Method of operating heat exchanger unit for changing physical state of substance of aqueous formulation

Abstract

The present invention provides a method of operating a heat exchanger unit for freezing or thawing an aqueous formulation, the method comprising the steps of: dividing a target temperature process into two distinct stages wherein at least one stage involves a change in the physical state of the aqueous formulation; determining a control parameter change based on which operation of the heat exchanger unit is to be controlled during an operating cycle; performing a test run operation cycle by operating the heat exchange unit based on the determined control parameter variation and by measuring an aqueous formulation temperature process; dividing the measured temperature process into two distinct phases, wherein at least one phase involves a change in the physical state of the substance; adapting the determined control parameter variation based on a comparison of the segmented measured substance temperature process and the segmented target temperature process; and operating the heat exchanger unit based on the adapted control parameter variation.

Description

Technical Field

[0001] The present invention relates to a method and system for operating a heat exchanger unit for changing the physical state of a substance of an aqueous preparation, in particular for freezing and / or thawing an aqueous preparation. Further, the present invention relates to a computer program comprising instructions which, when executed by a computer, cause the computer to perform such a method. Background Art

[0002] In order to properly and efficiently handle a drug product, for example in a drug product manufacturing procedure, it may be necessary to strictly follow predefined storage, transportation and handling requirements. This may be due to the labile nature of the drug product and may be particularly applicable to aqueous formulations containing proteins.

[0003] Depending on the storage temperature, aqueous preparations of proteins may undergo various changes, in particular chemical or biochemical changes, such as persistent microbial growth, foaming during transportation, aggregate formation, degradation over time, etc. When such aqueous protein solutions are used in pharmaceutical production, these changes may affect the properties of the drug product to be manufactured, such as the stability of the drug product. Therefore, in the pharmaceutical industry, a process of freezing and then thawing protein solutions or other aqueous preparations is commonly used in order to prevent undesired and unexpected changes.

[0004] However, the process steps of freezing and thawing aqueous formulations, especially those containing proteins, must follow a strictly controlled process, as both steps may affect the final properties of the drug product. For example, during both steps, denaturation may occur for different reasons, including: cryoconcentration and co-solutes, which may also cause pH shifts and cryopreservative crystallization; cold denaturation and unfolding / misfolding; aggregation, which may lead to immunogenicity, loss of potency, or other changes in desired critical quality attributes.

[0005] Therefore, the specification, implementation and validation of processes for freezing and thawing aqueous formulations to be used in pharmaceutical production are often time and cost intensive, as they require lengthy experiments and designs. In order to carry out these process steps in pharmaceutical production, it is known to use heat exchanger systems. However, operating and setting up such heat exchanger systems so that predefined freezing and thawing processes and requirements are met during operation can be particularly time and cost intensive.

[0006] Further technical background is available 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, December 23, 2010 (2010-12-23), pp. 13-26. Summary of the invention

[0007] Therefore, it is an object of the present invention 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, the method being particularly capable of operating the heat exchanger unit reliably and efficiently in accordance with predefined process requirements. Further, it is an object of the present invention to provide a computer program comprising instructions which, when executed by a computer, cause the computer to carry out such an improved method.

[0008] These objects are solved by the subject-matter of the independent claims.Preferred embodiments are set forth in the description, the drawings and the dependent claims.

[0009] Therefore, there is provided a method of operating a heat exchanger unit for changing the physical state of matter of an aqueous formulation by freezing or thawing, the aqueous formulation being contained in a container and the heat exchanger unit acting on the aqueous formulation in the container such that the temperature of the drug product is regulated during an operating cycle based on or according to a target temperature course. The method comprises the following steps:

[0010] - dividing the target temperature process into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation;

[0011] - based on the target temperature course, determining at least one control parameter change based on which operation of the heat exchanger unit will be controlled during an operating cycle;

[0012] -Perform a test run operation cycle, including the following sub-steps:

[0013] - operating the heat exchange unit based on the determined control parameter changes during the test run operation cycle, and

[0014] - measuring a temperature course indicating the course of the temperature of the aqueous formulation during an operating cycle of the test run.

[0015] The method further comprises the following steps:

[0016] - dividing the measured temperature course into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation;

[0017] - adapting the determined control parameter change based on a comparison of the segmented measured temperature course with the segmented target temperature course; and

[0018] - operating the heat exchanger unit for freezing and / or thawing the aqueous formulation based on the adapted control parameter change.

[0019] By providing a method in which a temperature process is segmented into distinct stages, at least one of which involves a change in the physical state of a substance of an aqueous formulation, the proposed method may allow for efficient and effective determination and / or adaptation of control parameter changes for reliable operation of a heat exchanger according to a target temperature process constituting a predefined process requirement.

[0020] The proposed method may be a computer-implemented method. That is, the method steps described below may at least partially involve a computer, a computer network or other programmable devices. In other words, at least one method step is implemented by means of a program.

[0021] In particular, the method of the present invention can be implemented using a computer, that is, by storing the method steps of the present invention in a memory (e.g., a non-transitory memory) and executing the stored method steps 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.

[0022] Further, the proposed method may be used in pharmaceutical production, where aqueous formulations may undergo predetermined and strictly controlled freezing and / or thawing process steps. However, the proposed method is not limited to such use, and may be applied to any suitable application where changing the physical state of matter of an aqueous formulation is to be performed in accordance with strict specifications and regulations. Thus, the proposed method may be applied to set up or readjust the appropriate operation of any heat exchanger unit intended for changing the physical state of matter of an aqueous formulation.

[0023] The term "physical state of matter" (which may also be referred to as aggregate state) as used herein means a physical state of matter such as solid, liquid or gas; the method of the present invention revolves around changing the physical state between solid and liquid (by freezing or thawing).

[0024] Preferably, the aqueous preparation to be frozen and / or thawed when carrying out the method comprises water as the main (or even the only) component and may further comprise a buffer, a cell culture medium and / or one or more pharmaceutical substances. The change of the physical state of a substance in the sense of the present invention mainly comprises the freezing or thawing of water in the aqueous preparation.

[0025] In the context of the present disclosure, the term "aqueous formulation of a drug substance" (also often referred to as "drug product") refers to any aqueous formulation comprising a drug substance (such as a buffer, cell culture medium, etc.) in an aqueous medium. A drug substance is a pharmaceutically active substance (often referred to as an active pharmaceutical ingredient "API").

[0026] Various types of drug substances are known to those skilled in the art and range from macromolecules such as proteins or peptides to small organic molecules. Especially in the case of macromolecules, changes in the physical state of aqueous formulations containing such drug substances may be particularly critical, as set out herein.

[0027] The term "protein" means a macromolecule consisting of an amino acid sequence. A protein may be a therapeutic protein, for example, a therapeutic protein for diagnosis, treatment and / or prevention of a disease or condition. A protein may be a natural protein, that is, a protein produced by a naturally occurring and non-recombinant cell; or it may be produced by a genetically engineered or recombinant cell and may include molecules having the amino acid sequence of a natural protein, or molecules having deletions, additions and / or substitutions 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. The term also includes amino acid polymers in which one or more amino acids are chemical analogs of the corresponding naturally occurring amino acid polymer.

[0028] Preferred protein drug substances are antibodies, which may include monoclonal antibodies and polyclonal antibodies, whole antibodies, antibody-drug conjugates, chimeric antibodies, humanized antibodies, human antibodies or hybrid antibodies with dual or multiple antigenic or epitope specificities, antibody fragments and antibody subfragments, such as Fab, Fab', F(ab')2 fragments, etc., including any immunoglobulin or hybrid fragment of any natural, synthetic or genetically engineered protein that acts like an antibody by binding to a specific antigen to form a complex.

[0029] Suitable aqueous media are known to those skilled in the art. Preferred aqueous media are water or an aqueous buffer.

[0030] The aqueous formulation may also contain at least one pharmaceutically acceptable excipient. Suitable excipients are known to those skilled in the art, such as stabilizers, pH modifiers, etc. In some embodiments, polysorbates such as polysorbate 20, 40, 60, or 80 may be used as stabilizers, which may improve the stability of the protein drug in the aqueous formulation.

[0031] A preferred embodiment of the aqueous formulation used in the proposed method is an aqueous formulation containing a drug substance. According to this embodiment, the change of the physical state of matter of the aqueous formulation may refer to a change of the physical state of matter of the water contained in the aqueous formulation containing the drug substance, i.e., freezing and / or thawing of water in the aqueous composition containing the drug substance.

[0032] As described above, the method is intended to be used for and applied to control the operation of a heat exchanger unit. The heat exchanger unit is configured to change the physical state of the material of the aqueous preparation by freezing and / or thawing the aqueous preparation, especially during the operating cycle. In the context of the present disclosure, the term "operating cycle" refers to a time period of a predefined length, during which the heat exchanger unit is operated to control the heat transfer to and / or from the aqueous preparation, and at least one change of the physical state of the aqueous preparation occurs during the time period. In other words, the heat exchanger unit can be configured to freeze and / or thaw the aqueous preparation during the operating cycle. For example, the heat exchanger unit can be operated so that during the operating cycle, the aqueous preparation is first frozen, then thawed, or vice versa. Therefore, the heat exchanger unit can also be referred to as a cooling unit, a freezing unit, a thawing unit or a freezing-thawing unit.

[0033] Generally speaking, the heat exchanger unit can be configured to control or manipulate the heat transfer, particularly heat flow, to or from the aqueous preparation. To this end, the heat exchanger unit can include a controllable heat transfer component, which can also be referred to as a cooling component. Therefore, the heat exchanger unit can be configured to control the heat transfer between the heat transfer component and the aqueous preparation during the operation cycle based on the determined control parameter changes. The heat transfer component can be configured to manipulate the amount and direction of the heat flow to or from the aqueous preparation. Specifically, the heat transfer component can be configured to transfer heat to or from the aqueous preparation by means of at least one of thermal conduction, thermal convection and thermal radiation. For example, the heat transfer component can include a heat transfer plate, which can be passed through by a heat transfer medium (also referred to as a "cooling medium"), and the flow rate and / or temperature of the heat transfer medium can be controlled by the heat exchanger unit during the operation cycle.

[0034] The heat exchanger unit may be configured to receive or accommodate an aqueous preparation to be treated. To this end, the heat exchanger unit may include a receiving space for accommodating the aqueous preparation during an operating cycle. The heat transfer component may at least partially define the receiving space. In a received state in which the aqueous preparation is received in the receiving space of the heat exchanger unit, a thermally conductive connection may be provided between the heat transfer component and the aqueous preparation. Specifically, a surface of the heat transfer component may constitute a surface of the receiving space, in particular an inner surface of the receiving space. The receiving space may constitute a reservoir for the aqueous preparation. According to one configuration, in the received state of the aqueous preparation, the aqueous preparation may be in direct contact or thermal contact with the surface of the receiving space.

[0035] Alternatively, the heat exchanger unit can be configured to receive or store the aqueous formulation in a container, such as a bag, a bottle, etc. In the context of the present disclosure, the term "container" refers to any component configured to accommodate or store an aqueous formulation. The container can be interchangeably received in the heat exchanger unit, particularly in the receiving space. That is, the container received in the heat exchanger unit can be replaced by another container that can be structurally identical or different, particularly having different sizes or volumes. For example, the container can have a volume in the range of 10l to 0.25l, but can also have a volume greater than 10l or less than 0.25l. For example, the container can have a volume of 9l or 5l or 0.4l. The container can be made of plastic, such as polyethylene and / or copolymers, particularly ethylene-vinyl alcohol copolymers. Further, the container can be intended to be used only for a single use, such as only for a single operating cycle of the heat exchanger unit. Further, the container can be intended to be used for multiple actions or cycles across multiple unit operations and within a given unit operation. The container may be at least partially in direct or thermal contact with a surface of the receiving space, in particular with a surface of a heat transfer component, thereby allowing heat to be transferred via thermal conduction and / or thermal convection. In order to allow the container to be correctly arranged in the receiving space, at least one insert component may be placed together with the container in the receiving space. In this way, it can be ensured that containers of different sizes and volumes can be correctly arranged in the receiving space.

[0036] As explained above, in order to change the physical state of the substance, the heat exchanger unit is configured to control or manipulate the heat flow to or from the aqueous preparation, in particular to or from the container. To this end, the heat exchanger unit may include a control unit configured to control the operation of the heat exchanger unit, in particular the heat transfer component, based on at least one control parameter. In the context of the present disclosure, the term "control parameter" refers to a parameter based on which the operation of the heat exchanger unit, in particular the heat transfer component, in particular the process variable is controlled. Therefore, when the control parameter is changed, the operation or process variable of the heat exchanger unit is affected. In other words, when the control parameter is changed during the operation of the heat exchanger unit, the heat transfer to or from the aqueous preparation can be manipulated. The control parameter can indicate the process variable of the heat exchanger unit to be set. For example, the control parameter can indicate or can refer to the temperature of the heat transfer component to be set during the operation of the heat exchanger unit. More specifically, the control parameter can indicate or can refer to the temperature of the cooling medium flowing through the heat transfer component. Preferably, the control parameter indicates a predetermined temperature of the heat transfer medium and can be a temperature set point of the cooling medium. Alternatively or additionally, the control parameter may indicate or may refer to the flow rate of the cooling medium flowing through the heat transfer component. In other words, the control parameter change (i.e. the change of the control parameter) affects the desired change of the control variable of the heat exchanger unit, in particular the change of the temperature and / or the flow rate of the heat transfer medium flowing through the heat transfer component. In other words, the control parameter change (i.e. the change of the control parameter) affects the desired change of the control variable of the heat exchanger unit, in particular the change of the temperature and / or the flow rate of the heat transfer medium flowing through the heat transfer component.

[0037] In this context, the term "control parameter variation" refers to a variation or course of at least one control parameter of a heat exchanger unit during an operating cycle. Thus, a control parameter variation indicates how at least one process variable of a heat exchanger unit will be set and changed over time (i.e. during an operating cycle). Thus, a control parameter variation associates one value of a control parameter to each of the different time points during an operating cycle. Thus, a control parameter variation may be provided or expressed in the form of a function or a curve that assigns exactly one value of a control parameter to a set of time points or each time point during an operating cycle or defines exactly one value of a control parameter for a set of time points or each time point during an operating cycle. For example, at least one control parameter variation may indicate a course of the temperature of a heat transfer component during an operating cycle. Alternatively or additionally, at least one control parameter variation may indicate a course of the temperature or flow rate of a heat transfer medium during an operating cycle. Preferably, the control parameter variation indicates or is a course of a predetermined temperature of the heat transfer medium (i.e. a course of a temperature set point).

[0038] Specifically, the control parameter change may define a change in a control parameter of the heat exchanger unit during a phase involving a change in the physical state of the aqueous preparation (i.e. during a freezing and / or thawing phase, in particular during a freezing phase and / or during at least one of a cooling and warming phase). A cooling or warming phase may refer to a phase during which the temperature of the aqueous preparation decreases or increases. More specifically, the control parameter change may define or indicate a change in the temperature of the heat transfer component during a phase involving a change in the physical state of the aqueous preparation (i.e. during a freezing and / or thawing phase, in particular during a freezing phase and / or during at least one of a cooling phase and a warming phase). Further, the control parameter change may define or indicate a change in the temperature and / or flow rate of the cooling medium flowing through the heat exchanger unit during a phase involving a change in the physical state of the aqueous preparation (i.e. during a freezing and / or thawing phase, in particular during a freezing phase and / or during at least one of a cooling phase and a warming phase).

[0039] In order to operate the heat exchanger unit based on the control parameter or the control parameter change, the control unit may apply feedback control, such as closed loop control, for ensuring that the process variable of the heat exchanger unit is correctly set according to the control parameter. For example, in case the control parameter is indicative of or refers to the temperature of the heat transfer component, the heat exchanger unit may be equipped with a temperature sensor configured for measuring the temperature of the heat transfer component and for sending a feedback signal indicative of the measured temperature to the control unit.

[0040] It will be appreciated by those skilled in the art that the method may be performed using different types of heat exchanger units, and that the present invention is not limited to a specific configuration of a 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 therefore will not be described in further detail. Instead, the characteristics of the method of operating such a heat exchanger unit for changing the physical state of a substance of an aqueous formulation that are interrelated with the present invention are addressed hereinafter.

[0041] The proposed method aims to operate the heat exchanger unit such that the aqueous formulation is subjected to temperature changes during an operating cycle which can follow or simulate a target temperature course. In the context of the present disclosure, the term "target temperature course" therefore refers to an expected or predefined course of temperature prevailing in the aqueous formulation during an operating cycle of the heat exchanger unit.

[0042] The target temperature course can be related to the temperature course of an aqueous preparation processed by another heat exchanger unit. The other heat exchanger unit can be a reference heat exchanger unit, and the heat exchanger unit will imitate the operation of the reference heat exchanger unit. In other words, the proposed method can be intended to be used to operate the heat exchanger unit so that the temperature course of the aqueous preparation to be processed simulates or corresponds to the temperature course experienced by the aqueous preparation when processed by the reference heat exchanger unit. Compared with the heat exchanger unit to be controlled by the proposed method, the reference heat exchanger unit can have different aqueous preparation processing characteristics. Specifically, the heat exchanger unit to be controlled by the method can be a scaled model of the reference heat exchanger unit, particularly a scaled-down model. For example, compared with the heat exchanger unit to be controlled by the method, the reference heat exchanger unit can have different, particularly larger aqueous preparation processing capabilities. In other words, the maximum amount of aqueous preparation to be processed during the operation cycle can be different between the heat exchanger unit and the reference heat exchanger unit.

[0043] Thus, the target temperature course may refer to or correspond to the temperature change to which the aqueous formulation is subjected when being processed by the reference heat exchanger unit for changing the physical state. To determine the target temperature course, the method may further comprise the steps of operating the reference heat exchanger unit during an operating cycle for changing the physical state of the aqueous formulation, and measuring the temperature course of the aqueous formulation when being processed in the reference heat exchanger unit during the operating cycle. Thus, the target temperature course may correspond to the temperature course of the aqueous formulation when being processed in or by the reference heat exchanger.

[0044] The method further includes the step of segmenting the target temperature process into at least two distinct phases. In the context of the present disclosure, the term "distinct phases" may refer to non-overlapping phases or segments of the target temperature process, but they are adjacent to each other with no gaps between them. By segmenting the target temperature process, different phases of the target temperature process are identified and defined.

[0045] The different phases of the target temperature process may refer to one of a temperature change phase, a temperature holding phase, or a change physical state phase. The temperature change phase may refer to the following time period in the operating cycle: during which the temperature of the aqueous formulation will change over time, i.e., without changing the physical state of the aqueous formulation. The temperature holding phase may refer to the following time period in the operating cycle: during which the temperature of the aqueous formulation will remain at a constant or substantially constant level without changing the physical state of the aqueous formulation. The change physical state phase may refer to the following time period in the operating cycle: during which the physical state of the aqueous formulation will be changed, i.e., without changing or substantially changing the temperature of the aqueous formulation.

[0046] When the aqueous formulation is frozen during the change of physical phase, then this change of physical phase may be referred to as a frozen phase.

[0047] When the aqueous formulation is thawed during the change of physical phase, then this change of physical phase may be referred to as a thaw phase.

[0048] The target temperature course may include a plurality of different and distinct temperature change phases that may differ from one another, for example, in terms of temperature change rate and / or temperature level. Alternatively or additionally, the target temperature course may include a plurality of different and distinct temperature holding phases that may differ from one another, for example, in terms of temperature level. Alternatively or additionally, the target temperature course may include a plurality of different changing physical state phases.

[0049] According to one configuration, the target temperature process may include at least two of the following eight stages:

[0050] - a first phase involving a temperature variation phase during which the aqueous preparation is cooled until solidification, ie until the freezing point of the aqueous preparation is reached;

[0051] - a second phase involving a change of physical state during which the aqueous preparation is frozen, i.e. the freezing phase;

[0052] - a third phase involving a further temperature variation phase during which the aqueous formulation is cooled until a predefined temperature below the freezing point is reached;

[0053] - a fourth phase involving a temperature holding phase during which the aqueous formulation is kept at the predefined temperature;

[0054] - a fifth phase involving a further temperature variation phase during which the aqueous preparation is warmed until the thawing point of the aqueous preparation is reached;

[0055] - a sixth phase involving a further change of the physical state phase, during which the aqueous preparation is thawed, i.e. the thawing phase;

[0056] - a seventh phase involving a further temperature variation phase during which the aqueous formulation will be heated until a further predefined temperature above the thawing point is reached; and

[0057] - an eighth phase involving a further temperature holding phase, during which the aqueous formulation is held at the further temperature;

[0058] The first and third stages can also be referred to as cooling stages.

[0059] The fifth and seventh stages may also be referred to as warming stages;

[0060] At least one of the two phases is a change in the phase of the physical state of the substance and at least the two phases are adjacent to each other.

[0061] Specifically, the step of dividing the target temperature process into at least two distinct stages is performed so that at least one of the divided stages (i.e., identified during this method step) involves a change in the physical state of the aqueous preparation, in particular freezing or thawing the aqueous preparation. In other words, at least one of the stages identified in the step of dividing the target temperature process involves a stage of changing the physical state 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 preparation is started and completed. The step of dividing the target temperature process can be performed to identify at least one of a freezing stage and a thawing stage, during which the freezing of the aqueous preparation will be performed, and during which the thawing of the aqueous preparation will be performed. Further, the step of dividing the target temperature process can be performed to divide the target temperature process into at least two stages of the first to eighth stages described above adjacent to each other, wherein one of the at least two stages of the first to eighth stages described above is a thawing stage or a freezing stage, and there is no gap between the stages. According to one configuration, the target temperature course may be divided into the first to eighth stages described above that follow one another consecutively.

[0062] The step of segmenting the target temperature process may include identifying the endpoints of the corresponding stages (which may also be referred to as cutoff points or limiting points or starting and ending points), i.e., the points where the different stages start and end. Each identified stage may be defined by its starting point and its ending point. In other words, the step of segmenting the target temperature process may include segmenting the target temperature process into stages by identifying the endpoints of the stages.

[0063] The step of segmenting the target temperature process can be realized by means of a computer program. Specifically, this step can be performed in an automated manner. For this reason, a computer program, for example, running on a control unit of a heat exchanger unit can be configured to analyze the target temperature process based on the freezing point and thawing point of the aqueous preparation to identify the following stage: during this stage, the aqueous preparation will be maintained at a temperature level corresponding to the freezing point and / or thawing point, and these stages change the physical state of the material. Further, the computer program can analyze the target temperature process to identify the following stage: during this stage, the temperature of the aqueous preparation changes with time, and these stages can be temperature change stages. Further, the program can analyze the target temperature process to identify the following stage: during this stage, the temperature of the aqueous preparation is maintained at a temperature level different from the freezing point and thawing point of the aqueous preparation, and these stages are temperature retention stages.

[0064] Alternatively or additionally, the segmentation of the target temperature process can be obtained from a database. Alternatively or additionally, the step of segmenting the target temperature process can be performed based on user interaction or user input. To this end, for example, the user can provide input to the computer program indicating the endpoints of different stages. Based on this input, the computer program can identify and define different stages of the target temperature process.

[0065] Alternatively or additionally, the step of segmenting the target temperature process may include processing the segmented target temperature process, i.e., the identified different stages of the segmented target temperature process. 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 adapted in segments (i.e., in stages). In order to apply linear regression, at least one of the identified stages of the target temperature process, in particular each stage in the stage, can be adapted so that the process of the target temperature within the different stages conforms to the following equation:

[0066] (1)Y=a+b*X

[0067] Where Y refers to the value of temperature, a refers to the coefficient or intercept, b refers to the slope, and X refers to the time point. Therefore, for each stage of the target temperature process, the coefficient a and the slope b can be determined. By applying linear regression, the computational workload for performing the method can be reduced. In particular, by applying linear regression to the target temperature process Tt(f), the target temperature process can be segmented into stages in a manner that reduces the computational power required to achieve the stage segmentation, thereby improving the speed and efficiency of deriving the segmented target temperature process.

[0068] The method further comprises the step of determining at least one control parameter change. Such control parameter change refers to the change of the control parameter described above over time, based on which the heat exchanger unit will be operated during the operating cycle. The step of determining the control parameter change is based on the target temperature process, in particular based on the segmented target temperature process (i.e. the target temperature process after being processed in the step of segmenting the target temperature process). In a further development, the step of determining the control parameter change can be based on the characteristics of the aqueous preparation, in particular based on the physical or chemical characteristics of the aqueous preparation, or can be performed as a function of the characteristics of the aqueous preparation. For example, the step of determining the control parameter change can be performed as a function of the volume of the aqueous preparation to be processed by the heat exchanger unit, in particular as a function of the volume of the container containing the aqueous preparation.

[0069] Alternatively or additionally, the step of determining the change in the control parameter can be performed as a function of the type of aqueous preparation or as a function of the thermal conductivity of the aqueous preparation. Specifically, the step of determining the change in the control parameter can be performed based on the thermodynamic properties of the aqueous preparation. Therefore, the change in the control parameter can be determined based on the freezing point or thawing point of the aqueous preparation. For example, in the case where the aqueous preparation is an aqueous preparation containing a drug substance, the step of determining the change in the control parameter can be performed based on or taking into account the freezing point and / or thawing point of water. Specifically, this step can be performed so that during the freezing stage, the temperature set point of the heat transfer medium is set to be lower than the freezing point of water, and during the thawing stage, the temperature set point of the heat transfer medium is set to be higher than the thawing point of water.

[0070] The step of determining the change in the control parameter may further comprise the sub-step of identifying a freezing phase in the target temperature course, in particular in the segmented target temperature course (i.e. the target temperature course provided as an output of the step of segmenting the target temperature course). Further, a time period of the operating cycle may be determined, which time period corresponds to the identified freezing phase, i.e. during which the aqueous formulation will be subjected to freezing during the operating cycle.

[0071] In the context of the present invention, it has been found that temperature shifts may occur during the freezing of an aqueous preparation, particularly when the volume of the aqueous preparation is relatively small. Such temperature shifts may be caused by a supercooling effect. Specifically, the temperature shift may occur due to a sudden release of energy, which may be caused by a sudden nucleation of the aqueous preparation. In order to prevent such sudden temperature shifts (i.e. caused by sudden nucleation during freezing), the step of determining the change in the control parameter may further include a sub-step of achieving a rise or fall (also referred to as a spike) in the change in the control parameter in a time period corresponding to the freezing phase and / or prior to the freezing phase. The rise or fall in the change in the control parameter may be defined as causing an increase in the cooling performance of the heat exchanger unit, particularly a temporary increase. Specifically, the rise or fall in the change in the control parameter may be defined as a reduction, temporarily reducing the temperature of the heat transfer component before and / or at the beginning of the freezing phase.

[0072] In the following, an exemplary embodiment is described in which a rise or fall of a control parameter change is implemented. In this exemplary embodiment, the control parameter may be a temperature set point of a cooling medium flowing through a heat transfer component. Specifically, in a stage prior to the freezing stage (e.g., in a temperature reduction stage), the control parameter (i.e., the temperature set point) may be reduced to a nucleation peak temperature. The nucleation peak temperature may be in the range of -22.5°C to -37.5°C, preferably between -25°C to -35°C, such as -30°C. Then, alternatively or additionally, the control parameter may be maintained at the nucleation peak temperature for a predetermined period of time, which may also be referred to as a nucleation peak holding time. Specifically, the nucleation peak holding time may be in the range of 5% to 50% of the duration of the stage prior to the freezing stage (e.g., the temperature reduction stage). Then, alternatively or additionally, the control parameter is raised from the nucleation peak temperature to the freezing temperature. This may be performed during a time period corresponding to the start of a determined freezing stage. In particular, the step of increasing the control parameter from the nucleation peak temperature to the freezing temperature may be performed during a time period having a duration in the range of 1% to 20% of the duration of the freezing phase. 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. Alternatively or additionally, thereafter, i.e. after the control parameter reaches the freezing temperature, the control parameter is maintained at this freezing temperature, in particular until the aqueous formulation is frozen.

[0073] Therefore, in an exemplary embodiment, in a phase preceding the freezing phase (e.g., a temperature reduction phase), the control parameter is reduced in a first sub-phase until the nucleation peak temperature is reached, and thereafter maintained at this temperature in a second sub-phase. Then, the control parameter is increased to the freezing phase in a first sub-phase of the freezing phase, and thereafter maintained at the freezing temperature in a second sub-phase of the freezing phase.

[0074] In a further development, the operator may set at least one of the nucleation peak temperature, the nucleation peak hold time, the freezing temperature and the thawing temperature.

[0075] In a further development, the characteristics of the rise or fall to be achieved in the control parameter change (such as its form, in particular its slope and height) can be set based on the properties of the aqueous preparation, in particular physical or chemical properties (such as the type or volume of the aqueous preparation).

[0076] The method further includes the step of performing a test run operation cycle. In the context of the present disclosure, the term "test run operation cycle" may refer to a test run of the heat exchanger unit, during which the correct operation of the heat exchanger unit may not be ensured and the test run is used to correctly set or readjust the operation of the heat exchanger unit. Specifically, this step includes a sub-step of operating the heat exchange unit based on the determined control parameter changes during the test run operation cycle. Therefore, the determined control parameter changes serve as a set of preliminary control parameters. In a further sub-step, the material temperature process is measured during the test run operation cycle. In the context of the present disclosure, the term "material temperature process" refers to the process of the temperature prevalent in the aqueous preparation during the operation of the heat exchanger unit. In other words, the material temperature process indicates the process of the temperature of the aqueous preparation during the test run operation cycle. In order to measure and monitor the temperature of the aqueous preparation, the heat exchanger unit may further include a temperature sensor, which is configured to measure the temperature prevalent in the aqueous preparation during the operation of the heat exchanger unit. Preferably, the temperature sensor can be configured to measure the temperature of the aqueous preparation at the center or substantially at the center of the aqueous material. For example, during the freezing process of aqueous preparations, freezing will start at the outer boundary of the aqueous preparation of the wall of the container that contacts wherein to hold the aqueous preparation, and will progress to the center of the aqueous preparation, until the whole volume of the aqueous preparation is frozen and becomes solid. Because known dissolved substances can reduce the freezing point of water, it may occur that the components of drug substances or any other dissolved components actually begin to accumulate in the center of the volume of the aqueous material. Placing the temperature sensor at the center of the aqueous material or substantially at the center takes into account the possible accumulation of the components of the aqueous preparation during the freezing process. Specifically, the temperature sensor can be configured to measure the temperature of the aqueous preparation at the center of the container that holds the aqueous preparation. According to one embodiment, the temperature of the aqueous preparation is detected by a sensor positioned in the aqueous preparation, particularly in the container.

[0077] The method further includes the step of segmenting the measured material temperature process into at least two distinct stages, wherein at least one stage involves a change in the physical state of the aqueous preparation. This step can be performed corresponding to the step of segmenting the target temperature process as described above. Therefore, all features described in conjunction with the step of segmenting the target temperature process can also be applicable, and therefore the step of segmenting the measured material temperature process is disclosed. Specifically, the step of segmenting the measured temperature process can be performed to identify at least one of a freezing stage and a thawing stage, during which the aqueous preparation has been frozen, and during which the thawing stage the aqueous preparation has been thawed. Alternatively or additionally, the step of segmenting the measured material temperature process can be performed to identify different stages, which correspond to those stages identified as a result of the step of segmenting the target temperature process in view of their number and type. Further, the step of segmenting the measured material temperature process can include segmenting the measured material temperature process into stages by identifying the endpoints of the stages. Alternatively or additionally, the step of segmenting the measured temperature course of the substance may comprise adapting the phases of the measured temperature course by applying a linear regression.

[0078] The method further includes a step of adapting the determined control parameter change based on the comparison of the segmented measured material temperature process and the segmented target temperature process. Specifically, the comparison of the segmented measured material temperature process and the segmented target temperature process can be performed in stages. That is, the corresponding stages between the segmented measured temperature process and the segmented target temperature process can be identified and compared. In the context of the present disclosure, the term "corresponding stage" can refer to the following stages in the target temperature process and the following stages in the measured temperature process: during this stage, the process of temperature in the target temperature process and the process of temperature in the measured temperature process both involve a temperature rise stage, or a temperature drop stage, or a temperature holding stage, or a freezing stage or a thawing stage, during which the temperature rise stage increases, the temperature decreases during the temperature drop stage, and the temperature is maintained at a constant temperature level different from the freezing point or the thawing point during the temperature holding stage. Further, the stages in the target temperature process and the stages in the measured temperature process that constitute the corresponding stages can occur at overlapping or substantially the same or close time periods during the operation cycle.

[0079] Specifically, the step of adapting the control parameter change may include the following sub-steps: identifying the corresponding stages between the segmented measured material temperature process and the segmented target temperature process; determining the duration of the corresponding stage and / or determining the average temperature of the corresponding stage; and adapting the determined control parameter change based on a comparison of the determined duration and / or average temperature of the corresponding stage.

[0080] Alternatively or additionally, the step of adapting the control parameter change may include the following sub-steps: identifying a corresponding freezing stage or a corresponding thawing stage between the segmented measured material temperature process and the segmented target temperature process; determining the duration and average temperature of the corresponding freezing stage or the corresponding thawing stage; and determining the average value of the control parameter change within the time period corresponding to the freezing stage or the corresponding thawing stage in the segmented measured temperature process; and adapting the control parameter change according to 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 change.

[0081] Further, a data processing system or device is provided, which includes a component for implementing the steps of the method as described above. 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 include a control unit. In one embodiment, the data processing system may include a CPU and a memory. In another embodiment, the data processing system may further include a central server for running at least a portion of the software away from the control unit. The data processing system may be or include a computer. The computer may be any computing unit that is particularly suitable for or configured to interact with the heat exchanger unit, such as a control unit, a personal computer or a special-purpose computer. Generally speaking, such a data processing system includes at least a central processing unit (CPU) for executing digital instructions, and a memory for storing digital instructions (e.g., computer programs) to be executed by the CPU, as will be understood by those skilled in the art in view of the present disclosure. Alternatively or additionally, the data processing system may include sensors and / or actuators, for example, sensors and / or actuators carried by or connected to the heat exchanger of the present invention, as will be discussed in further detail later. Alternatively or additionally, the data processing system may include an interface for communicating with the sensor and / or actuator.

[0082] The invention also relates to a computer program for carrying out the method according to the invention. In particular, a computer program is provided, the computer program comprising instructions which, when executed by a computer, cause the computer to carry out the steps according to the method as described above. The computer may be any computing unit, such as a control unit, a personal computer or a special purpose computer, which is particularly suitable for or configured to interact with a heat exchanger unit. As indicated above, and as will be understood by a person skilled in the art, the computer typically comprises, in particular, a CPU and a memory for storing a computer program to be used to control the heat exchanger unit.

[0083] Furthermore, a computer-readable medium is provided, on which the computer program mentioned above is stored.

[0084] Still further, a system is provided, the system comprising a heat exchanger unit and a control unit for operating the heat exchanger unit for changing the physical state of the aqueous formulation such that the temperature of the aqueous formulation is adjusted based on a target temperature course during an operating cycle, wherein the control unit is configured to implement the steps of the method as described above. It will be understood that the control unit may include the aforementioned computer for implementing the steps of the method as described above, if desired. BRIEF DESCRIPTION OF THE DRAWINGS

[0085] The present disclosure will be more readily understood by reference to the following detailed description when considered in conjunction with the accompanying drawings, in which:

[0086] Figure 1 is a schematic diagram of an embodiment of a heat exchanger system;

[0087] Figure 1a is a schematic diagram of an embodiment of a control unit;

[0088] Figure 2 Shows the drawing operation Figure 1 A flow chart of an embodiment of a method of a heat exchanger unit of a heat exchanger system as depicted in;

[0089] Figure 3 showing a diagram illustrating an example target temperature process;

[0090] Figure 4 and Figure 5 showing a graph illustrating the segmented target temperature course; and

[0091] Figure 6 A diagram illustrating changes in control parameters is shown. DETAILED DESCRIPTION

[0092] Hereinafter, the present invention will be explained in more detail with reference to the accompanying drawings. In the accompanying drawings, similar elements are denoted by the same reference numerals, and repeated descriptions thereof may be omitted in order to avoid redundancy.

[0093] Figure 1 A heat exchanger system 10 , also referred to hereinafter as a “system,” is shown which is designed and configured to subject an aqueous formulation 12 to a predetermined and strictly controlled freezing and thawing program.

[0094] The system 10 shown may be used in the field of pharmaceutical production, but is not limited to this application. The system 10 comprises 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 .

[0095] Figure 1a An embodiment of the control unit 16 is shown in FIG. 1 , wherein the control unit comprises a central processing unit CPU 16A and a memory 16B.

[0096] The heat exchanger unit 14 may include a heat transfer component 18 having two heat transfer plates 20 that partially define (i.e., in opposing positions) a receiving space 22 for accommodating an 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 may be interchangeably received in the receiving space 22. Further, the container 24 may be made of polyethylene and / or ethylene-vinyl alcohol copolymer and may be intended for a single use only. Specifically, as from Figure 1 It can be seen that the container 24 is received in the receiving space 22 such that it is in thermal contact with the heat transfer component 18 , in particular with the heat transfer plate 20 thereof.

[0097] Further, 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 to be guided through the heat transfer plate 20. To this end, the temperature control unit 26 is fluidly connected to the heat transfer plate 20 via a feed line 28 and a discharge line 30 to form a heat transfer medium loop, thereby allowing the heat transfer medium to be continuously circulated through the temperature control unit 26 and the heat transfer component 18. The feed line 28 is configured to supply the heat transfer medium after being processed in the temperature control unit 26 to the heat transfer component 18. The discharge line 30 is configured to recirculate the heat transfer medium after being guided through the heat transfer component 18 to the temperature control unit 26. With this configuration, the heat transfer medium is configured to be heated and cooled while flowing through the heat transfer plate 20. Heat transfer occurs between the aqueous formulation 12 and the heat transfer element 18, particularly as Figure 1 Further, the heat exchanger unit 14 comprises a temperature sensor 32, which is configured to measure the temperature prevailing in the aqueous preparation 12, in particular the temperature prevailing in the central region of the aqueous preparation. By means of the temperature sensor 32, monitoring data indicating the temperature prevailing in the substance 12 over time can be recorded by a separate measuring device or the control unit 16.

[0098] In the illustrated configuration, the heat exchanger system 10 is depicted in a state in which the aqueous formulation 12 received in the heat exchanger unit 14 is subjected to a freezing process. In this state, nucleation of the aqueous formulation 12 propagates from the end of the container 24 in thermal contact with the heat transfer plate toward the center of the container. Figure 1 As depicted, the aqueous formulation 12 is partially in a solid state 12a and partially in a liquid state 12b. In this state, heat can be transferred from the aqueous formulation 12 toward the heat transfer plate, and thus toward the heat transfer medium flowing therethrough, such as Figure 1 Heat flow in indicated in the direction of.

[0099] As described above, the control unit 16 is configured to control the operation of the heat exchanger unit 14. In one form of the invention, the control unit 16 includes a computer configured to perform the method steps of the invention. More specifically, the control unit 16 generally includes a central processing unit (CPU) 16A configured to execute digital instructions and provide outputs, and a memory 16B for storing digital instructions (e.g., computer programs) and / or outputs received from the CPU 16A, as will be understood by those skilled in the art in view of the present disclosure. In order to control the operation of the heat exchanger unit 14, the control unit 16 is communicatively connected to the heat exchanger unit 14, in particular to the temperature control unit 26, via at least one data interface 34. The data interface 34 can be a wireless interface or a wired interface. Specifically, the control unit 16 is configured to send a control signal to the heat exchanger unit 14, in particular to the temperature control unit 26, via the data interface 34, and control the operation of the heat exchanger unit 14 based on the control signal.

[0100] In the illustrated configuration, the control unit 16 includes a computer, such as a personal computer or a dedicated computer, provided separately from the heat exchange unit 14. Therefore, the control unit 16 is provided as a separate component, which is communicatively and detachably connected to the heat exchanger unit 14 via the data interface 34. Alternatively, the control unit 16 may be provided as a part of the heat exchanger unit 14. That is, the control unit 16 may be a dedicated computer integrated in the structural configuration of the heat exchanger unit 14.

[0101] The control unit 16 is configured to implement a method of operating the heat exchanger unit 14 for changing the physical state of the aqueous formulation 12 so that the temperature of the aqueous formulation 12 is based on the target temperature process T during the operation cycle. T (t) make adjustments. Specifically, the control unit 16 constitutes or is part of a data processing device or system. Further, as indicated above, the control unit may include (or have access to) a computer program or computer program product or computer readable medium including or storing instructions that, when executed by the control unit 16, cause the control unit 16 to implement the method of operating the heat exchanger unit 14.

[0102] exist Figure 2The method of operating the heat exchanger unit 14 implemented by the control unit 16 is described in the form of a flow chart. Figures 2 to 6 The method and its individual steps carried out by the control unit 16 are described in detail.

[0103] In the first step S1 of the method, a target temperature process T is obtained, for example, from a database. T (t). Specifically, the target temperature process T T (t) may be provided as an input to the control unit 16. More specifically, the target temperature process T T (t) may be provided in the form of a function or a plurality of sets of points which assign exactly one value of the temperature to a point in time during an operating cycle. Thus, the target temperature course may be provided in the form of a continuous or discontinuous function or in the form of discontinuous data points.

[0104] Figure 3 An exemplary target temperature course is depicted as a curve diagram in the figure. The ordinate of the figure depicts temperature, in particular the target temperature prevailing in the aqueous formulation 12. The abscissa of the figure depicts time, wherein t0 refers to the starting point of the operating cycle, and t E Refers to the end point of the operation cycle.

[0105] The target temperature course indicates a desired or expected change in the temperature of the aqueous formulation during an operating cycle of the heat exchanger unit 14. T (t) may correspond to the temperature course to which the aqueous formulation is subjected when being treated by another heat exchanger unit, in particular a reference heat exchanger unit. T (t) may specifically correspond to a predetermined temperature course specific to an aqueous formulation, such as empirically derived using a reference heat exchanger unit and stored in a database (e.g., stored in memory 16B or otherwise accessible by CPU 16A and / or control unit 16). T (t) When operating the heat exchanger unit 16, the heat exchanger unit 16 may mimic the operation of the reference heat exchanger unit. Specifically, the heat exchanger unit 16 may be a scaled model, in particular a reduced-scale model, of the reference heat exchanger unit.

[0106] In the next step S2, the target temperature process T T (t) is divided into at least two distinct stages P 1-8 , wherein at least one phase P2, P6 involves a change in the physical state of the aqueous formulation 12. In the configuration of the invention, the method can distinguish the following different types of phases: temperature change phase, temperature holding phase, freezing phase and thawing phase. In order to segment the target temperature process, in a first substep, the endpoints E of the different phases can be identified.0-8 , the endpoints are specific points in time during the operating cycle. This can be done by first identifying phases during which no or only small temperature changes occur. These phases can then be compared with the freezing and thawing points of the aqueous formulation in order to decide whether these phases correspond to temperature holding phases, freezing phases or thawing phases. Thereafter, temperature change phases are identified, which can be arranged between the identified phases, the temperature holding phases, the freezing phases and the thawing phases. Specifically, the target temperature process T is set to the target temperature. T (t) performing a segmentation step S2 to identify at least one of a freezing stage P2 during which the aqueous preparation 12 is to be frozen and a thawing stage P6 during which the aqueous preparation 12 is to be thawed.

[0107] More specifically, when the target temperature process T T (t) When undergoing step S2, the Figure 4 The eight distinct stages P 1-8 . The first stage P1 involves a temperature change stage, during which the temperature of the aqueous formulation 12 will continuously decrease from 20°C to a freezing point of about 0°C. The second stage P2 involves a freezing stage, during which the aqueous formulation 12 will be frozen. The third stage P3 involves a temperature change stage, during which the temperature of the aqueous formulation 12 will continuously decrease from the freezing point to about -80°C. The fourth stage P4 involves a temperature holding stage, during which the temperature of the aqueous formulation 12 will be held at about -80°C. The fifth stage P5 involves a temperature change stage, during which the temperature of the aqueous formulation 12 will continuously increase from about -80°C to a thawing point. The sixth stage P6 involves a thawing stage, during which the aqueous formulation 12 will be thawed. The seventh stage P7 involves a temperature change stage, during which the temperature of the aqueous formulation 12 will continuously increase from the thawing point to about 25°C. The eighth stage P8 involves a temperature holding stage, during which the temperature of the aqueous formulation 12 will be held at about 25°C.

[0108] Optionally, in a next sub-step, the target temperature process T is adapted by applying a linear regression T (t) different stages P 1-8 By applying linear regression, we can associate different stages of P 1-8 The data points of the target temperature process in one stage are represented as a linear function. Figure 5 The result of this sub-step is depicted in 1-8 It is represented and defined by a linear function, thereby generating the segmented target temperature process T sT (t).

[0109] In step S3, based on the target temperature process T T (t), especially based on the segmented target temperature process T sT (t), determining at least one preliminary control parameter change C(t). In general, based on the control parameter change C(t), the control unit 16 is configured to control the operation of the heat exchanger unit 14. To this end, the control unit 16 can use the control parameter change C(t) as a control command, or can derive a control command therefrom, which is provided to the heat exchanger unit 14 as a control signal via the data interface 34. Therefore, based on the control parameter change C(t), 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 operation cycle. In a further development, the step S3 of determining the control parameter change can be further performed based on properties of the aqueous preparation, in particular on physical or chemical properties of the aqueous preparation (e.g. as a function of the volume of the aqueous preparation), and / or on properties of the container 24, in particular on the type or volume of the container 24.

[0110] In the configuration shown, at least one control parameter variation C(t) is indicative of the course of the temperature of the heat transfer element 18 during an operating cycle. More specifically, the control parameter variation C(t) is a variation of the temperature set point of the heat transfer medium guided through the heat transfer element 18. In particular, the step of determining the control parameter variation is performed based on the thermodynamic properties of the aqueous preparation, in particular based on the freezing point and the thawing point of the diluent (here: water). In particular, this step is performed such that during the freezing phase, the temperature set point of the heat transfer medium is set below the freezing point of the diluent (here: water), and during the thawing phase, the temperature set point of the heat transfer medium is set above the thawing point of the diluent (here: water). As shown from Figure 6 As can be seen from the control parameter change C(t) depicted in FIG, this step is performed so that the temperature set point of the heat transfer medium is different during the freezing phase P2, the cooling phases P1 and P3, and the warming phases P5 and P7. In other words, the control parameter change C(t) defines the change of the temperature set point of the heat transfer medium during the cooling phases P1, P3; the freezing phase P2, and the warming phases P5 and P7. Alternatively, this step can be performed so that the control parameter change C(t) defines the change of the temperature set point of the heat transfer medium during at least one of the first cooling phase P1, the freezing phase P2, the second cooling phase P3, the temperature holding phase P4, the first warming phase P5, the thawing phase P6, and the second warming phase P6.

[0111] Alternatively or additionally, a further control parameter change may be determined, which may be indicative of the flow rate of the heat transfer medium passing through the heat transfer component 18. Thus, the control parameter change may define a change in the flow rate of the heat transfer medium during at least one of the first cooling phase P1, the freezing phase P2, the second cooling phase P3, the temperature holding phase P4, the first warming phase P5, the thawing phase P6 and the second warming phase P6, in particular during at least one of the first cooling phase P1, the freezing phase P2 and the second cooling phase P3.

[0112] Figure 6 An exemplary control parameter variation C(t) determined in step S3 is depicted in the figure as a graph, wherein a target temperature course T sT (t). An exemplary control parameter variation C(t) depicts the course of the temperature set point of the heat transfer medium. The ordinate of the graph depicts the temperature corresponding to the value of the control variable, i.e., indicating the temperature of the heat transfer medium, in particular the set point of the temperature of the heat transfer medium. The abscissa of the graph depicts the time during the operating cycle. Figure 6 It can be seen that the control parameter changes C (t) The determination is based on the segmented target temperature process T sT (t) different stages P 1-8 The type of and the time period associated with it. Figure 6 It can be seen that the temperature set point of the heat transfer medium is determined so that it is below the freezing point of water during the freezing stage P2 and above the thawing point of water during the thawing stage P6. Specifically, during the thawing stage P6, the temperature set point can be in the range of 2.5°C to 20°C, preferably between 5°C and 15°C. Further, the temperature set point of the heat transfer medium is determined so that it is substantially below the target temperature course during the cooling stage and substantially above the target temperature course during the warming stage. Further, in the case where the aqueous formulation 12 is to be maintained at a temperature below the ambient temperature (i.e., about 21°C) (i.e., during the temperature holding stage), the temperature set point of the heat transfer medium is determined so that it is substantially below the target temperature course (i.e., during most of the time in the temperature holding stage). However, in the case where the aqueous formulation is to be maintained at a temperature above the ambient temperature (i.e., during the temperature holding stage), the temperature set point of the heat transfer medium is determined so that it is substantially above the target temperature course.

[0113] For example, for a process associated with a target temperature T T The control unit 16 can define the control parameter changes C(t) in the temperature change phases, especially the temperature reduction or increase phases, or the temperature maintenance phases in the temperature change ...

[0114]

[0115] in Refers to the target temperature process T at time t T (t) is the rate of change of temperature; A and B are constants or coefficients, particularly those specific to aqueous formulations and heat exchangers; C t is the value of the control parameter at time t; and T T_t Refers to the target temperature process T at time t T (t) is the temperature value in .

[0116] Alternatively or additionally, to carry out step S3, the control unit 16 may use a reference control parameter variation which may be stored in a memory of the control unit 16 and may refer to a temperature profile in which the aqueous formulation continuously undergoes a temperature profile corresponding to the segmented target temperature profile T sT Alternatively or additionally, to determine the control parameter change C(t), the control unit 16 may utilize a mathematical or computational model capable of predicting or calculating the temperature process prevailing in the aqueous formulation 12 as the control parameter changes. When using such a mathematical or computational model, the segmented target temperature process T sT (t) may be used as an input based on which a preliminary control parameter change C(t) may be determined.

[0117] Further, the step (S3) of determining the control parameter change C(t) may include identifying the segmented target temperature process T sT Then, in a further sub-step, in the operation cycle preceding the target temperature process T divided by sT The decrease in the control parameter change C(t) is achieved during the time period associated with the freezing phase in (t) and / or during the time period overlapping therewith, such as from Figure 6 It can be seen that the decrease in the control parameter variation C(t) is designed so as to cause a temporary increase in the cooling performance of the heat exchanger unit during the freezing phase P2 in the operating cycle, in particular before and at the beginning of the freezing phase P2.

[0118] Specifically, in the configuration shown, the control parameter change C(t) is designed so that during the first phase P1, the temperature set point is reduced to the nucleation peak temperature, which is preferably in the range between -25°C and -35°C, for example -30°C. More specifically, in the first sub-phase of the first phase P1, the temperature set point is reduced from the ambient temperature to the nucleation peak temperature. Then, the temperature set point is maintained at the nucleation peak temperature for a predetermined period of time (i.e., during the second sub-phase of the first phase P1). Specifically, the nucleation peak holding time can be in the range of 5% to 50% of the duration of the first phase P1. Then, in the first sub-phase of the second phase P2, the temperature set point is increased from the nucleation peak temperature to the freezing temperature. The freezing temperature can be in the range of -5°C to -20°C, preferably in the range of -10°C to -17.5°C, and more preferably in the range of -12.5°C to -17.5°C. Thereafter, in the second sub-phase of the second phase P2, the temperature set point is maintained at the freezing temperature. The duration of the first subphase of the second phase P2 may be in the range of 1% to 20% of the duration of the second phase P2. In a further development, the method may be provided such that step S4 is performed based on predefined temperature set points and timing, in particular based on at least one of a predetermined nucleation peak temperature, a predetermined nucleation peak hold time, a predetermined freezing temperature and a predetermined thawing temperature. In particular, these set points or parameters may be set by an operator.

[0119] In the next step S4, the control unit 16 operates the heat exchanger unit 14 to perform a test run operation cycle. Specifically, this step includes a sub-step S4.1 of operating the heat exchanger unit 14 based on the determined preliminary control parameter change C(t) during the test run operation cycle. At the same time, a process of measuring the temperature of the substance T is carried out. M (t) of sub-step 4.2, where the material temperature process T M (t) The process of indicating the temperature of the aqueous formulation during the test run operating cycle. This sub-step is performed by collecting measurement signals from the temperature sensor 32.

[0120] Then, in step S5, the measured temperature process T M (t) divided into at least two different stages to obtain the divided measured temperature process T sM (t), wherein at least one stage involves a change in the physical state of the aqueous formulation 12. This step S5 may correspond to the above-described step of setting the target temperature process T T(t) The step S2 of segmenting is performed. Specifically, the step S5 is performed to identify the freezing stage during which the aqueous preparation 12 has been frozen and the thawing stage during which the aqueous preparation 12 has been thawed. Further, the step S5 may include identifying the stage P 1-8 The measured temperature process T M (t) splitting into phase sub-steps; and adapting the measured temperature course T by applying linear regression M (t) stage P 1-8 , thereby obtaining the segmented measured temperature process T sM (t) sub-step.

[0121] In the next step S6, the control unit 16 determines the temperature profile T sM (t) and the target temperature process T sT (t) to adapt the determined control parameter change C(t). To this end, the control unit 16 can first identify the segmented measured temperature course T sM (t) and the segmented target temperature process T sT In one embodiment, the control unit 16 can determine the duration and / or average temperature value of all identified phases. Then, based on the comparison of the determined duration and / or the determined average temperature value of the corresponding phases, the determined control parameter change C(t) can be adapted.

[0122] Alternatively or additionally, the step S6 of adapting the control parameter variation C(t) may comprise the following sub-steps: identifying the segmented measured temperature course T sM (t) and the segmented target temperature process T sT (t) corresponding to the freezing stage P2 or the corresponding thawing stage P6; determine the duration and average temperature of the corresponding freezing stage P2 or the corresponding thawing stage P6; and determine the measured temperature process T corresponding to the segmentation sM (t); and adapting the control parameter change C(t) according to 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 change.

[0123] Specifically, for this purpose, the control unit 16 has already identified the segmented measured temperature course T sM (t) and the segmented target temperature process T sTIn the case of a corresponding physical state phase in (t), especially a corresponding freezing phase or a thawing phase, the control parameter change C(t) can be adapted based on the following equation:

[0124]

[0125] in

[0126] It means that when the adaptive control parameter changes C(t), the target temperature process T T (t) a set value defining an average control parameter value set during the time period of the corresponding phase;

[0127] refers to the temperature process T S (t) is the average control parameter value of the control parameter change C(t) during the time period corresponding to the stage;

[0128] refers to the temperature process T M The temperature process T measured during the time period of the corresponding stage in (t) M (t) or the segmented measured temperature process T sM (t) the average temperature;

[0129] D M_P Refers to the measured temperature process T M The duration of the corresponding phase in (t);

[0130] D T_P It refers to the target temperature process T M the duration of the corresponding phase in (t); and

[0131] It refers to the process involving the target temperature T M The target temperature process T during the time period of the corresponding stage in (t) T (t) or the divided target temperature process T sT (t) is the average temperature.

[0132] Furthermore, for the process associated with the target temperature T T (t), in particular, the temperature reduction or increase phase, or the temperature maintenance phase, the control unit 16 can adapt the control parameter change C(t) in these phases based on the equation (2) described above. Further, in order to adapt the control parameter change C(t), the control unit 16 can further use the mathematical or computational model used in step S3 to determine the control parameter change C (t) .

[0133] In a next optional step S7, the control unit 16 may determine a similarity parameter indicating the target temperature process T T (t) or the divided target temperature process T sT (t) and the measured temperature process T M (t) or the segmented measured temperature process T sM Specifically, the similarity parameter can be calculated based on the following equation:

[0134]

[0135] Where s refers to the quantitative target temperature process T T (t) and the measured temperature process T M Similarity parameter of the similarity between (t).

[0136] Then, in an optional step S8, the determined similarity parameter s is compared with a threshold value S. If the similarity parameter s is below the threshold value S, the method proceeds to step S9, in which the control unit 16 allows the heat exchanger unit 14 to be operated correctly, i.e. according to the target temperature course T T (t). If the similarity parameter s is equal to or greater than the threshold value S, the method returns to step S4 to perform a further test run operation cycle, based on which the control parameter change C(t) is further adapted. With this configuration, the method allows iteratively adapting the control parameter change C(t) until a satisfactory result is achieved. In an alternative configuration, method step S6 may be performed after step S8, in particular if the similarity parameter s is equal to or greater than the threshold value S. According to one embodiment, method step S9 may be performed subsequently, in particular immediately after step S6.

[0137] It will be apparent to those skilled in the art that these embodiments and projects merely depict the various possibilities for implementing the invention as defined in the independent claims. Therefore, the embodiments shown herein should not be construed as forming limitations to these features and configurations. Any possible combination and configuration of the features described can be selected according to the scope of the invention.

[0138] The present invention and its embodiments will be described again in the following clauses:

[0139] 1. A method of operating a heat exchanger unit (14) for changing the physical state of a substance of an aqueous preparation (12) by freezing or thawing,

[0140] The aqueous preparation (12) is contained in a container and the heat exchanger unit acts on the aqueous preparation (12) in the container,

[0141] The temperature of the aqueous formulation (12) is adjusted during the operating cycle based on a target temperature process (T T (t)) is adjusted, the method comprising the following steps:

[0142] -(S2) the target temperature process (T T (t)) into at least two distinct phases (P), wherein at least one phase (P2, P6) involves a change in the physical state of the substance of the aqueous preparation (12);

[0143] -(S3) based on the target temperature process (T T (t)), determining a control parameter change (C(t)), based on which operation of the heat exchanger unit (14) is controlled during an operating cycle;

[0144] -(S4) performing a test run operation cycle, comprising the following sub-steps:

[0145] - (S4.1) operating the heat exchange unit (14) based on the determined control parameter change (C(t)) during the test run operation cycle, and

[0146] --(S4.2) Temperature measurement process (T M (t)), wherein the temperature course indicates the course of the temperature of the aqueous formulation during an operating cycle of the test run;

[0147] -(S5) The measured temperature process (T M (t)) into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation (12);

[0148] - (S6) based on the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)) to adapt the determined control parameter change (C(t)); and

[0149] - operating the heat exchanger unit (14) for changing the physical state by freezing or thawing the aqueous formulation (12) based on an adapted change of control parameters.

[0150] 2. The method according to clause 1, wherein the aqueous formulation (12) comprises water and optionally further at least one selected from the group consisting of a buffer, a cell culture medium and at least one or more drug substances.

[0151] 3. A method according to clause 1 or 2, wherein the temperature of the aqueous formulation is measured by a sensor positioned in the container, and preferably wherein the sensor is positioned in contact with the aqueous formulation in the container.

[0152] 4. A method according to any one of clauses 1 to 3, wherein 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 based on the determined control parameter change (C(t)).

[0153] 5. A method according to clause 4, wherein the at least one control parameter variation (C(t)) is indicative of the course of the temperature of the heat transfer component (18), in particular the course of the temperature of the heat transfer medium flowing through the heat exchanger unit (14), during the operating cycle.

[0154] 6. A method according to any one of clauses 1 to 5, wherein the control parameter change (C(t)) defines a change in a control parameter of the heat exchanger unit (14) during the phase involving the change in the physical state of the aqueous formulation (12).

[0155] 7. A method according to any one of clauses 1 to 6, wherein the control parameter is indicative of 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 is indicative of the flow rate of the heat transfer medium.

[0156] 8. A method according to any one of clauses 1 to 7, wherein the target temperature process (T T (t)) corresponds to the temperature change to which the aqueous formulation (12) is subjected when being treated by a reference heat exchanger unit for changing the physical state of the aqueous formulation (12), wherein in particular, the heat exchanger unit (14) is a scaled model of the reference heat exchanger unit.

[0157] 9. The method according to any one of clauses 1 to 8, wherein the target temperature process (T T (t)) is divided into steps (S2) and the measured temperature process (T M (t)) performs at least one of the segmentation steps (S5) to identify at least one of a freezing stage (P2) during which the aqueous preparation (12) will be or has been frozen, and a thawing stage (P6) during which the aqueous preparation (12) will be or has been thawed.

[0158] 10. The method according to any one of clauses 1 to 9, wherein the target temperature process (TT (t)) is divided into steps (S2) and the measured temperature process (T M (t)) At least one of the steps (S5) of performing segmentation includes at least one of the following:

[0159] - The target temperature process (T T (t)) or the measured temperature course (T M (t)) into stages; and

[0160] - Adapting the target temperature process (T T (t)) or the measured temperature course (T M (t)) of the said stage.

[0161] 11. A method according to any one of clauses 1 to 10, wherein the step (S3) of determining the change in the control parameter (C(t)) is performed based on the properties of the aqueous preparation, in particular based on the volume of the aqueous preparation (12).

[0162] 12. The method according to any one of clauses 1 to 11, wherein the step (S3) of determining the control parameter change (C(t)) comprises:

[0163] - Identify the target temperature process (T T (t)) in the freezing phase (P2); and

[0164] - an increase or decrease in the control parameter change (C(t)) is achieved within a time period of the operating cycle, which time period of the operating cycle precedes or overlaps with a time period associated with the freezing phase (P2), wherein the increase or the decrease in the control parameter change (C(t)) causes a temporary increase in the cooling performance of the heat exchanger unit.

[0165] 13. The method according to any one of clauses 1 to 12, wherein the step (S6) of adapting the control parameter variation C(t) comprises the following sub-steps:

[0166] - Identify the segmented measured temperature course (T sM (t)) and the segmented target temperature process (T sT (t)) between the corresponding stages;

[0167] - determining the duration of said corresponding phase and / or determining the average temperature of said corresponding phase; and

[0168] - adapting the control parameter change (C(t)) based on a comparison of the determined durations and / or average temperatures of the corresponding phases.

[0169] 14. The method according to any one of clauses 1 to 13, wherein the step (S6) of adapting the control parameter change (C(t)) comprises the following sub-steps:

[0170] - Identify the segmented measured temperature course (T sM (t)) and the segmented target temperature process (T sT (t)) corresponding to the freezing stage or the corresponding thawing stage;

[0171] - determining the duration and the average temperature of the corresponding freezing phase or the corresponding thawing phase; and

[0172] - Determine the temperature course (T sT an average value of the control parameter variation (C(t)) during the freezing phase or the thawing phase in the freezing phase (t)); and

[0173] - adapting the control parameter change (C(t)) as a function of the determined duration of the corresponding freezing phase or the corresponding thawing phase, the determined average temperature of the corresponding freezing phase or the corresponding thawing phase and the determined average value of the control parameter change C(t).

[0174] 15. A data processing system for controlling a heat exchanger unit (14), the heat exchanger unit being 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 and the heat exchanger unit acts on the aqueous formulation (12) in the container so that the temperature of the aqueous formulation (12) changes during an operating cycle based on a target temperature course (T T (t)), and further wherein the data processing system comprises a central processing unit, a memory and software stored in the memory, the software performing the following steps when executed by the central processing unit:

[0175] -(S2) the target temperature process (T T (t)) into at least two distinct phases (P), wherein at least one phase (P2, P6) involves a change in the physical state of the substance of the aqueous preparation (12);

[0176] -(S3) based on the target temperature process (T T (t)), determining a control parameter change (C(t)), based on which operation of the heat exchanger unit (14) is controlled during an operating cycle;

[0177] -(S4) performing a test run operation cycle, comprising the following sub-steps:

[0178] - (S4.1) operating the heat exchange unit (14) based on the determined control parameter change (C(t)) during the test run operation cycle, and

[0179] --(S4.2) Temperature measurement process (T M (t)), wherein the temperature course indicates the course of the temperature of the aqueous formulation during an operating cycle of the test run;

[0180] -(S5) The measured temperature process (T M (t)) into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation (12);

[0181] - (S6) based on the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)) to adapt the determined control parameter change (C(t)); and

[0182] - operating the heat exchanger unit (14) for changing the physical state by freezing or thawing the aqueous formulation (12) based on an adapted change of control parameters.

[0183] 16. A computer program for controlling a heat exchanger unit (14), the heat exchanger unit being 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 and the heat exchanger unit acts on the aqueous formulation (12) in the container so that the temperature of the aqueous formulation (12) changes during an operating cycle based on a target temperature course (T T (t)) is adjusted, wherein the computer program includes instructions, and when the computer program is executed by a computer, the instructions cause the computer to perform the following steps:

[0184] -(S2) the target temperature process (T T (t)) into at least two distinct phases (P), wherein at least one phase (P2, P6) involves a change in the physical state of the substance of the aqueous preparation (12);

[0185] -(S3) based on the target temperature process (T T (t)), determining a control parameter change (C(t)), based on which operation of the heat exchanger unit (14) is controlled during an operating cycle;

[0186] -(S4) performing a test run operation cycle, comprising the following sub-steps:

[0187] - (S4.1) operating the heat exchange unit (14) based on the determined control parameter change (C(t)) during the test run operation cycle, and

[0188] --(S4.2) Temperature measurement process (T M (t)), wherein the temperature course indicates the course of the temperature of the aqueous formulation during an operating cycle of the test run;

[0189] -(S5) The measured temperature process (T M (t)) into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation (12);

[0190] - (S6) based on the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)) to adapt the determined control parameter change (C(t)); and

[0191] - operating the heat exchanger unit (14) for changing the physical state by freezing or thawing the aqueous formulation (12) based on an adapted change of control parameters.

[0192] 17 A computer program according to clause 16, wherein the computer program is stored on a computer readable medium.

[0193] 18. A computer readable medium having stored thereon a computer program for controlling a heat exchanger unit (14), the heat exchanger unit being 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 and the heat exchanger unit acts on the aqueous formulation (12) in the container so that the temperature of the aqueous formulation (12) changes during an operation cycle based on a target temperature course (T T (t)) is adjusted, wherein the computer program includes instructions, and when the computer program is executed by a computer, the instructions cause the computer to perform the following steps:

[0194] -(S2) the target temperature process (T T (t)) into at least two distinct phases (P), wherein at least one phase (P2, P6) involves a change in the physical state of the substance of the aqueous preparation (12);

[0195] -(S3) based on the target temperature process (T T(t)), determining a control parameter change (C(t)), based on which operation of the heat exchanger unit (14) is controlled during an operating cycle;

[0196] -(S4) performing a test run operation cycle, comprising the following sub-steps:

[0197] - (S4.1) operating the heat exchange unit (14) based on the determined control parameter change (C(t)) during the test run operation cycle, and

[0198] --(S4.2) Temperature measurement process (T M (t)), wherein the temperature course indicates the course of the temperature of the aqueous formulation during an operating cycle of the test run;

[0199] -(S5) The measured temperature process (T M (t)) into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation (12);

[0200] - (S6) based on the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)) to adapt the determined control parameter change (C(t)); and

[0201] - operating the heat exchanger unit (14) for changing the physical state by freezing or thawing the aqueous formulation (12) based on an adapted change of control parameters.

[0202] 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) such that the temperature of the aqueous formulation (12) changes during an operation cycle based on a target temperature course (T T (t)) is adjusted, wherein the control unit (16) is configured to perform the following steps:

[0203] -(S2) the target temperature process (T T (t)) into at least two distinct phases (P), wherein at least one phase (P2, P6) involves a change in the physical state of the substance of the aqueous preparation (12);

[0204] -(S3) based on the target temperature process (T T (t)), determining a control parameter change (C(t)), based on which operation of the heat exchanger unit (14) is controlled during an operating cycle;

[0205] -(S4) performing a test run operation cycle, comprising the following sub-steps:

[0206] - (S4.1) operating the heat exchange unit (14) based on the determined control parameter change (C(t)) during the test run operation cycle, and

[0207] --(S4.2) Temperature measurement process (T M (t)), wherein the temperature course indicates the course of the temperature of the aqueous formulation during an operating cycle of the test run;

[0208] -(S5) The measured temperature process (T M (t)) into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation (12);

[0209] - (S6) based on the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)) to adapt the determined control parameter change (C(t)); and

[0210] - operating the heat exchanger unit (14) for changing the physical state by freezing or thawing the aqueous formulation (12) based on an adapted change of control parameters.

[0211] Reference numerals list

[0212] 10 Heat exchanger system

[0213] 12 Aqueous preparations

[0214] 14 Heat exchanger unit

[0215] 16 Control Unit

[0216] 16A CPU

[0217] 16B memory

[0218] 18 Heat transfer components

[0219] 20 Heat transfer plate

[0220] 22 Receiving Space

[0221] 24 Container

[0222] 26 Temperature Control Unit

[0223] 28 Feed line

[0224] 30 Discharge line

[0225] 32 Temperature Sensor

[0226] 34 Data Interface

[0227] C(t) Control parameter change

[0228] E-Stage Endpoint

[0229] P phase

[0230] Heat flow

[0231] t time point

[0232] s Similarity measure

[0233] S Threshold

[0234] T T (t) Target temperature process

[0235] T sT (t) Target temperature process segmented

[0236] T M (t) Measured temperature course

[0237] T sM (t) Segmented measured temperature process

Claims

1. A method of operating a heat exchanger unit (14) for changing the physical state of a substance of an aqueous preparation (12) by freezing or thawing, The aqueous preparation (12) is contained in a container and the heat exchanger unit acts on the aqueous preparation (12) in the container, The temperature of the aqueous formulation (12) is adjusted during the operating cycle based on a target temperature process (T T (t)) is adjusted, the method comprising the following steps: -(S2) the target temperature process (T T (t)) into at least two distinct phases (P), wherein at least one phase (P2, P6) involves a change in the physical state of the substance of the aqueous preparation (12); -(S3) based on the target temperature process (T T (t)), determining a control parameter change (C(t)), based on which operation of the heat exchanger unit (14) is controlled during an operating cycle; -(S4) performing a test run operation cycle, comprising the following sub-steps: - (S4.1) operating the heat exchange unit (14) based on the determined control parameter change (C(t)) during the test run operation cycle, and --(S4.2) Temperature measurement process (T M (t)), wherein the temperature course indicates the course of the temperature of the aqueous formulation during an operating cycle of the test run; -(S5) The measured temperature process (T M (t)) into at least two distinct phases, wherein at least one phase involves a change in the physical state of the aqueous formulation (12); - (S6) based on the segmented measured temperature process (T sM (t)) and the segmented target temperature process (T sT (t)) to adapt the determined control parameter change (C(t)); and - operating the heat exchanger unit (14) based on an adapted change of control parameters for changing the physical state by freezing or thawing the aqueous formulation (12).

2. The method according to claim 1, wherein the aqueous preparation (12) comprises water and optionally further buffers, cell culture media and / or one or more pharmaceutical substances.

3. The method according to claim 1 or 2, wherein the temperature of the aqueous preparation is measured by a sensor positioned in the aqueous preparation, in particular in the container.

4. The method according to any one of claims 1 to 3, wherein 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 change (C(t)).

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

6. A method according to any one of claims 1 to 5, wherein the control parameter variation (C(t)) defines a change in a control parameter of the heat exchanger unit (14) during the phase involving the change in the physical state of the aqueous formulation (12).

7. The method according to any one of claims 1 to 6, wherein the control parameter is indicative of a temperature of the heat transfer component (18), in particular a temperature of the heat transfer medium flowing through the heat exchanger unit (16), or a flow rate of the heat transfer medium.

8. The method according to any one of claims 1 to 7, wherein the target temperature process (T T (t)) corresponds to the temperature change to which the aqueous formulation (12) is subjected when being treated by a reference heat exchanger unit for changing the physical state of the aqueous formulation (12), wherein in particular, the heat exchanger unit (14) is a scaled model of the reference heat exchanger unit.

9. The method according to any one of claims 1 to 8, wherein the target temperature process (T T (t)) is divided into steps (S2) and the measured temperature process (T M (t)) performs at least one of the segmentation steps (S5) to identify at least one of a freezing stage (P2) during which the aqueous preparation (12) will be or has been frozen, and a thawing stage (P6) during which the aqueous preparation (12) will be or has been thawed.

10. The method according to any one of claims 1 to 9, wherein the target temperature process (T T (t)) is divided into steps (S2) and the measured temperature process (T M (t)) At least one of the steps (S5) of performing segmentation includes at least one of the following: - The target temperature process (T T (t)) or the measured temperature course (T M (t)) into stages; and - Adapting the target temperature process (T T (t)) or the measured temperature course (T M (t)) of the said stage.

11. The method according to any one of claims 1 to 10, wherein the step (S3) of determining the control parameter change (C(t)) is performed based on the properties of the aqueous preparation, in particular based on the volume of the aqueous preparation (12).

12. The method according to any one of claims 1 to 11, wherein the step (S3) of determining the control parameter change (C(t)) comprises: - Identify the target temperature process (T T (t)) in the freezing phase (P2); and - an increase or decrease in the control parameter change (C(t)) is achieved within a time period of the operating cycle, which time period of the operating cycle precedes or overlaps with a time period associated with the freezing phase (P2), wherein the increase or the decrease in the control parameter change (C(t)) causes a temporary increase in the cooling performance of the heat exchanger unit.

13. The method according to any one of claims 1 to 12, wherein the step (S6) of adapting the control parameter variation C(t) comprises the following sub-steps: - Identify the segmented measured temperature course (T sM (t)) and the segmented target temperature process (T sT (t)) between the corresponding stages; - determining the duration of said corresponding phase and / or determining the average temperature of said corresponding phase; and - adapting the control parameter change (C(t)) based on a comparison of the determined durations and / or average temperatures of the corresponding phases.

14. The method according to any one of claims 1 to 13, wherein the step (S6) of adapting the control parameter variation (C(t)) comprises the following sub-steps: - Identify the segmented measured temperature course (T sM (t)) and the segmented target temperature process (T sT (t)) corresponding to the freezing stage or the corresponding thawing stage; - determining the duration and the average temperature of the corresponding freezing phase or the corresponding thawing phase; and - Determine the temperature course (T sT an average value of the control parameter variation (C(t)) during the freezing phase or the thawing phase in the freezing phase (t)); and - adapting the control parameter change (C(t)) as a function of the determined duration of the corresponding freezing phase or the corresponding thawing phase, the determined average temperature of the corresponding freezing phase or the corresponding thawing phase and the determined average value of the control parameter change C(t).

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

16. A computer program comprising instructions which, when executed by a computer, cause the computer to carry out the steps of the method according to any one of claims 1 to 14.

17. A computer readable medium having stored thereon a computer program as defined in claim 16.

18. 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) such that the temperature of the aqueous formulation (12) changes during an operation cycle based on a target temperature course (T T (t)) is adjusted, wherein the control unit (16) is configured to carry out the steps of the method according to any one of claims 1 to 14.

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