the control parameter with each of different points in time during the operating cycle. Thus, the control parameter variable may be provided or represented in the form of a function or curve that assigns or defines exactly one value of the control parameter for a series of points in time or each point in time during the operating cycle. For example, at least one control parameter variable may indicate the course of the temperature of the heat transfer component during the operating cycle. Alternatively or additionally, at least one control parameter variable may indicate the course of the temperature or flow rate of the heat transfer medium during the operating cycle. Preferably, the control parameter variable indicates or is the course of a predetermined temperature of the heat transfer medium, i.e., a temperature setpoint.

[0030] Specifically, the control parameter variable can define the change in the control parameter of the heat exchanger unit at a stage indicating a change in the physical state of the aqueous formulation, i.e., the freezing stage and / or the thawing stage, particularly the freezing stage, and / or at least one of the cooling stage and the heating stage. The cooling stage or the heating stage may refer to the stage where the temperature of the aqueous formulation decreases or increases. More specifically, the control parameter variable can define or indicate the change in the temperature of the heat transfer component at a stage indicating a change in the physical state of the aqueous formulation, i.e., the freezing stage and / or the thawing stage, particularly the freezing stage and / or at least one of the cooling stage and the heating stage. Further, the control parameter variable can define or indicate the change in the temperature and / or flow rate of the cooling medium flowing through the heat exchanger unit at a stage indicating a change in the physical state of the aqueous formulation, i.e., the freezing stage and / or the thawing stage, particularly the freezing stage and / or at least one of the cooling stage and the heating stage.

[0031] In order to operate the heat exchanger unit based on control parameters or control parameter variables, the control unit can apply feedback control such as closed-loop control to ensure that the process variables of the heat exchanger unit are properly set according to the control parameters. For example, when the control parameter indicates or refers to the temperature of the heat transfer component, the heat exchanger unit may be equipped with a temperature sensor configured to measure the temperature of the heat transfer component and transmit a feedback signal indicating the measured temperature to the control unit.

[0032] Those skilled in the art will understand that this method can be implemented using different types of heat exchanger units and that the present invention is not limited to a specific configuration of the heat exchanger unit. The structure and function of such heat exchanger units and their components are well known to those skilled in the art and will therefore not be specified further. Rather, the features of the method for operating such a heat exchanger unit for changing the physical state of the aqueous formulation, which is interrelated with the present invention, will be described below.

[0033] The proposed method is intended to operate the heat exchanger unit such that the aqueous formulation undergoes a temperature change during an operating cycle in which it can follow or mimic a target temperature profile. Thus, in the context of the present disclosure, the term "target temperature profile" refers to the intended or predetermined profile of the temperature present in the aqueous formulation during the operating cycle of the heat exchanger unit.

[0034] The target temperature profile may be related to the temperature profile of an aqueous formulation that is processed by another heat exchanger unit. The other heat exchanger unit may be a reference heat exchanger unit whose operation is mimicked by the heat exchanger unit. In other words, the proposed method may be intended to operate the heat exchanger unit such that the temperature profile of the aqueous formulation being processed mimics or corresponds to the temperature profile that the aqueous formulation undergoes when processed by the reference heat exchanger unit. The reference heat exchanger unit may have different processing characteristics for different aqueous formulations compared to the heat exchanger unit controlled by the proposed method. Specifically, the heat exchanger unit controlled by this method may be a scaled-down model, in particular a scaled-down model of the reference heat exchanger unit. For example, the reference heat exchanger unit may have a different, in particular greater, processing capacity for different aqueous formulations compared to the heat exchanger unit controlled by this method. In other words, the maximum amount of aqueous formulation processed during an operating cycle may differ between the heat exchanger unit and the reference heat exchanger unit.

[0035] Accordingly, the target temperature profile can refer to or correspond to the temperature change that the aqueous formulation undergoes when processed by the reference heat exchanger unit to change its physical state. To determine the target temperature profile, the method may further include operating the reference heat exchanger unit to change the physical state of the aqueous formulation during an operating cycle and measuring the temperature profile of the aqueous formulation when processed by the reference heat exchanger unit during the operating cycle. Accordingly, the target temperature profile may correspond to the temperature profile of the aqueous formulation within or when processed by the reference heat exchanger.

[0036] The method further includes segmenting the target temperature profile into at least two distinct stages. In the context of the present disclosure, the term "distinct stages" may refer to non-overlapping stages or segments of the target temperature profile that are adjacent to each other without gaps. By segmenting the target temperature profile, different stages of the target temperature profile are identified and defined.

[0037] A separate stage of the target temperature process can refer to one of a temperature change stage, a temperature holding stage, or a physical state change stage. The temperature change stage can refer to a period during an operating cycle in which the temperature of the aqueous formulation changes over time, i.e., without changing the physical state of the aqueous formulation. The temperature holding stage can refer to a period during an operating cycle in which the temperature of the aqueous formulation is maintained at a constant or substantially constant level without changing the physical state of the aqueous formulation. The physical state change stage can refer to a period during an operating cycle in which the physical state of the aqueous formulation changes, i.e., without changing the temperature of the aqueous formulation or without substantially changing the temperature of the aqueous formulation.

[0038] If the aqueous formulation freezes during the physical state change stage, such a physical state change stage may be referred to as a freezing stage.

[0039] If the aqueous formulation is thawed during the physical state change stage, such a physical state change stage may be referred to as a thawing stage.

[0040] The target temperature process may include a plurality of different separate temperature change stages that may differ from each other, for example, from the perspective of the temperature change rate and / or the temperature level. Alternatively or additionally, the target temperature process may include a plurality of different separate temperature holding stages that may differ from each other, for example, from the perspective of the temperature level. Alternatively or additionally, the target temperature process may include a plurality of different physical state change stages.

[0041] According to one configuration, the target temperature process is - a first stage referring to a temperature change stage in which the aqueous formulation is cooled until it freezes, i.e., until it reaches the freezing point of the aqueous formulation, - a second stage referring to a physical state change while the aqueous formulation freezes, i.e., a freezing stage, - a third stage referring to a further temperature change stage in which the aqueous formulation is cooled until it reaches a predetermined temperature lower than the freezing point, - a fourth stage referring to a temperature holding stage in which the aqueous formulation is held at a predetermined temperature, - A fifth stage that refers to a further temperature change stage in which the aqueous formulation is heated until it reaches the thawing point of the aqueous formulation, - A sixth stage that refers to a further change in the physical state while the aqueous formulation is thawed, i.e., the thawing stage, - A seventh stage that refers to a further temperature change stage in which the aqueous formulation is heated until it reaches a further predetermined temperature higher than the thawing point, and - An eighth stage that refers to a further temperature holding stage in which the aqueous formulation is held at a further temperature, and at least two of the eight stages can be included, The first stage and the third stage may sometimes be referred to as the cooling stage, The fifth stage and the seventh stage may sometimes be referred to as the heating stage, At least one of the two stages is a change in the physical state of the substance phase, and at least two stages are adjacent to each other.

[0042] Specifically, the step of segmenting the target temperature process into at least two distinct stages is performed such that at least one of the segmented stages, i.e., the stages identified during this method step, refers to a change in the physical state of the aqueous formulation, particularly the freezing or thawing of the aqueous formulation. In other words, at least one of the stages identified in the step of segmenting the target temperature process refers to a physical state change stage as described above, such as a freezing stage or a thawing stage. Preferably, during this stage, the change in the physical state of the aqueous formulation is initiated and completed. The step of segmenting the target temperature process may be performed to identify at least one of a freezing stage in which the aqueous formulation is frozen and a thawing stage in which the aqueous formulation is thawed. Further, the step of segmenting the target temperature process may be performed to segment the target temperature process into at least two of the above-described first to eighth stages that are adjacent to each other, and at least one of the at least two of the above-described first to eighth stages is a thawing stage or a freezing stage, and there is no gap between the stages. According to one configuration, the target temperature process can be segmented into the above-described first to eighth stages that continuously follow each other.

[0043] The step of segmenting the target temperature process may include identifying the end points of each stage, i.e., the points at which different stages start and end, and said end points may also be referred to as cut-off points or limit points or start and end points. Each identified stage may be defined by its start point and its end point. In other words, the step of segmenting the target temperature process may include segmenting the target temperature process into stages by identifying the end points of the stages.

[0044] The step of segmenting the target temperature path may be implemented by a computer program. Specifically, this step may be executed in an automated manner. To do so, for example, a computer program executed on a control unit of a heat exchanger unit may be configured to analyze the target temperature process based on the freezing point and thawing point of an aqueous formulation and identify the stages in which the aqueous formulation is held at temperature levels corresponding to the freezing point and / or thawing point, and these stages are changes in the physical state of the substance phase. Further, the computer program may be able to analyze the target temperature process to identify the stages in which the temperature of the aqueous formulation changes over time, and these stages may be temperature change stages. Furthermore, the program may be able to analyze the target temperature process to identify the stages in which the temperature of the aqueous formulation is held at temperature levels different from the freezing point and thawing point of the aqueous formulation, and these stages are temperature holding stages.

[0045] Alternatively or additionally, the segmentation of the target temperature process may be obtained from a database. Alternatively or additionally, the step of segmenting the target temperature process may be executed based on user interaction or user input. To do so, for example, a user may provide an input indicating the end points of different stages to a computer program. Based on this input, the computer program may identify and define different stages of the target temperature process.

[0046] Alternatively or additionally, the step of segmenting the target temperature process may include processing the segmented target temperature process, i.e., its identified different stages. Specifically, the step of segmenting the target temperature process may include adapting the stages of the target temperature process by applying a regression analysis method. Specifically, the step of segmenting the target temperature process may include adapting the stages of the target temperature process by applying linear regression. Alternatively or additionally, the step of segmenting the target temperature process may include adapting the stages of the target temperature process by applying the least squares method or any other suitable regression analysis method. By doing so, the process of the target temperature process can be adaptively adjusted in a segmented manner, i.e., stage by stage. To apply linear regression, at least one of the identified stages of the target temperature process, particularly each of the stages, can be adapted such that the process of the target temperature within a separate stage follows the following equation.

Number

[0047] This method further includes the step of determining at least one control parameter variable. Such a control parameter variable refers to the variable of the above-mentioned control parameter over time based on the operation of the heat exchanger unit during the operation cycle. The step of determining the control parameter variable is executed based on the target temperature process, particularly the segmented target temperature process, i.e., the target temperature process after being processed by the step of segmenting the target temperature process. In a further development, the step of determining the control parameter variable may be executed based on the characteristics of the aqueous formulation, particularly the physical or chemical characteristics of the aqueous formulation, or as a function thereof. For example, the step of determining the control parameter variable may be executed as a function of the volume of the aqueous formulation processed by the heat exchange unit, particularly as a function of the volume of the container containing the aqueous formulation.

[0048] Alternatively or additionally, the step of determining the control parameter variable may be executed as a function of the type of the aqueous formulation or as a function of the thermal conductivity of the aqueous formulation. Specifically, the step of determining the control parameter variable may be executed based on the thermodynamic characteristics of the aqueous formulation. Thus, the control parameter variable may be determined based on the freezing point or thawing point of the aqueous formulation. For example, when the aqueous formulation is an aqueous formulation containing a drug substance, the step of determining the control parameter variable may be executed based on the freezing point and / or thawing point of water or by taking into account the freezing point and / or thawing point. Specifically, this step may be executed such that during the freezing stage, the temperature setpoint of the heat transfer medium is set lower than the freezing point of water, and during the thawing stage, the temperature setpoint of the heat transfer medium is set higher than the thawing point of water.

[0049] The step of determining the control parameter variable may further include a sub-step of identifying the freezing stage in the target temperature process, particularly the segmented target temperature process, i.e., the target temperature process provided as the output of the step of segmenting the target temperature process. Further, the duration of the operation cycle corresponding to the identified freezing stage, i.e., the period during which the aqueous formulation is subjected to freezing during the operation cycle, can be determined.

[0050] In the context of the present invention, it has been found that a temperature shift may occur during freezing of an aqueous formulation, particularly when the volume of the aqueous formulation is relatively small. This temperature shift may be caused by the supercooling effect. Specifically, the temperature shift may occur due to a sudden release of energy that may be caused by sudden nucleation of the aqueous formulation. To prevent such a sudden temperature shift, i.e., a temperature shift caused by sudden nucleation during freezing, the step of determining the control parameter variable may further include a sub-step of implementing an increase or decrease (also referred to as a spike) of the control parameter variable during a period corresponding to the freezing stage and / or a period preceding the freezing stage. The increase or decrease of the control parameter variable may be defined to cause an improvement, particularly a temporary improvement, in the cooling performance of the heat exchanger unit. Specifically, the increase or decrease of the control parameter variable may be defined to lower or temporarily lower the temperature of the heat transfer component before and / or at the start of the freezing stage.

[0051] The following describes an exemplary embodiment for implementing an increase or decrease in a control parameter variable. In this exemplary embodiment, the control parameter may be the temperature setpoint of the cooling medium flowing through the heat transfer component. Specifically, at a certain stage, for example, in the temperature decrease stage preceding the freezing stage, the control parameter, i.e., the temperature setpoint, may decrease to the nucleation spike temperature. The nucleation spike temperature may be in the range of -22.5°C to -37.5°C, preferably -25°C to -35°C, for example -30°C. Thereafter, alternatively or additionally, the control parameter may be held at the nucleation spike temperature for a predetermined period, also referred to as the nucleation spike holding time. Specifically, the nucleation spike holding time may be within the range of 5% to 50% of the duration of a stage such as the temperature decrease stage preceding the freezing stage. Next, alternatively or additionally, the control parameter increases from the nucleation spike temperature to the freezing temperature. This may be performed during the period corresponding to the determined start of the freezing stage. Specifically, the step of increasing the control parameter from the nucleation spike temperature to the freezing temperature may be performed during a period having a duration in the range of 1% to 20% of the duration of the freezing stage. The freezing temperature may be in the range of -5°C to -20°C, preferably -10°C to -17.5°C, more preferably -12.5°C to -17.5°C. Alternatively or additionally, thereafter, i.e., after the control parameter reaches the freezing temperature, especially until the aqueous formulation freezes, the control parameter is maintained at this freezing temperature.

[0052] Therefore, in the exemplary embodiment, in the stage preceding the freezing stage, for example, the temperature decrease stage, the control parameter decreases to reach the nucleation spike temperature in the first sub-stage and is then maintained at this temperature in the second sub-stage. Next, the control parameter increases to the freezing stage in the first sub-stage of the freezing stage and is then maintained at the freezing temperature in the second sub-stage of the freezing stage.

[0053] In a further development, the operator can set at least one of the nucleation spike temperature, the nucleation spike holding time, the freezing temperature, and the thawing temperature.

[0054] In a further development, the ascending or descending characteristics implemented in the control parameter variables, such as its shape, in particular its slope and height, may be set based on the characteristics of the aqueous formulation, such as the type or volume of the aqueous formulation, in particular the physical or chemical characteristics.

[0055] This method further includes the step of performing a commissioning operation cycle. In the context of the present disclosure, the term "commissioning operation cycle" may refer to a commissioning of the heat exchanger unit that may not guarantee proper operation of the heat exchanger unit and is used to properly set or readjust the operation of the heat exchanger unit. Specifically, this step includes the sub-step of operating the heat exchanger unit during the commissioning operation cycle based on the determined control parameter variables. Accordingly, the determined control parameter variables function as a set of preliminary control parameters. In a further sub-step, the substance temperature process is measured during the commissioning operation cycle. In the context of the present disclosure, the term "substance temperature process" refers to the process of the temperature present in the aqueous formulation during the operation of the heat exchanger unit. In other words, the substance temperature process indicates the process of the temperature of the aqueous formulation during the commissioning operation cycle. To measure and monitor the temperature of the aqueous formulation, the heat exchanger unit may further comprise a temperature sensor configured to measure the temperature present in the aqueous formulation during the operation of the heat exchanger unit. Preferably, the temperature sensor may be configured to measure the temperature of the aqueous formulation at or substantially at the center of the aqueous substance. For example, in the process of freezing of the aqueous formulation, the freezing starts from the outer edge of the aqueous formulation in contact with the wall of the container containing the aqueous formulation and progresses towards the center of the aqueous formulation until the entire aqueous formulation freezes into a solid. Since the depression of the freezing point of water by dissolved substances is known, it may happen that the active ingredient or other dissolved components actually start to accumulate at the center of the volume of the aqueous substance. Placing the temperature sensor at or near the center of the aqueous substance takes into account the possibility of accumulation of the components of the aqueous formulation during the freezing process. Specifically, the temperature sensor may be configured to measure the temperature of the aqueous formulation at the center of the container containing the aqueous formulation. According to one embodiment, the temperature of the aqueous formulation is detected by a sensor disposed within the aqueous formulation, in particular within the container.

[0056] This method further includes the step of segmenting the measured substance temperature process into at least two distinct stages, with at least one stage referring to a change in the physical state of the aqueous formulation. This step can be carried out corresponding to the step of segmenting the above-described target temperature path. Thus, all the features described in relation to the step of segmenting the target temperature process can also be applied to the step of segmenting the measured substance temperature process and are thus disclosed. Specifically, the step of segmenting the measured temperature process can be carried out to identify at least one of a freezing stage where freezing of the aqueous formulation is carried out and a thawing stage where thawing of the aqueous formulation is carried out. Alternatively or additionally, the step of segmenting the measured substance temperature process can be carried out to identify different stages corresponding to the stages identified as a result of the step of segmenting the target temperature process, taking into account their number and type. Further, the step of segmenting the measured substance temperature process may include segmenting the measured substance temperature process into stages by identifying the end points of the stages. Alternatively or additionally, the step of segmenting the measured substance temperature process may include adapting the stages of the measured temperature process by applying linear regression.

[0057] This method further includes the step of adapting the determined control parameter variable based on the comparison between the segmented measured substance temperature process and the segmented target temperature process. Specifically, the comparison between the segmented measured substance temperature process and the segmented target temperature process can be performed step by step. That is, corresponding steps can be identified and compared between the segmented measured substance temperature process and the segmented target temperature process. In the context of the present disclosure, the term "corresponding step" refers to the step in the target temperature process and the step in the measured temperature process. Both the temperature process in the target temperature process and the temperature process in the measured substance temperature process refer to either a temperature increase step in which the temperature rises, or a temperature decrease step in which the temperature drops, or a temperature holding step in which the temperature is maintained at a certain temperature level different from the freezing point or the thawing point, or a freezing step or a thawing step. Further, the step in the target temperature process and the step in the measured temperature process that constitute the corresponding step may occur repeatedly during the operation cycle, or may occur in substantially the same or similar periods.

[0058] Specifically, the step of adapting the control parameter variable may include a sub-step of identifying corresponding steps between the segmented measured substance temperature process and the segmented target temperature process, a sub-step of determining the duration of the corresponding step and / or the average temperature of the corresponding step, and a sub-step of adapting the determined control parameter variable based on the comparison of the determined duration and / or the average temperature of the corresponding step.

[0059] Alternatively or additionally, the step of adapting the control parameter variable may include a sub-step of identifying a corresponding freezing stage or a corresponding thawing stage between the segmented measured substance temperature profile and the segmented target temperature profile, a sub-step of determining the duration and average temperature of the corresponding freezing stage or the corresponding thawing stage, a sub-step of determining the average value of the control parameter variable during a period corresponding to the freezing stage or the thawing stage in the segmented measured temperature profile, and a sub-step of adapting the control parameter variable as a function of the determined duration of the corresponding freezing stage or the corresponding thawing stage, the determined average temperature of the corresponding freezing stage or the corresponding thawing stage, and the determined average value of the control parameter variable.

[0060] Furthermore, there is provided a data processing system or apparatus comprising means for performing the steps of the above-described method. In particular, the present invention relates to a data processing system for performing the method according to the present invention. The data processing system may comprise a control unit. In one embodiment, the data processing system may comprise a CPU and a memory. In another embodiment, the data processing system may further comprise a central server for remotely executing at least a part of the software from the control unit. The data processing system may be a computer or may include a computer. The computer may be any computing unit such as a control unit, a personal computer, or a special-purpose computer that is particularly suitable for or configured to interact with the heat exchanger unit. Generally, such a data processing system comprises, among other things, at least a central processing unit (CPU) for executing digital instructions and a memory for storing digital instructions (e.g., a computer program) executed by the CPU, which will be apparent to those skilled in the art in view of the present disclosure. Alternatively or additionally, the data processing system may comprise sensors and / or actuators, e.g., sensors and / or actuators carried by or connected to the heat exchanger of the present invention, as will be described in more detail below. Alternatively or additionally, the data processing system may comprise an interface for communicating with the sensors and / or actuators.

[0061] The present invention also relates to a computer program for performing the method according to the present invention. In particular, there is provided a computer program comprising instructions that cause a computer to perform the steps of the above-described method when the program is executed by the computer. The computer may be any computing unit such as a control unit, a personal computer, or a special-purpose computer that is particularly suitable for or configured to interact with the heat exchanger unit. As described above and as will be understood by those skilled in the art, a computer generally comprises, among other things, a CPU and a memory for storing a computer program that is used, inter alia, to control the heat exchanger unit.

[0062] Furthermore, a computer-readable medium storing the above-described computer program is provided.

[0063] Furthermore, a system is provided that includes a heat exchanger unit for changing the physical state of an aqueous formulation so that the temperature of the aqueous formulation is adjusted during an operating cycle based on a target temperature profile, and a control unit for operating the heat exchanger unit, the control unit being configured to perform the steps of the above method. It will be understood that, if desired, the control unit may comprise the aforementioned computer for performing the above method steps.

[0064] The present disclosure will be more readily understood by reference to the following detailed description in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0065]

Figure 1

Figure 1a

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

[0066] Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings. In the drawings, like elements are denoted by the same reference numerals, and redundant descriptions may be omitted to avoid redundancy.

[0067] Figure 1 shows a heat exchanger system 10, hereinafter also referred to as a "system", which is intended and configured to subject an aqueous formulation 12 to a predetermined, tightly controlled freezing and thawing procedure.

[0068] The illustrated system 10 can be used in the field of pharmaceutical manufacturing, but is not limited to this application. The system 10 includes a heat exchanger unit 14 configured to freeze and thaw an aqueous formulation 12, and a control unit 16 configured to control the operation of the heat exchanger unit 14.

[0069] An embodiment of the control unit 16 is shown in Figure 1a, and the control unit includes a central processing unit CPU 16A and a memory 16B.

[0070] The heat exchanger unit 14 may include a heat transfer component 18 having two heat transfer plates 20 that partially, i.e., on opposite sides, define a receiving space 22 for accommodating the aqueous formulation 12 to be processed during operation of the heat exchanger unit 14. Specifically, the receiving space 22 is configured to accommodate a container 24 in which the aqueous formulation 12 is received. The container 24 can be removably received within the receiving space 22. Further, the container 24 may be made of polyethylene and / or an ethylene-vinyl alcohol copolymer and may be intended for single use only. Specifically, as can be seen from Figure 1, the container 24 is received within the receiving space 22 so as to be in thermal contact with the heat transfer component 18, particularly its heat transfer plates 20.

[0071] Furthermore, the heat exchanger unit 14 includes a temperature control unit 26 configured to adjust the heat transfer performance of the heat transfer component 18 by controlling the temperature and flow rate of the heat transfer medium guided through the heat transfer plate 20. To do so, the temperature control unit 26 is fluidly connected to the heat transfer plate 20 via a supply line 28 and a discharge line 30 so as to form a heat transfer medium circuit that enables the heat transfer medium to continuously circulate through the temperature control unit 26 and the heat transfer component 18. The supply line 28 is configured to supply the heat transfer medium to the heat transfer component 18 after being processed by the temperature control unit 26. The discharge line 30 is configured to recirculate the heat transfer medium to the temperature control unit 26 after being guided through the heat transfer component 18. With such a configuration, when the heat transfer medium flows through the heat transfer plate 20, heat transfer occurs between the aqueous formulation 12 and the heat transfer component 18, particularly a heat flow as shown in FIG. 1 [Chemical formula] is caused to occur. Furthermore, the heat exchanger unit 14 includes a temperature sensor 32 configured to measure the temperature present in the aqueous formulation 12, particularly the temperature present in the central region of the aqueous formulation. Monitoring data indicating the temperature present in the substance 12 over time can be recorded by a separate measuring device or the control unit 16 by the temperature sensor 32.

[0072] In the illustrated configuration, the heat exchanger system 10 is shown with the aqueous formulation 12 received within the heat exchanger unit 14 undergoing a freezing procedure. In this state, the nucleation of the aqueous formulation 12 propagates from the end of the container 24 in thermal contact with the heat transfer plate towards the center of the container. Thus, as shown in FIG. 1, a part of the aqueous formulation 12 is in a solid state 12a and a part is in a liquid state 12b. In this state, heat can be transferred from the aqueous formulation 12 towards the heat transfer plate and thus towards the heat transfer medium flowing therethrough, as indicated by the direction of the heat flow in FIG. 1 [Chemical formula] is shown.

[0073] As described above, the control unit 16 is configured to control the operation of the heat exchanger unit 14. In one embodiment of the present invention, the control unit 16 includes a computer configured to execute the method steps of the present invention. More specifically, the control unit 16 generally includes a central processing unit (CPU) 16A configured to execute digital instructions to provide an output, and a memory 16B for storing digital instructions (e.g., a computer program) and / or the output received from the CPU 16A, which will be apparent to those skilled in the art in view of the present disclosure. To control the operation of the heat exchanger unit 14, the control unit 16 is communicably connected to the heat exchanger unit 14, particularly the temperature control unit 26, via at least one data interface 34. The data interface 34 may be a wireless interface or a wired interface. Specifically, the control unit 16 is configured to transmit a control signal to the heat exchanger unit 14, particularly the temperature control unit 26, via the data interface 34 based on the operation of the heat exchanger unit 14 being controlled.

[0074] In the illustrated configuration, the control unit 16 includes a computer provided separately from the heat exchange unit 14, such as a personal computer or an application-specific computer. Accordingly, the control unit 16 is provided as a separate component communicably and removably connected to the heat exchanger unit 14 via the data interface 34. Alternatively, the control unit 16 may be provided as part of the heat exchanger unit 14. That is, the control unit 16 may be an application-specific computer integrated into the structural configuration of the heat exchanger unit 14.

[0075] The control unit 16 determines that the temperature of the aqueous formulation 12 during the operating cycle is the target temperature profile T TIt is configured to execute a method for operating a heat exchanger unit 14 to change the physical state of the aqueous formulation 12 so as to be adjusted based on (t). Specifically, the control unit 16 constitutes or is part of a data processing device or system. Further, as described above, the control unit may include (or be accessible to) a computer program or computer program product, or a computer-readable medium, that includes or stores instructions that cause the control unit 16 to execute a method for operating the heat exchanger unit 14 when executed by the control unit 16.

[0076] The method executed by the control unit 16 for operating the heat exchanger unit 14 is shown in FIG. 2 in the form of a flowchart. Hereinafter, the method executed by the control unit 16 and its individual steps will be described with reference to FIGS. 2 to 6.

[0077] In the first step S1 of this method, the target temperature profile T T (t) is obtained from, for example, a database. Specifically, the target temperature profile T T (t) may be provided as an input to the control unit 16. More specifically, the target temperature profile T T (t) may be provided in the form of a function that assigns exactly one value of temperature to a point in time during the operating cycle or a set of multiple points. Thus, the target temperature profile may be provided in the form of a continuous function or a discontinuous function, or in the form of discontinuous data points.

[0078] FIG. 3 shows an exemplary target temperature profile shown as a graph in the figure. The vertical axis of the figure indicates temperature, particularly the target temperature present in the aqueous formulation 12. The horizontal axis of the figure indicates time, where t0 refers to the start point of the operating cycle and t E refers to the end point of the operating cycle.

[0079] The target temperature profile indicates the desired or intended change in the temperature of the aqueous formulation during the operating cycle of the heat exchanger unit 14. The target temperature profile T T(t) can correspond to the temperature process, and the aqueous formulation is applied when being processed by another heat exchanger unit, in particular the reference heat exchanger unit. The target temperature process T T (t) can in particular correspond to a predetermined temperature process specific to the aqueous formulation, which is empirically derived using the reference heat exchanger unit and stored in a database (for example, a database stored in the memory 16B, or a database accessible by the CPU 16A and / or the control unit 16 in other ways). Therefore, when operating the heat exchanger unit 16 according to the target temperature process T T (t), the operation of the reference heat exchanger unit can be mimicked by the heat exchanger unit 16. Specifically, the heat exchanger unit 16 may be a reduced model of the reference heat exchanger unit, in particular a reduced model.

[0080] In the next step S2, the target temperature process T T (t) is segmented into at least two separate stages P 1~8 and at least one of the stages P2, P6 refers to a change in the physical state of the aqueous formulation 12. In this configuration, this method can distinguish different types of stages such as a temperature change stage, a temperature holding stage, a freezing stage, and a thawing stage. To segment the target temperature process, in a first sub-step, the end points E 0~8 of different stages, which refer to specific points in time during the operating cycle, can be identified. This can be done by first identifying the stages where little or no temperature change occurs. Then, by comparing these stages with the freezing point and thawing point of the aqueous formulation, it can be determined whether these stages correspond to the temperature holding stage, the freezing stage, or the thawing stage. Thereafter, the temperature change stages that can be arranged between the identified stages, the temperature holding stage, the freezing stage, and the thawing stage are identified. Specifically, the step S2 of segmenting the target temperature process T T (t) is performed to identify the freezing stage P2 in which the freezing of the aqueous formulation 12 is carried out and the thawing stage P6 in which the thawing of the aqueous formulation 12 is carried out.

[0081] More specifically, the target temperature process T TWhen applying (t) to step S2, as shown in FIG. 4, eight distinct stages P 1~8 can be determined. The first stage P1 refers to a temperature change stage in which the temperature of the aqueous formulation 12 continuously decreases from 20° C. to about 0° C., the freezing point. The second stage P2 refers to a freezing stage in which the aqueous formulation 12 is frozen. The third stage P3 refers to a temperature change stage in which the temperature of the aqueous formulation 12 continuously decreases from the freezing point to about -80° C. The fourth stage P4 refers to a temperature holding stage in which the temperature of the aqueous formulation 12 is held at about -80° C. The fifth stage P5 refers to a temperature change stage in which the temperature of the aqueous formulation 12 continuously increases from about -80° C. to the thawing point. The sixth stage P6 refers to a thawing stage in which the aqueous formulation 12 is thawed. The seventh stage P7 refers to a temperature change stage in which the temperature of the aqueous formulation 12 continuously increases from the thawing point to about 25° C. The eighth stage P8 refers to a temperature holding stage in which the temperature of the aqueous formulation 12 is held at about 25° C.

[0082] Optionally, in the next sub-step, by applying linear regression, the target temperature profile T T (t) for different stages P 1~8 is adapted. By applying linear regression, the data points of the target temperature profile related to one of the different stages P 1~8 are represented as a linear function. The result of this sub-step is shown in FIG. 5, and each identified stage P 1~8 is represented and defined by a linear function that results in a segmented target temperature profile T sT (t).

[0083] In step S3, based on the target temperature profile T T (t), particularly the segmented target temperature profile T sTBased on (t), at least one preliminary control parameter variable C(t) is determined. Generally, based on the control parameter variable C(t), the control unit 16 is configured to control the operation of the heat exchanger unit 14. To do so, the control unit 16 may use the control parameter variable C(t) as a control command, or derive a control command therefrom, and provide it as a control signal to the heat exchanger unit 14 via the data interface 34. Thus, based on the control parameter variable C(t), the heat exchanger unit 14 is configured to control the heat transfer between the heat transfer component 18 and the aqueous formulation 12 during the operating cycle. In a further development, the step S3 of determining the control parameter variable may be further performed based on the properties of the aqueous formulation, in particular based on the physical or chemical properties of the aqueous formulation, for example as a function of the volume of the aqueous formulation and / or based on the properties of the container 24, in particular the type or capacity of the container 24.

[0084] In the illustrated configuration, at least one control parameter variable C(t) represents the temperature profile of the heat transfer component 18 during the operating cycle. More specifically, the control parameter variable C(t) is a variable of the temperature setpoint of the heat transfer medium conducted through the heat transfer component 18. Specifically, the step of determining the control parameter variable is performed based on the thermodynamic properties of the aqueous formulation, in particular based on the freezing point and melting point of the diluent (here water). Specifically, this step is performed such that during the freezing stage, the temperature setpoint of the heat transfer medium is set lower than the freezing point of the diluent (here water), and during the thawing stage, the temperature setpoint of the heat transfer medium is set higher than the melting point of the diluent (here water). As can be seen from the control parameter variable C(t) shown in FIG. 6, this step is performed such that the temperature setpoint of the heat transfer medium changes during the freezing stage P2, the cooling stages P1 and P3, and the heating stages P5 and P7. In other words, the control parameter variable C(t) defines the change in the temperature setpoint of the heat transfer medium during the cooling stages P1, P3, the freezing stage P2, and the heating stages P5 and P7. Alternatively, this step may be performed such that the control parameter variable C(t) defines the change in the temperature setpoint of the heat transfer medium during at least one of the first cooling stage P1, the freezing stage P2, the second cooling stage P3, the temperature holding stage P4, the first heating stage P5, the thawing stage P6, and the second heating stage P6.

[0085] Alternatively or additionally, a further control parameter variable may be determined that represents the flow rate of the heat transfer medium through the heat transfer component 18. Thus, the control parameter variable may define the change in the flow rate of the heat transfer medium during at least one of the first cooling stage P1, the freezing stage P2, the second cooling stage P3, the temperature holding stage P4, the first heating stage P5, the thawing stage P6, and the second heating stage P6, in particular during at least one of the first cooling stage P1, the freezing stage P2, and the second cooling stage P3.

[0086] FIG. 6 is a graph showing an example of the control parameter variable C(t) determined in step S3, and the segmented target temperature profile T sTA graph representing (t) is also shown. The exemplary control parameter variable C(t) shows the process of the temperature setpoint of the heat transfer medium. The vertical axis of the figure indicates the temperature corresponding to the value of the control variable, i.e., the temperature of the heat transfer medium, particularly the setpoint of the temperature of the heat transfer medium. The horizontal axis of the figure indicates the time during the operating cycle. As can be seen from Figure 6, the control parameter variable C (t) is determined based on the different stages P sT of the segmented target temperature process T 1~8 (t) and the time associated therewith. As can be seen from Figure 6, the temperature setpoint of the heat transfer medium is determined to be lower than the freezing point of water during the freezing stage P2 and higher than the thawing point of water during the thawing stage P6. Specifically, during the thawing stage P6, the temperature setpoint may be in the range of 2.5°C to 20°C, preferably between 5°C and 15°C. Further, the temperature setpoint of the heat transfer medium is determined to be substantially lower than the target temperature process during the cooling stage and higher than the target temperature process during the heating stage. Further, when the aqueous formulation 12 is held at a temperature lower than the ambient temperature (i.e., about 21°C), i.e., during the temperature holding stage, the temperature setpoint of the heat transfer medium is determined to be substantially lower than the target temperature process, i.e., over most of the time of the temperature holding stage. However, when the aqueous formulation is held at a temperature higher than the ambient temperature, i.e., during the temperature holding stage, the temperature setpoint of the heat transfer medium is determined to be higher than the target temperature process.

[0087] For example, for the temperature change stage, particularly the temperature drop or rise stage in the target temperature process T T (t), or the period related to the temperature holding stage, the control unit 16 can define the control parameter variable C(t) in these stages based on the following equation.

Number

Chemistry

[0088] Alternatively or additionally, in order to perform step S3, the control unit 16 may use a reference control parameter variable that can be stored in the memory of the control unit 16 and that can refer to an operating cycle that successively passes through different stages corresponding to the stages specified in the segmented target temperature profile T sT (t). Alternatively or additionally, in order to determine the control parameter variable C(t), the control unit 16 can utilize a mathematical or computational model that can predict or calculate the course of the temperature present in the aqueous formulation 12 as a function of the control parameter variable. When using such a mathematical or computational model, the segmented target temperature profile T sT (t) can be used as an input, and based on this, the preliminary control parameter variable C(t) can be determined.

[0089] Furthermore, the step (S3) of determining the control parameter variable C(t) may include a sub-step of identifying the freezing stage P2 in the segmented target temperature profile T sT (t). Next, in a further sub-step, as can be seen from FIG. 6, during the period preceding and / or overlapping the period of the operating cycle related to the freezing stage of the segmented target temperature profile T sT (t), a decrease in the control parameter variable C(t) is carried out. The decrease in the control parameter variable C(t) is designed to cause a temporary improvement in the cooling performance of the heat exchanger unit during the freezing stage P2 of the operating cycle, in particular before and at the start of the freezing stage P2.

[0090] Specifically, in the illustrated configuration, the control parameter variable C(t) is designed such that during the first stage P1, the temperature setpoint decreases to the nucleation spike temperature, preferably in the range of -25°C to -35°C, for example -30°C. More specifically, in the first sub-stage of the first stage P1, the temperature setpoint decreases from the ambient temperature to the nucleation spike temperature. Next, the temperature setpoint is maintained at the nucleation spike temperature for a predetermined period, i.e., during the second sub-stage of the first stage P1. Specifically, the nucleation spike holding time may be in the range of 5% to 50% of the duration of the first stage P1. Next, in the first sub-stage of the second stage P2, the temperature setpoint increases from the nucleation spike temperature to the freezing temperature. The freezing temperature may be in the range of -5°C to -20°C, preferably in the range of -10°C to -17.5°C, more preferably in the range of -12.5°C to -17.5°C. Thereafter, in the second sub-stage of the second stage P2, the temperature setpoint is maintained at the freezing temperature. The duration of the first sub-stage of the second stage P2 may be in the range of 1% to 20% of the duration of the second stage P2. In a further development, a method may be provided such that step S4 is executed based on a predetermined temperature setpoint and timing, in particular based on at least one of a predetermined nucleation spike temperature, a predetermined nucleation spike holding time, a predetermined freezing temperature, and a predetermined thawing temperature. Specifically, these setpoints or parameters may be set by an operator.

[0091] In the next step S4, the control unit 16 operates the heat exchanger unit 14 to execute a commissioning operation cycle. Specifically, this step includes a sub-step S4.1 of operating the heat exchange unit 14 during the commissioning operation cycle based on the determined preliminary control parameter variable C(t). At the same time, a sub-step 4.2 of measuring the substance temperature process T M (t) is executed, and the substance temperature process T M (t) indicates the temperature process of the aqueous formulation during the commissioning operation cycle. This sub-step is executed by collecting a measurement signal from the temperature sensor 32.

[0092] Next, in step S5, the measured temperature process TM Segment (t) into at least two distinct stages to obtain a segmented measured temperature profile T sM (t), where at least one stage indicates a change in the physical state of the aqueous formulation 12. This step S5 can be carried out corresponding to the above-mentioned step S2 of segmenting the target temperature profile T T (t). Specifically, step S5 is carried out to identify a freezing stage in which the freezing of the aqueous formulation 12 is carried out and a thawing stage in which the thawing of the aqueous formulation 12 is carried out. Further, step S5 identifies the end point of stage P 1~8 to segment the measured temperature profile T M (t) into stages, and a sub-step of adapting the stage P M of the measured temperature profile T 1~8 by applying linear regression, thereby obtaining a segmented measured temperature profile T sM (t), and may include.

[0093] In the next step S6, the control unit 16 adapts the determined control parameter variable C(t) based on the comparison between the segmented measured temperature profile T sM (t) and the segmented target temperature profile T sT (t). To do so, the control unit 16 first identifies corresponding stages between the segmented measured temperature profile T sM (t) and the segmented target temperature profile T sT (t), i.e., stages that occur during overlapping, substantially the same, or close periods during the operating cycle and are of the same type. Further, the control unit 16 can determine the duration and / or average temperature value of all the identified stages. Next, the determined control parameter variable C(t) can be adapted based on the comparison of the determined duration and / or determined average temperature value of the corresponding stages.

[0094] Alternatively or additionally, the step S6 of adapting the control parameter variable C(t) is the segmented measured temperature profile T sM (t) and the segmented target temperature profile TsT (t) during, a sub-step of identifying the corresponding freezing stage P2 or the corresponding thawing stage P6, a sub-step of determining the duration and average temperature of the corresponding freezing stage P2 or the corresponding thawing stage P6, and the segmented measured temperature process T sM (t) a sub-step of determining the average value of the control parameter variable C(t) during the period corresponding to the freezing stage P2 or the thawing stage P6, and a sub-step of adapting the control parameter variable C(t) as a function of the determined duration of the corresponding freezing stage or the corresponding thawing stage, the determined average temperature of the corresponding freezing stage or the corresponding thawing stage, and the determined average value of the control parameter variable, may be included.

[0095] Specifically, to do so, the control unit 16 segments the measured temperature process T sM (t) and the segmented target temperature process T sT (t) when identifying the corresponding physical state change stage, particularly the corresponding freezing stage or thawing stage, the control parameter variable C(t) can be adapted based on the following equation.

Number

Chemistry

Chemistry

Chemistry

Chem.

Chem.

Chem.

[0096] Furthermore, for the temperature change stage, particularly the temperature drop stage or the temperature rise stage in the target temperature process T T (t), or the period related to the temperature holding stage, the control unit 16 can adapt the control parameter variable C(t) in these stages based on the above equation (2). Additionally, in order to adapt the control parameter variable C(t), the control unit 16 can further utilize the mathematical or computational model used in step S3 to determine the control parameter variable C (t) .

[0097] In the following step S7 of the option, the control unit 16 can determine a similarity parameter indicating the correlation or similarity between the target temperature process T T (t) or the segmented target temperature process T sT (t) and the measured temperature process T M (t) or the segmented measured temperature process T sM (t). Specifically, the similarity parameter can be calculated based on the following equation. [Number] Here, s is a similarity parameter that quantifies the similarity between the target temperature profile T T (t) and the measured temperature profile T M (t).

[0098] Next, in optional step S8, the determined similarity parameter s is compared with a threshold S. If the similarity parameter s is below the threshold S, the method proceeds to step S9, where the control unit 16 can operate the heat exchanger unit 14 appropriately, i.e., according to the target temperature profile T T (t). If the similarity parameter s is greater than or equal to the threshold S, the method returns to step S4 to perform a further test run operation cycle and further adapt the control parameter variable C(t) based thereon. With this configuration, in this method, the control parameter variable C(t) can be repeatedly adapted until a satisfactory result is obtained. In an alternative configuration, method step S6 may be performed after step S8, particularly if the similarity parameter s is greater than or equal to the threshold S. According to one embodiment, method step S9 may then be performed, particularly immediately after method step S6.

[0099] It will be apparent to those skilled in the art that these embodiments and items merely illustrate a plurality of possibilities for implementing the invention defined in the independent claims. Therefore, the embodiments shown herein should not be understood as limiting these features and configurations. Any possible combination and configuration of the described features can be selected according to the scope of the invention defined in the independent claims.

[0100] The present invention and its embodiments will be described again in the following clauses. 1. A method for operating a heat exchanger unit (14) for changing the physical state of a substance of an aqueous formulation (12) by freezing or thawing, wherein the aqueous formulation (12) is contained in a container and the heat exchanger unit acts on the aqueous formulation (12) in the container, The temperature of the aqueous formulation (12) during the operating cycle is adjusted based on a target temperature profile (T T (t)), and the method comprises: -(S2) Segmenting the target temperature profile (T T (t)) into at least two distinct stages (P), wherein at least one stage (P2, P6) refers to a change in the physical state of the substance of the aqueous formulation (12); -(S3) Determining a control parameter variable (C(t)) for controlling the operation of the heat exchanger unit (14) during the operating cycle based on the target temperature profile (T T (t)); -(S4) --(S4.1) Operating the heat exchange unit (14) during a test operating cycle based on the determined control parameter variable (C(t)); --(S4.2) Measuring a temperature profile (T M (t)) indicating the temperature profile of the aqueous formulation during the test operating cycle, and executing a test operating cycle including these sub-steps; -(S5) Segmenting the measured temperature profile (T M (t)) into at least two distinct stages, wherein at least one stage refers to a change in the physical state of the aqueous formulation (12); -(S6) Adapting the determined control parameter variable (C(t)) based on a comparison between the segmented measured temperature profile (T sM (t)) and the segmented target temperature profile (T sT (t)); and - Operating the heat exchanger unit (14) based on the adapted control parameter variable to change the physical state by freezing or thawing the aqueous formulation (12). A method comprising these steps. 2. The method according to clause 1, wherein the aqueous formulation (12) contains water and optionally further contains at least one selected from the group consisting of a buffer solution, a cell culture medium, and at least one or more active pharmaceutical ingredients. 3. The temperature of the aqueous preparation is measured by a sensor arranged in the container, and preferably, the sensor is arranged in contact with the aqueous preparation in the container, according to the method of clause 1 or 2. 4. The heat exchanger unit (14) is configured to control the heat transfer between the heat transfer component (18) and the aqueous preparation (12) during the operating cycle based on the determined control parameter variable (C(t)), according to the method of any one of clauses 1 to 3. 5. At least one control parameter variable (C(t)) represents the course of the temperature of the heat transfer component (18) during the operating cycle, in particular the course of the temperature of the heat transfer medium flowing through the heat exchanger unit (14), according to the method of clause 4. 6. The control parameter variable (C(t)) defines the change in the control parameter of the heat exchanger unit (14) during the stage indicating the change in the physical state of the aqueous preparation (12), according to the method of any one of clauses 1 to 5. 7. The control parameter indicates the temperature of the heat transfer component (18), in particular the temperature of the heat transfer medium flowing through the heat exchanger unit (16), or the flow rate of the heat transfer medium, according to the method of any one of clauses 1 to 6. 8. The target temperature profile (T T (t)) corresponds to the temperature change and is applied when the aqueous preparation (12) is processed by a reference heat exchanger unit for changing the physical state of the aqueous preparation (12). In particular, the heat exchanger unit (14) is a reduced model of the reference heat exchanger unit, according to the method of any one of clauses 1 to 7. 9. At least one of the step (S2) of segmenting the target temperature profile (T T (t)) and the step (S5) of segmenting the measured temperature profile (T M (t)) is performed to identify at least one of the freezing stage (P2) where the freezing of the aqueous preparation (12) occurs or has occurred and the thawing stage (P6) where the thawing of the aqueous preparation (12) occurs or has occurred, according to the method of any one of clauses 1 to 8. 10. The step (S2) of segmenting the target temperature profile (T T (t)) and the measured temperature profile (T MAt least one of the steps (S5) of segmenting (t) includes - Segmenting the target temperature process (T T (t)) or the measured temperature process (T M (t)) into stages by identifying the end points of the stages, and - Adapting the stages of the target temperature process (T T (t)) or the measured temperature process (T M (t)) by applying linear regression, including at least one of the above, the method according to any one of clauses 1 to 9. 11. The step (S3) of determining the control parameter variable (C(t)) is performed based on the characteristics of the aqueous formulation, particularly based on the volume of the aqueous formulation (12), the method according to any one of clauses 1 to 10. 12. The step (S3) of determining the control parameter variable (C(t)) - Identifying the freezing stage (P2) in the target temperature process (T T (t)), and - Increasing or decreasing the control parameter variable (C(t)) during the period preceding or overlapping with the period of the freezing stage (P2), where the increase or decrease of the control parameter variable (C(t)) causes a temporary improvement in the cooling performance of the heat exchanger unit, the method according to any one of clauses 1 to 11. 13. The step (S6) of adapting the control parameter variable C(t) - A sub-step of identifying corresponding stages between the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)), and - A sub-step of determining the duration of the corresponding stage and / or determining the average temperature of the corresponding stage, and - A sub-step of adapting the control parameter variable (C(t)) based on the comparison of the determined duration and / or average temperature of the corresponding stage, the method according to any one of clauses 1 to 12. 14. The step (S6) of adapting the control parameter variable (C(t)) - The segmented measured temperature profile (T sM (t)) and the segmented target temperature profile (T sT (t)), a sub-step of identifying corresponding freezing or thawing stages, and - A sub-step of determining the duration and average temperature of the corresponding freezing or thawing stage, and - A sub-step of determining the average value of the control parameter variable (C(t)) during the period corresponding to the freezing or thawing stage in the segmented measured temperature profile (T sT (t)), and - A sub-step of adapting the control parameter variable (C(t)) as a function of the determined duration of the corresponding freezing or thawing stage, the determined average temperature of the corresponding freezing or thawing stage, and the determined average value of the control parameter variable C(t), the method according to any one of clauses 1 to 13. 15. A data processing system for controlling a heat exchanger unit (14) configured to change the physical state of a substance of an aqueous formulation (12) by freezing or thawing, wherein the aqueous formulation (12) is contained in a container, the heat exchanger unit acts on the aqueous formulation (12) in the container, and the temperature of the aqueous formulation (12) during an operating cycle is adjusted based on a target temperature profile (T T (t)), and further, the data processing system includes a central processing unit, a memory, and software stored in the memory, and when the software is executed by the central processing unit, -(S2) A step of segmenting the target temperature profile (T T (t)) into at least two distinct stages (P), wherein at least one stage (P2, P6) refers to a change in the physical state of the substance of the aqueous formulation (12), and -(S3) Based on the target temperature profile (T T (t)), a step of determining a control parameter variable (C(t)) for controlling the operation of the heat exchanger unit (14) during an operating cycle, and -(S4) --(S4.1) Based on the determined control parameter variable (C(t)), a sub-step of operating the heat exchange unit (14) during the test run operation cycle, and --(S4.2) A sub-step of measuring the temperature process (T M (t)) showing the process of the temperature of the aqueous formulation during the test run operation cycle, and including the step of executing a test run operation cycle including these sub-steps, -(S5) A step of segmenting the measured temperature process (T M (t)) into at least two separate stages, where at least one stage refers to a change in the physical state of the aqueous formulation (12), (S6) Based on the comparison between the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)), a step of adapting the determined control parameter variable (C(t)), - A step of operating the heat exchanger unit (14) based on the adapted control parameter variable in order to change the physical state by freezing or thawing the aqueous formulation (12). A data processing system that executes these steps. 16. A computer program for controlling a heat exchanger unit (14) configured to change the physical state of a substance of an aqueous formulation (12) by freezing or thawing, where the aqueous formulation (12) is contained in a container, the heat exchanger unit acts on the aqueous formulation (12) in the container, and the temperature of the aqueous formulation (12) during the operation cycle is adjusted based on a target temperature process (T T (t)). When the computer program is executed by a computer, the computer program causes the computer to, -(S2) A step of segmenting the target temperature process (T T (t)) into at least two separate stages (P), where at least one stage (P2, P6) refers to a change in the physical state of the substance of the aqueous formulation (12), -(S3) The target temperature process (T TBased on (t), determining a control parameter variable (C(t)) for controlling the operation of the heat exchanger unit (14) during the operating cycle; -(S4) --(S4.1) Based on the determined control parameter variable (C(t)), a sub-step of operating the heat exchange unit (14) during the test run operating cycle; --(S4.2) Measuring the temperature process (T M (t)) showing the process of the temperature of the aqueous formulation during the test run operating cycle; and executing a test run operating cycle including this step; -(S5) Segmenting the measured temperature process (T M (t)) into at least two separate stages, with at least one stage indicating a change in the physical state of the aqueous formulation (12); -(S6) Based on the comparison between the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)), adapting the determined control parameter variable (C(t)); - Operating the heat exchanger unit (14) based on the adapted control parameter variable to change the physical state by freezing or thawing the aqueous formulation (12). A computer program including an instruction to execute this step. 17. The computer program according to clause 16, stored in a computer-readable medium. 18. A computer-readable medium storing a computer program for controlling a heat exchanger unit (14) configured to change the physical state of a substance of an aqueous formulation (12) by freezing or thawing, wherein the aqueous formulation (12) is contained in a container, the heat exchanger unit acts on the aqueous formulation (12) in the container, and the temperature of the aqueous formulation (12) during the operating cycle is adjusted based on a target temperature process (T T (t)), and when the computer program is executed by a computer, the computer program causes the computer to -(S2) Target temperature process (TT Segmenting (t) into at least two separate stages (P), wherein at least one stage (P2, P6) refers to a change in the physical state of the substance of the aqueous formulation (12); -(S3) Target temperature process (T T Determining a control parameter variable (C(t)) for controlling the operation of the heat exchanger unit (14) during the operating cycle based on (t); -(S4) --(S4.1) Operating the heat exchange unit (14) during a commissioning operating cycle based on the determined control parameter variable (C(t)); --(S4.2) Measuring the temperature process (T M Measuring the temperature process (T(t)) of the aqueous formulation during the commissioning operating cycle; -(S5) Segmenting the measured temperature process (T M (t)) into at least two separate stages, wherein at least one stage refers to a change in the physical state of the aqueous formulation (12); -(S6) Adapting the determined control parameter variable (C(t)) based on a comparison between the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)); - Operating the heat exchanger unit (14) based on the adapted control parameter variable to change the physical state by freezing or thawing the aqueous formulation (12). A computer-readable medium containing instructions for execution. 19. A system (10) comprising a heat exchanger unit (14) and a control unit (16) for operating the heat exchanger unit (14) to change the physical state of an aqueous formulation (12), wherein the temperature of the aqueous formulation (12) is adjusted during the operating cycle based on a target temperature process (T T (t)), and the control unit (16) is -(S2) Target temperature process (T TThe step of segmenting (t) into at least two separate stages (P), wherein at least one stage (P2, P6) refers to a change in the physical state of the substance of the aqueous formulation (12), -(S3) Target temperature process (T T Based on (t), determining a control parameter variable (C(t)) for controlling the operation of the heat exchanger unit (14) during the operating cycle, -(S4) --(S4.1) Sub-step of operating the heat exchange unit (14) during the commissioning operation cycle based on the determined control parameter variable (C(t)), --(S4.2) Sub-step of measuring the temperature process (T M (t)) showing the temperature process of the aqueous formulation during the commissioning operation cycle, and executing a commissioning operation cycle including this, -(S5) Segmenting the measured temperature process (T M (t)) into at least two separate stages, wherein at least one stage refers to a change in the physical state of the aqueous formulation (12), -(S6) Based on the comparison between the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)), adapting the determined control parameter variable (C(t)), - Operating the heat exchanger unit (14) based on the adapted control parameter variable in order to change the physical state by freezing or thawing the aqueous formulation (12). A system configured to execute this.

[0101] List of reference numbers 10 Heat exchanger system 12 Aqueous formulation 14 Heat exchanger unit 16 Control unit 16A CPU 16B Memory 18 Heat transfer component 20 Heat transfer plate 22 Receiving space 24 containers 26 temperature control unit 28 supply line 30 discharge line 32 temperature sensor 34 data interface C(t) control parameter variable E stage end point P stage

Chem.

Claims

1. A method for operating a heat exchanger unit (14) to change the physical state of a substance in an aqueous formulation (12) by freezing or thawing, The aqueous formulation (12) is contained in a container, and the heat exchanger unit acts on the aqueous formulation (12) in the container. The temperature of the aqueous formulation (12) during the operating cycle reaches the target temperature process (T Ｔ (t)) is adjusted based on the method, -(S2) The target temperature process (T Ｔ A step of segmenting (t) into at least two distinct stages (P), wherein at least one stage (P ２ , P ６ ) refers to a step that indicates a change in the physical state of the substance of the aqueous formulation (12), -(S3) The target temperature process (T Ｔ The steps include determining a control parameter variable (C(t)) for controlling the operation of the heat exchanger unit (14) during the operating cycle based on (t), - (S4) -- (S4.1) A substep in which the heat exchange unit (14) is operated during the trial operation cycle based on the determined control parameter variable (C(t)), -- (S4.2) Temperature process showing the temperature of the aqueous formulation during the trial operation cycle (T Ｍ A step of performing a commissioning operation cycle that includes a substep of measuring (t), -(S5) The measurement temperature process (T Ｍ (t)) is segmented into at least two distinct stages, the step of which at least one stage refers to a change in the physical state of the aqueous formulation (12), -(S6) adapting the determined control parameter variable (C(t)) based on comparison of the segmented measured temperature process (T ｓＭ (t)) and the segmented target temperature process (T ｓＴ (t)); A method comprising the step of operating the heat exchanger unit (14) based on the adapted control parameter variable in order to change the physical state of the aqueous formulation (12) by freezing or thawing it.

2. The aqueous formulation (12) contains water and optionally a buffer, cell culture medium, and / or 1 The method according to claim 1, further comprising one or more active pharmaceutical ingredients.

3. The method according to claim 1, wherein the temperature of the aqueous formulation is measured by a sensor placed in the aqueous formulation, particularly in the container.

4. The method according to claim 1, wherein the heat exchanger unit (14) is configured to control heat transfer between the heat transfer component (18) and the aqueous formulation (12) during the operating cycle based on the determined control parameter variable (C(t)).

5. The method according to claim 4, wherein the at least one control parameter variable (C(t)) indicates a temperature course of the heat transfer component (18) during the operating cycle, in particular a temperature course of the heat transfer medium flowing through the heat exchanger unit (14).

6. The method according to claim 1, wherein the control parameter variable (C(t)) defines a change in the control parameter of the heat exchanger unit (14) during the step referring to the change in the physical state of the aqueous formulation (12).

7. The method according to claim 1, wherein the control parameter indicates the temperature of the heat transfer component (18), and in particular the temperature of the heat transfer medium flowing through the heat exchanger unit (16), or the flow rate of the heat transfer medium.

8. The target temperature process (T Ｔ The method according to claim 1, wherein (t) corresponds to a temperature change, and the aqueous formulation (12) is applied when it is processed by a reference heat exchanger unit for changing the physical state of the aqueous formulation (12), in particular the heat exchanger unit (14) is a scaled-down model of the reference heat exchanger unit.

9. The target temperature process (T Ｔ The step (S2) of segmenting (t) and the measurement temperature process (T Ｍ (t)) at least one of the steps (S5) to segment the aqueous formulation (12) is either frozen or the frozen step (P ２ ), and the thawing of the aqueous formulation (12) is performed or the thawing stage has been performed (P ６ The method according to claim 1, which is performed to identify at least one of the following.

10. The target temperature process (T Ｔ The step (S2) of segmenting (t) and the measurement temperature process (T Ｍ At least one of the steps (S5) of segmenting (t) is, - By identifying the endpoint of the above step, the target temperature process (T Ｔ (t)) or the measured temperature process (T Ｍ (t)) to be segmented into stages, and - By applying linear regression, the target temperature process (T Ｔ (t)) or the measured temperature process (T Ｍ The method according to claim 1, comprising at least one of applying the steps of (t)).

11. The method according to claim 1, wherein the step (S3) of determining the control parameter variable (C(t)) is performed based on the properties of the aqueous formulation, and in particular based on the volume of the aqueous formulation (12).

12. The step (S3) of determining the control parameter variable (C(t)) is, - the target temperature process (T Ｔ (t)) Freezing stage (P ２ ) to identify, - The freezing stage (P ２ During the period of the operation cycle that precedes or overlaps with the period related to ), the control parameter variable (C(t)) is raised or lowered, wherein the raising or lowering of the control parameter variable (C(t)) is performed on the heat exchanger unit The method according to claim 1, comprising causing a temporary improvement in the cooling performance of a device.

13. The step (S6) of applying the control parameter variable C(t) is, - The segmented measurement temperature process (T ｓＭ (t) and the segmented target temperature process (T ｓＴ (t)) a substep to identify the corresponding stage, - A substep of determining the duration of the corresponding stage and / or determining the average temperature of the corresponding stage, The method according to claim 1, comprising: a substep of adapting the control parameter variable (C(t)) based on a comparison of the determined duration and / or mean temperature of the corresponding steps.

14. The step (S6) of applying the control parameter variable (C(t)) is, - The segmented measurement temperature process (T ｓＭ (t) and the segmented target temperature process (T ｓＴ (t)) a substep to identify the corresponding freezing stage or the corresponding thawing stage, - A substep for determining the duration and average temperature of the corresponding freezing or thawing stage, - The segmented measurement temperature process (T ｓＴ A substep of determining the mean value of the control parameter variable (C(t)) during the period corresponding to the freezing or thawing stage in (t), The method according to claim 1, comprising the substep of adapting the control parameter variable (C(t)) as a function of the determined duration of the corresponding freezing or thawing stage, the determined average temperature of the corresponding freezing or thawing stage, and the determined average value of the control parameter variable C(t).

15. A data processing system comprising means for performing the steps of the method according to any one of claims 1 to 14.

16. A computer program that includes instructions causing a computer to perform a step of the method according to any one of claims 1 to 14 when executed by the computer.

17. A computer-readable medium storing the computer program described in claim 16.

18. The system comprises a heat exchanger unit (14) and a control unit (16) for operating the heat exchanger unit (14) to change the physical state of the aqueous formulation (12), wherein the temperature of the aqueous formulation (12) reaches a target temperature process (T Ｔ A system (10) which is adjusted during an operating cycle based on (t), wherein the control unit (16) is configured to perform a step of the method according to any one of claims 1 to 14.

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