Computer-implemented method, computer program product, control device and system for controlling sample preparation system

Abstract

A computer-implemented method is provided for controlling a sample preparation system (1) for preparing chemical, pharmaceutical and / or biotechnological samples, the sample preparation system (1) comprising a fluid path and at least one consumable (2a), such as a filter, disposed on the fluid path. The method comprises: controlling said sample preparation system (1) such that a sample fluid comprising a target substance flows through said at least one consumable (2a) within said fluid path; obtaining (S14) system information; determining (S16) a regression function using the system information obtained with respect to a specified time period prior to the current point in time (tcurrent); it is determined (S18) whether a first specified condition is satisfied, where it is determined that the first specified condition is satisfied when a value indicative of a predicted clogging amount (Vpb) corresponds to an amount (Vintcurrent) of the sample fluid that has been introduced into the fluid path at the current point in time (tcurrent), where the first specified condition is satisfied when a value of the dependent variable (y) is a specified maximum pressure difference, where the value indicative of the predicted clogging amount (Vpb) corresponds to the amount (Vintcurrent) of the sample fluid that has been introduced into the fluid path at the current point in time (tcurrent). The predicted amount of clogging (Vpb) is the value of the independent variable (x) of the regression function; if the first specified condition is met, controlling (S20) the sample preparation system (1) to stop introducing the sample fluid into the fluid path; if the first specified condition is not met, controlling the sample preparation system (1) to continue introducing the sample fluid into the fluid path, and repeating the steps of obtaining (S14) system information, determining (S16) a regression function, and determining (S18) whether the first specified condition is met.

Description

Technical Field

[0001] The present application relates to computer implemented methods, computer program products, control devices and systems for controlling a sample preparation system. Background Art

[0002] In order to produce a target substance such as a protein by purification, it is usually necessary to perform a clarification step on the sample containing the target substance before purification to remove contaminants, including host cell-derived contaminants (e.g., intact cells, cell debris, host cell nucleic acids, and host cell proteins), culture medium-derived contaminants (e.g., proteinaceous and non-proteinaceous culture medium components), and vector-derived contaminants, including vector nucleic acids and viral vectors. For example, in the clarification step, the sample can be filtered with a filter.

[0003] In order to obtain a high yield of target substance, it may be desirable to leave as little target substance as possible in a sample preparation system configured to process a sample (eg, within a filter used in the sample preparation system, within a fluid path included in the sample preparation system, etc.). Summary of the invention

[0004] According to one aspect, the problem relates to improving the yield efficiency of a target substance contained in a sample. This problem is solved by the features disclosed in the independent claims. Further exemplary embodiments are defined by the dependent claims.

[0005] According to one aspect, a computer-implemented method is provided for controlling a sample preparation system for preparing a chemical sample, a pharmaceutical sample, and / or a biotechnological sample, the sample preparation system comprising a fluid path and at least one consumable (such as a filter) disposed on the fluid path. The method comprises:

[0006] controlling the sample preparation system so that a sample fluid including a target substance flows within the fluid path through the at least one consumable, wherein the sample fluid is allowed to sequentially pass through an upstream point within the fluid path, the at least one consumable, and a downstream point within the fluid path;

[0007] Obtain system information indicating at least the following:

[0008] an amount of the sample fluid that has been introduced into the fluid path;

[0009] the upstream pressure at the upstream point; and

[0010] a downstream pressure at the downstream point;

[0011] Use relative to the current time point (t current ) before the specified time period (Δt), and determining a regression function, wherein the regression function is determined by assuming the following conditions:

[0012] At different time points (t i -Δt,…,t i ), a pressure difference across the at least one consumable obtained based on the upstream pressure and the downstream pressure

[0013] (dP_t i -Δt,…,dP_t i ) is the value of the dependent variable (y) of the regression function, and the different time points (t i -Δt,......,t i ) obtained by introducing the sample fluid into the fluid path (Vin_t i -Δt, ..., Vin_t i )

[0014] is the value of the independent variable (x) of the regression function;

[0015] Determine whether the first specified condition is satisfied, wherein when the value indicating the predicted congestion amount (Vpb) is equal to the value at the current time point (t current ) has been introduced into the fluid path (Vin_t current ), determining that the first specified condition is satisfied when the value of the dependent variable (y) is the specified maximum pressure difference, wherein the predicted blockage amount (Vpb) is the value of the independent variable (x) of the regression function;

[0016] controlling the sample preparation system to stop introducing the sample fluid into the fluid path if the first specified condition is met;

[0017] If the first specified condition is not met,

[0018] controlling the sample preparation system to continue introducing the sample fluid into the fluid path, and

[0019] The steps of obtaining system information, determining a regression function, and determining whether the first specified condition is satisfied are repeated.

[0020] In various aspects and embodiments described herein, a "fluid path" can be formed, for example, by at least one or more tubes. In some exemplary embodiments, the material of the tube(s) can be selected from the plastics polyvinyl chloride, polypropylene, polyethylene, polytetrafluoroethylene, and perfluoroethylene propylene. Thus, the tube(s) can provide flexibility and chemical resistance.

[0021] In various aspects and embodiments described herein, the "at least one consumable" can be a filter. More specifically, the "at least one consumable" can be a clarification filter for clarifying a sample fluid including a target substance. In some exemplary embodiments, the "clarification filter" can be a depth filter and / or a membrane, preferably a depth filter. In addition, in some cases, the "clarification filter" can be a cell culture clarification filter, which is configured to separate cells and other contaminants from a sample.

[0022] In various aspects and embodiments described herein, at least one consumable may be a disposable consumable. The term "disposable consumable" as used herein refers to a consumable that cannot be recycled in a cost-effective manner and is discarded after use due to reasons such as filter clogging.

[0023] In various aspects and embodiments described herein, "target substance" is not specifically limited. For example, the target substance can be any biomolecule of interest, such as protein, such as antibody, hormone, vaccine, nucleic acid, exosome and virus, and virus-like particles. In some exemplary embodiments, the target substance can be an antibody, more specifically a monoclonal antibody (mAb), or a fragment or derivative thereof, or a nanobody. Examples of monoclonal antibodies may include, but are not limited to, adalimumab, cetuximab, rituximab, infliximab, omalizumab and denosumab. For example, the target substance can be obtained from mammalian cells, bacterial cells or insect cells, media and cell lines such as "Chinese hamster ovary cells" (CHO cells), HeLa or human umbilical vein endothelial cells (HUVEC)).

[0024] In various aspects and embodiments described herein, "sample fluid" is not particularly limited, as long as it comprises multiple components, wherein at least one of the multiple components of the sample fluid is one of the above-mentioned target substances. Other (impurity) components (contaminants) are not particularly limited and may depend on the preparation conditions of the target substance. Examples of other ingredients may include, but are not limited to, aggregates, host cell proteins, deoxyribonucleic acids, and fragments and charge variants thereof. The sample fluid can be obtained by applying any biological, biochemical, chemical or pharmaceutical method. Thus, the sample fluid can be obtained by a purification method previously using different purification units. For example, the target substance can be produced, for example, by perfusion culture, by an appropriate cell line (such as a CHO cell line).

[0025] In various aspects and embodiments described herein, at least some of the "system information" may be obtained from sensors arranged at locations suitable for collecting respective pieces of system information relative to the sample preparation system. In addition, in various aspects and embodiments described herein, at least some of the "system information" may be obtained by accessing a storage medium storing (pieces of) relevant system information. The storage medium may be internal or external to a control device configured to perform the method according to any of the various aspects and embodiments described herein.

[0026] For example, system information indicating the amount of sample fluid that has been introduced into the fluid path can be obtained from a rotational speed sensor disposed on a pump configured to move the sample fluid within the fluid path, wherein the rotational speed sensor can measure the rotational speed of the pump. Since the amount of sample fluid that has been introduced into the fluid path may be proportional to the amount of rotation of the pump, the amount of sample fluid can be calculated based on the measured rotational speed of the pump (e.g., by multiplying the rotational speed by the time elapsed since the start of the sample preparation process performed by the sample preparation system). In various aspects and embodiments described herein, the "amount" of a fluid (e.g., a sample fluid) can be understood as the volume of the fluid. In some exemplary embodiments, the amount of rotation of the pump used to calculate the amount of sample fluid that has been introduced into the fluid path can be obtained without a rotational speed sensor. For example, a calibration value of the rotation of a pump (e.g., driven by a DC motor or a stepper motor) can be obtained from a storage medium as described above, and the obtained calibration value of the rotation of the pump can be used to calculate the amount of sample fluid.

[0027] In addition, for example, system information indicating the upstream pressure and the downstream pressure can be obtained from a pressure sensor respectively provided at an upstream point and a pressure sensor provided at a downstream point. However, with respect to the downstream pressure, in some exemplary embodiments, the downstream pressure may be atmospheric pressure rather than the pressure measured by the pressure sensor provided at the downstream point. For example, in these exemplary embodiments, the storage medium as described above may store the value of the atmospheric pressure, and the value of the atmospheric pressure as the downstream pressure may be obtained from the storage medium.

[0028] In various aspects and embodiments described herein, a "specified time period" Δt can be specified by a time unit (e.g., seconds, minutes, etc.) and / or by a change in the amount (e.g., volume) of fluid introduced into the fluid path. In the case where the "specified time period" is specified by changing the amount of fluid introduced into the fluid path, x milliliters of the "specified time period" can be expressed as Δt=x milliliters, and can indicate, for example, the time period during which x milliliters of fluid are introduced into the fluid path. For example, the amount of fluid introduced into the fluid path can be calculated from the rotational speed of the pump as described above. It is noteworthy that when the "specified time period" is specified by a change in the amount of fluid introduced into the fluid path, the actual time that the same amount of fluid passes within the "specified time period" can change in different iterations of the steps of obtaining system information, determining a regression function, and determining whether the first specified condition is met.

[0029] In addition, in various aspects and embodiments described herein, the “current time point” t current and “different time points” (e.g., t i -Δt,......,t i Each of the time points t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t t current It can also be understood as the current amount of fluid that has been introduced into the fluid path. More generally, at time point t i It can also be understood to mean the amount of fluid that has been introduced into the fluid path up to that point in time.

[0030] In some exemplary embodiments, “relative to” the current time point t current The system information "obtained" before the specified time period Δt may include one or more system information obtained during the specified time period Δt. In addition, in some exemplary embodiments, the system information "obtained relative to" the specified time period Δt may also include one or more system information obtained outside the specified time period Δt but considered applicable to the specified time period Δt. For example, in the case where there is no pressure sensor at the downstream point and the atmospheric pressure is obtained as the downstream pressure, the atmospheric pressure does not necessarily need to be obtained "during" the specified time period Δt, but the obtained atmospheric pressure may also be regarded as the downstream pressure during the specified time period Δt. .

[0031] In various aspects and embodiments described herein, at a particular time point t i The "pressure difference across at least one consumable" can be calculated at that specific time point t iThe downstream pressure at that specific time point t i It is obtained by the difference between the upstream pressure and the downstream pressure.

[0032] In various aspects and embodiments described herein, the current time point t current The previous specified time period Δt may include a discrete number of time points. The number of discrete time points may be related to or depend on the sampling rate of the sensor involved (e.g., the pressure sensor). In addition, the current time point t current The specified time period Δt before can indicate the time from time point t i -Δt to time point ti, where t i It can be the current time point t current , or the current time point t current In some exemplary embodiments, t i It can be the current time point t current The single point before, in other words, immediately before the current time point t current In some other exemplary embodiments, t i may be further away from the current time point t than a single point current , and preferably within a certain fraction (e.g., 1 / 10) of the expected total time of the sample preparation process (or the total amount of sample fluid).

[0033] In some exemplary embodiments, the “specified time period”, the “specified maximum pressure difference”, and the “first specified condition” may be specified by a user using an input device.

[0034] In some exemplary embodiments, when the “value indicating the predicted blockage amount (Vpb)” is equal to the “amount of sample fluid that has been introduced into the fluid path at the current time point (Vin_t current )” is equal to or less than a specified threshold, it can be determined that the “first specified condition” is satisfied (in other words, the value indicating the predicted clogging amount (Vpb) can be considered to be equal to the amount of sample fluid that has been introduced into the fluid path at the current time point (Vin_t current )). When the difference is greater than the "specified threshold", it can be determined that the "first specified condition" is not satisfied (in other words, the value indicating the predicted clogging amount (Vpb) can be considered to be consistent with the amount of sample fluid (Vin_t current ) does not correspond).

[0035] In various aspects and embodiments described herein, “at the current time point (t current ) has been introduced into the fluid path (Vin_t current )” can be understood as the amount of sample fluid currently in the fluid path.

[0036] In the various aspects and embodiments described herein, the "predicted amount of blockage" can be considered to be the amount of sample fluid that can block the flow through at least one consumable (e.g., a filter) when the sample fluid is committed to the at least one consumable. Therefore, as in the method according to the above aspects, when a specified threshold is met, the sample preparation system is controlled to stop introducing the sample fluid into the fluid path, which can reduce the amount of sample fluid introduced into the fluid path but unable to pass through at least one consumable, in other words, the amount of sample fluid that may be wasted can be reduced. This may help to improve the output efficiency of the target substance included in the sample fluid.

[0037] In some exemplary embodiments, the method according to the above aspects may further include:

[0038] In the event that the first specified condition is met, the sample preparation system is further controlled such that a flushing liquid flows within the fluid path through the at least one consumable.

[0039] By the flow of the flushing fluid, the sample fluid still present in the fluid path upstream of at least one consumable and / or the sample fluid still contained in at least one consumable can be pushed through the at least one consumable. This may help to increase the yield of the target substance in the sample fluid.

[0040] In some exemplary embodiments, the method according to the above aspects may further include:

[0041] In the event that the first specified condition is met, the sample preparation system is further controlled such that air flows within the fluid path through the at least one consumable.

[0042] By air flow, the sample fluid still present in the fluid path before reaching at least one consumable (in other words, the sample fluid still present in the fluid path upstream of at least one consumable) and / or the sample fluid still contained in at least one consumable can be pushed to pass through at least one consumable. This may help to increase the yield of the target substance in the sample fluid.

[0043] In some exemplary embodiments, the method according to the above aspects may further include:

[0044] The sample preparation system is further controlled to remove the at least one consumable from the fluid path if the first specified condition is met.

[0045] In addition, the method according to the above aspect may further include:

[0046] After controlling the sample preparation system to remove the at least one consumable from the fluid path, controlling the sample preparation system to provide a new consumable on the fluid path.

[0047] In the event that a second specified condition is met, controlling the sample preparation system to provide new consumables on the fluid path may be performed. The second specified condition may include a condition on the amount of remaining sample fluid to be processed by the sample preparation system. For example, a threshold value for the amount of remaining sample fluid may be specified (e.g., by a user), and if the amount of remaining sample fluid is above the threshold value, it is determined that the second specified condition is met. In addition, in some exemplary embodiments, the threshold value for the amount of remaining sample may be determined by a control device configured to control the sample preparation system.

[0048] In some exemplary embodiments, the at least one consumable may be a filter. In such exemplary embodiments, the sample preparation system may further include a filter processing device configured to:

[0049] receiving the at least one consumable disposed on the fluid path; and

[0050] The at least one consumable is provided on the fluid path.

[0051] Furthermore, controlling the sample preparation system to remove the at least one consumable from the fluid path may include outputting a control signal to the filter processing device to remove the at least one consumable from the fluid path by receiving the at least one consumable. Furthermore, controlling the sample preparation system to provide a new consumable on the fluid path may include outputting a control signal to the filter processing device to provide a new consumable on the fluid path.

[0052] In some exemplary embodiments, the sample preparation system may also include a pump configured to move the fluid within the fluid path. The pump may be, for example, a peristaltic pump, a diaphragm pump, or a piston pump. In exemplary embodiments where the sample preparation system also includes a pump, controlling the sample preparation system so that the sample fluid flows through the at least one consumable within the fluid path may include: outputting a control signal to the pump so that the sample fluid within the fluid path moves toward the at least one consumable. In addition, controlling the sample preparation system to stop introducing the sample fluid into the fluid path may include: outputting a control signal to the pump to stop moving the sample fluid within the fluid path.

[0053] In some exemplary embodiments, the sample preparation system may further include a valve configured to switch between at least the following states:

[0054] an open state, wherein the sample fluid is allowed to flow within the fluid path toward the at least one consumable; or

[0055] A closed state wherein the sample fluid is prevented from flowing within the fluid path toward the at least one consumable.

[0056] In an exemplary embodiment where the sample preparation system further comprises the valve described above, controlling the sample preparation system so that the sample fluid flows through the at least one consumable within the fluid path may include: outputting a control signal to the valve to set the valve to the open state. In addition, controlling the sample preparation system to stop introducing the sample fluid into the fluid path may include: outputting a control signal to the valve to set the valve to the closed state.

[0057] In some exemplary embodiments, the valve can be a three-way valve (e.g., a three-way diaphragm valve or a three-way ball valve) having three ports (e.g., a first port, a second port, and a third port), and can be switched between three states, namely a closed state that prevents fluid from flowing through the valve, a first open state that allows fluid to flow from the first port to the second port (or vice versa), or a second open state that allows fluid to flow from the first port to the third port (or vice versa). In these exemplary embodiments, for example, the first port of the three-way valve can be connected to a sample fluid source, and the second port or the third port of the three-way valve can be connected to a portion of the fluid path leading to at least one consumable. The remaining ports of the three-way valve can be connected to, for example, another portion of the fluid path leading to a waste container of the sample preparation system.

[0058] In some example embodiments, determining the regression function may include:

[0059] obtaining one or more values ​​of one or more parameters associated with the sample fluid and / or the sample preparation system;

[0060] generating, for each of the one or more parameters, an equation to determine an amount of occlusion as a function of one of the one or more parameters, the amount of occlusion indicating an amount of the sample fluid that, when introduced into the at least one consumable, can cause the at least one consumable to block the flow of the sample fluid;

[0061] For each of the one or more parameters, a coefficient is determined that indicates a ratio between:

[0062] At the current time point (t current ) The amount of the sample fluid that has been introduced into the fluid path (Vin_t current) or the total amount of the sample fluid to be introduced into the fluid path, and

[0063] The amount of blockage obtained using the generated equation; and

[0064] The regression function is determined using the coefficients determined for each of the one or more parameters. In such an exemplary embodiment, the one or more parameters may include one or more of the following:

[0065] a cell density of the sample fluid;

[0066] turbidity of the sample fluid;

[0067] a particle size distribution of the sample fluid;

[0068] The optical density of the sample fluid;

[0069] a filter resistance index, wherein the at least one consumable is a filter;

[0070] A filtration surface area, wherein the at least one consumable is a filter.

[0071] In some exemplary embodiments, as described above, one or more values ​​of one or more parameters may be stored in and obtained from a storage medium (eg, within or external to a control device configured to control a sample preparation system).

[0072] Furthermore, determining the regression function using the coefficients determined for each of the one or more parameters may include:

[0073] determining a sensitivity factor using the coefficients determined for each of the one or more parameters; and

[0074] Based on the sensitivity factor, one type of regression function is selected from a plurality of types of regression functions to be used as the regression function.

[0075] In various aspects and embodiments described herein, a sample preparation system can be used to prepare a sample, which is a cell culture comprising a protein. In this case, the sample fluid can be the cell culture, and the protein included in the cell culture can be the target substance.

[0076] According to another aspect, a computer program product is provided, which includes computer-readable instructions, and when the computer-readable instructions are loaded and executed on a suitable system, the system is caused to perform the method according to any one of the above aspects and exemplary embodiments thereof.

[0077] According to another aspect, a control device is provided. The control device comprises:

[0078] A processor configured to execute the method according to any one of the above aspects and exemplary embodiments thereof; and

[0079] A storage medium is in communication with the processor.

[0080] According to another aspect, a system is provided. The system comprises:

[0081] Sample preparation system, including:

[0082] Fluid paths, and

[0083] at least one consumable, such as a filter, disposed on the fluid path; and

[0084] A control device according to the above aspect.

[0085] The various aspects and embodiments described herein can be applied to single filtration of biopharmaceutical cell suspensions, for example, small-scale clarification of mammalian suspension cell cultures expressing mAbs. Since cell suspensions may contain high-loaded particulate matter, and a clarification process of a few seconds or minutes may have caused filter clogging, the pressure changes of the last few seconds or minutes (or the last few milliliters, depending on the scale) may be crucial to the predicted filter clogging. In the various aspects and embodiments described herein, for example, by setting the "specified time period" to a few seconds or minutes, it is possible to predict the filter clogging in the clarification process. In addition, in such a clarification process, the volume of cell suspension in the (depth) filter and the supply tube may account for a large part of the volume to be filtered. In addition, the volume of cell suspension present in the (depth) filter and the supply tube may significantly cause the filter to be blocked. The various aspects and embodiments described herein can consider such a volume (as the amount of sample fluid introduced into the fluid path) to predict filter clogging.

[0086] Furthermore, in a single filtration of a biopharmaceutical cell suspension, the value of the product (e.g., target substance) in the filter (e.g., depth filter) may be quite significant. Even if clogging does not occur, at the end of filtration, a small amount (e.g., 5% to 20%) of product will always be trapped in each filter. Therefore, accurate prediction of clogging may be important. If the prediction is too conservative, then more filters will be used, resulting in more product loss. If the prediction is not conservative enough, then clogging is more likely to result in greater product loss (e.g., perhaps 50% product loss).

[0087] Additionally, the various aspects and embodiments described herein can accommodate a (user-definable) amount of non-contaminating flush liquid that is added after the input liquid is injected to achieve maximum recovery of product.

[0088] The various aspects and embodiments described herein may be compatible with simultaneous clarification and cleanup processes used on a sample preparation system.

[0089] The various aspects and embodiments described herein may be used in any clarification application in which an appropriate control system is available.

[0090] Furthermore, the various aspects and embodiments described herein may be used in any application that uses dead-end filters that may become clogged and require optimal recovery.

[0091] Furthermore, the various aspects and embodiments described herein can be applied to microbial cultures, cultures of varying scales, and as methods or systems for output fractionation.

[0092] Because various aspects and embodiments described herein do not rely on historical data to determine the regression function, any aspect and embodiment described herein can provide flexible, robust and real-time sample preparation system control, which may be ideal for research and development and early process development. The batch differences of the filter (especially small-scale) and the culture itself can indeed reduce the impact of the predetermined model. The adaptability of various aspects and embodiments described herein can adapt to this variability.

[0093] Any of the various aspects and embodiments described herein can provide one or more of the following technical effects:

[0094] - Achieve the best ratio between output volume and pollutant concentration;

[0095] - obtain maximum product recovery from consumables (e.g. filters) which may become completely clogged before flushing is complete;

[0096] - Optimize the efficiency of the clarification process to provide the largest volume and highest quality output sample with the smallest possible time requirement and maximum sample / time / cost;

[0097] - The sample preparation process is fully automated, reducing the time required by operators.

[0098] The subject matter described in this application may be implemented as a method or system, possibly in the form of one or more computer program products. The subject matter described in this application may be implemented in a data signal or on a machine-readable medium, where the medium is embodied in one or more information carriers, such as a CD-ROM, a DVD-ROM, a semiconductor memory, or a hard disk. Such a computer program product may cause a data processing device to perform one or more operations described in this application.

[0099] In addition, the subject matter described in this application can also be implemented as a system comprising a processor and a memory coupled to the processor. The memory can encode one or more programs so that the processor executes one or more methods described in this application. In some examples, the system can be a general-purpose computer system. In other examples, the system can be a special-purpose computer system including an embedded system. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] The details of one or more implementations are set forth in the following exemplary drawings and description. Other features will be apparent from the specification, drawings, and claims. However, it should be understood that even if the various embodiments are described separately, individual features of different embodiments may be combined into further embodiments.

[0101] Figure 1 An exemplary sample preparation system is shown.

[0102] Figure 2 A side view of a portion of an exemplary sample preparation system is shown.

[0103] Figure 3 An exemplary filter processing device included in an exemplary sample preparation system is shown.

[0104] Figure 4 An exemplary pipetting robot and an exemplary pipette wash station that may be used in an exemplary sample preparation system are shown.

[0105] Figure 5 A schematic diagram illustrating the flow of control and sensor signals between an exemplary control device and an exemplary sample preparation system is shown.

[0106] Figure 6 A graph showing exemplary recorded online data obtained by running an exemplary sample preparation system without a control process according to the present disclosure is shown.

[0107] Figure 7 A flow chart of an exemplary process for controlling a sample preparation system is shown.

[0108] Figure 8A graph showing exemplary recorded online data obtained by running an exemplary sample preparation system controlling a process according to the present disclosure is shown.

[0109] Fig. 9 A graph showing further exemplary recorded online data obtained by running an exemplary sample preparation system for controlling a process according to the present disclosure is shown.

[0110] Fig.10 A graph showing the predicted plugging volume of a filter disposed on a fluid path of a sample preparation system during a control process according to the present disclosure is shown.

[0111] Fig.11 An exemplary hardware configuration of a computer that can be used to implement at least part of a system according to the present disclosure is shown. DETAILED DESCRIPTION

[0112] Hereinafter, a detailed description of the examples will be given with reference to the accompanying drawings. It should be understood that various modifications may be made to the examples. In particular, one or more elements in one example may be combined and used in other examples to form new examples.

[0113] Sample preparation system

[0114] In the present disclosure, a sample preparation system may be understood as a system for preparing a chemical sample, a pharmaceutical sample and / or a biotechnological sample, for example to produce a target substance included in the sample. For example, the sample may be a cell culture containing a protein as a target substance.

[0115] In some exemplary embodiments, the sample preparation system can be configured to perform one or more unit operations on the sample, such as clarification and purification. For each of the one or more unit operations, consumables such as filters can be provided on the sample preparation system. For example, a clarification filter can be provided for clarification. In addition, for example, a purification filter or a purification chromatographic column can be provided for purification. More specifically, the sample preparation system can include a fluid path and one or more consumables that can be provided on the fluid path for one or more unit operations, so that a sample fluid containing a target substance can flow through the one or more consumables in the fluid path and undergo one or more unit operations.

[0116] In the following, Figure 1 As shown, exemplary embodiments will be described with respect to an exemplary sample preparation system configured to perform clarification and / or cleanup on a sample. However, it should be noted that the various aspects and embodiments described herein may also be used to control and Figure 1 The exemplary sample preparation systems shown in FIG. 1 are configured differently for sample preparation systems.

[0117] Figure 1 An exemplary sample preparation system is shown, which is configured to perform clarification and / or cleanup on a sample. Figure 1 As shown, the sample preparation system 1 may include a fluid path including an input line 12, a first line 6, a second line 7, a third line 8, a fourth line 19, an output line 22, and / or a waste container line 44. Some or all of the lines 12, 6, 7, 8, 19, 22, and 44 may be made of a flexible tube having chemical resistance. In the sample preparation system 1, a fluid (e.g., a sample fluid including a target substance) may be placed in the fluid path. Figure 1 . Hereinafter, the term "upstream" relative to a reference point in the fluid path may be understood as any point in the portion of the fluid path through which the fluid can pass during the process of the fluid flowing from the fluid source to the reference point. In addition, the term "downstream" relative to the reference point may be understood as any point in the portion of the fluid path through which the fluid can flow after passing the reference point during the fluid flow.

[0118] Furthermore, the sample preparation system 1 may include a series arrangement of a first mechanism 2 configured to be connected to a first consumable 2a and a series arrangement of a second mechanism 3 configured to be connected to a second consumable 3a. Figure 1 In a specific example, the first consumable 2a is a clarification filter, and the second consumable 3a is a purification filter or a purification chromatography column. The clarification filter can be a depth filter and / or a membrane.

[0119] The purification filter can be a membrane, and the purification chromatographic column can include, for example, functionalized beads. The second consumable 3a can be configured to bind and elute the target substance. The second mechanism 3 can be located downstream of the first mechanism 2 in the sample preparation system 1, and the first mechanism 2 and the second mechanism 3 can be integrally connected to each other in the sample preparation system 1. The term "integrally connected" used herein refers to being arranged in one device (e.g., in the sample preparation system 1) and not arranged in a separate device.

[0120] The sample preparation system 1 can be configured to perform clarification as a first unit operation and purification as a second unit operation in combination in one device in an automated manner. Therefore, compared with methods performed in two separate devices, the corresponding method can be performed quickly and the processing efficiency is significantly improved.

[0121] In the sample preparation system 1, a sample fluid may be introduced from an input cup 13 configured to hold a fluid into an input line 12 disposed upstream of the first mechanism 2, for example, a sample fluid prepared by the sample preparation system 1. In some exemplary embodiments, the volume of the input cup may be 10 ml to 150 ml, preferably 20 ml to 80 ml. The input line 12 may provide fluid communication between the first mechanism 2 and the input cup 13.

[0122] Furthermore, in the sample preparation system 1, the input sample valve 14 may be disposed on the input line 12 downstream of the input cup 13 and upstream of the first mechanism 2. Thus, the input sample valve 14 may divide the input line 12 into a portion located upstream of the input sample valve 14 and a portion located downstream of the input sample valve 14. The input sample valve 14 may be configured to direct the fluid to the input line 12 located downstream of the input sample valve 14 or to a waste container (not shown). For example, in the case where the fluid is directed to the input line 12 downstream of the input sample valve 14, the fluid flowing to the waste container may be blocked. Furthermore, for example, in the case where the fluid is directed to the waste container, the fluid flowing to the input line 12 downstream of the input sample valve may be blocked. The input sample valve 14 may be a three-way valve (e.g., a three-way diaphragm valve or a three-way ball valve).

[0123] In addition, the sample preparation system 1 may include a process fluid input valve 24 disposed upstream of the first mechanism 2. Each of the process fluid input valves 24 may be a two-way valve that can be switched between an open state that allows fluid to flow through the valve and a closed state that blocks fluid from flowing through the valve. For example, each process fluid may be stored in a bottle and connected to one of the process fluid input valves 24 via a line. Each of the process fluid input valves 24 may allow or stop the corresponding type of process fluid from flowing toward the input line 12.

[0124] The different types of process fluids that may flow into the input line 12 through the process fluid input valve 24 may include, for example, fluids for cleaning the sample preparation system 1 and / or fluids for clarification and / or purification. Examples of process fluids for cleaning the sample preparation system 1 may include, but are not limited to, buffer, sodium hydroxide, and / or water. Figure 1 In the particular example shown, the process fluid input valve 24 includes at least valves for allowing or stopping the flow of flushing liquid and air.

[0125] Other examples of process fluids may include, but are not limited to, phosphate buffered saline (PBS), elution buffer, low pH stripping buffer, etc. The elution buffer is not particularly limited, and its selection may depend on the substance to be eluted. For example, the elution buffer may be selected from citrate buffer, glycine / HCl buffer, and acetate buffer.

[0126] In addition, the sample preparation system 1 may include a pump 9 disposed on the input line 12 downstream of the input sample valve 14 and the process fluid input valve 24. In addition, the pump 9 may be disposed upstream of the first mechanism 2. The pump 9 may be configured to move fluid within the fluid path of the sample preparation system 1. Figure 1 In the specific example of , the pump 9 is a peristaltic pump. In other exemplary embodiments, the pump 9 can be a diaphragm pump or a piston pump.

[0127] The input line 12 may provide fluid communication between one or more of the input sample valve 14 and the process fluid input valve 24 and the first mechanism 2 .

[0128] exist Figure 1 In a specific example, the first mechanism 2 is a first filter holder, which includes a first clamp 10a configured to clamp a first consumable 2a (e.g., a clarifying filter) on an upper surface (in other words, an upstream surface), and a second clamp 10b configured to clamp the first consumable 2a on a lower surface (in other words, a downstream surface). Thus, during operation, the first consumable 2a can be safely supported to resist internal pressure. Each of the first clamp 10a and the second clamp 10b may include an O-ring configured to connect the upstream and downstream fluid paths of the first mechanism 2 when in a compressed state (in other words, when the clamp is closed). In some exemplary embodiments, one of the first clamp 10a and the second clamp 10b may be a static clamp (in other words, it does not move), and the other is a movable clamp. Thus, the first consumable 2a can be clamped by pressing the movable clamp against the static clamp. Preferably, the first clamp 10a may be a static clamp and the second clamp 10b may be a movable clamp.

[0129] In some exemplary embodiments, the first mechanism 2 need not necessarily be a first filter holder having a first clamp 10a and a second clamp 10b as described above. For example, the first mechanism 2 may be an upstream end member of the first line 6 that supports the first consumable 2a from its downstream side. In the case where the first consumable 2a is supported from its downstream side by the upstream end member of the first line 6, the first consumable 2a may be supported on the upstream side of the first consumable 2a by a downstream end member of the input line 12 connected to the first mechanism 2.

[0130] In addition, the sample preparation system 1 may include an input stack 11 configured to hold at least one first consumable 2a. In some exemplary embodiments, the input stack 11 may be configured to hold 1 to 150 first consumables 2a, preferably 1 to 50 first consumables 2a. The sample preparation system 1 may also include a filter processing device (not shown). Figure 1), the filter processing device can be connected to the first mechanism 2. The filter processing device can be configured to provide the first consumable 2a to the first mechanism 2 and receive the first consumable 2a from the first mechanism 2. Figure 2 and Figure 3 , the details of the filter processing device are described.

[0131] like Figure 1 As shown, the first line 6 can provide fluid communication between the first mechanism 2 and the first valve 4 arranged between the first mechanism 2 and the second mechanism 3. The first valve 4 can be set on the fluid path between the first mechanism 2 and the second mechanism 3. The first valve 4 can be configured to guide the fluid from the first line 6 to the second line 7 or the third line 8 of the sample preparation system 1. For example, in the case where the fluid is guided to the second line 7, the fluid flowing to the third line 8 may be blocked. In addition, for example, in the case where the fluid is guided to the third line 8, the fluid flowing to the second line 7 may be blocked. The first valve 4 can be, for example, a three-way diaphragm valve or a three-way ball valve.

[0132] like Figure 1 As shown, the second line 7 can provide fluid communication between the first valve 4 and the second valve 5 located downstream of the second mechanism 3 through the second mechanism 3. In addition, the third line 8 can provide fluid communication directly between the first valve and the second valve 5. Therefore, the third line 8 can be configured to bypass the second mechanism 3.

[0133] The second mechanism 3 can be configured to be connected to and support the second consumable 3a (e.g., a purification filter or a purification chromatographic column). For example, the second mechanism 3 can be a second filter holder, or can correspond to a component of the second line 7 that provides fluid communication between the first valve 4 and the second valve 5.

[0134] In the case where the second mechanism 3 is a second filter holder, the second line 7 may be interrupted between the first valve 4 and the second valve 5, and the second filter holder as the second mechanism 3 may be located at the interruption and connected to the first end member on the upstream side of the interrupted second line 7 and the second end member on the downstream side of the interrupted second line 7. In some exemplary embodiments, the second filter holder as the second mechanism 3 may include a first clamp and a second clamp, which are configured to clamp the second consumable 3a in a manner similar to the first clamp 10a and the second clamp 10b of the first mechanism 2 described above.

[0135] In the case where the second mechanism 3 corresponds to a component of the second line 7, the second line 7 can be interrupted between the first valve 4 and the second valve 5, and the second consumable 3a can be located at the interruption and supported by the first end component on the upstream side of the interrupted second line 7 and the second end component on the downstream side of the interrupted second line 7.

[0136] The second valve 5 arranged downstream of the second mechanism 3 can be configured to direct the fluid to the fourth line 19 downstream of the second valve 5. For example, the second valve 5 can be a three-way valve having three ports, two inlets of which are connected to the second line 7 and the third line 8, and the three-way valve can be in one of two states to direct the flow from one of its two inlets (e.g., the second line 7 and the third line 8) to the fourth line 19 downstream of the second valve 5. In some exemplary embodiments, the second valve can be a three-way diaphragm valve or a three-way ball valve.

[0137] The fourth line 19 can provide fluid communication between the second valve 5 and the output valve 20 disposed downstream of the second valve 5. The output valve 20 can be configured to direct the fluid to the output line 22 that provides fluid communication between the output valve 20 and the output cup 23, or to direct the fluid to the waste container line 44 that provides fluid communication between the output valve 20 and the waste container (not shown). For example, in the case where the fluid is directed to the output line 22, the fluid flowing to the waste container line 44 may be blocked. In addition, for example, in the case where the fluid is directed to the waste container line 44, the fluid may be blocked from flowing to the output line 22. The output valve 20 can be a three-way valve having three ports, and can be in one of two states, directing the flow to one of its two outlets (e.g., the output line 22 and the waste container line 44). In some exemplary embodiments, the output valve 20 can be a three-way diaphragm valve or a three-way ball valve.

[0138] The output cup 23 may be configured to hold the fluid output by the sample preparation system 1. In some exemplary embodiments, the volume of the output cup may be 10 ml to 150 ml, preferably 20 ml to 80 ml.

[0139] also, Figure 1 The sample preparation system 1 shown in FIG. 1 may include a waste pump 25 configured to pump the fluid in the fluid path so as to direct the fluid toward a waste container (not shown). For example, by operating the waste pump 25, the fluid discharged from the output valve 20 into the waste container line 44 and / or the fluid flowing out of the input sample valve 14 (when the input sample valve 14 is set to prevent the sample fluid from flowing to the first mechanism) can be directed to the waste container.

[0140] exist Figure 1 A plurality of sensors may be provided on the sample preparation system 1 shown.

[0141] For example, the first liquid sensor 15 may be disposed on the input line 12 at a position downstream of the input sample valve 14 and upstream of the first mechanism 2. The first liquid sensor 15 may be configured to detect the presence of liquid at the position where the first liquid sensor 15 is disposed. According to this configuration, the first liquid sensor 15 may detect, for example, whether the input cup 13 has been emptied.

[0142] In addition, for example, the second liquid sensor 16 may be disposed on the fluid path at a position downstream of the first mechanism 2 and upstream of the second mechanism 3. The second liquid sensor 16 may be configured to detect whether liquid is present at the position where the second liquid sensor is disposed. Preferably, the second liquid sensor 16 may be disposed on the first line 6, upstream of the first valve 4. For example, according to this configuration, based on the detection result of the second liquid sensor 16, the first valve 4 and the second valve 5 may be switched to guide the fluid through the second mechanism 3 through the second line 7, or through the third line 8 to bypass the second mechanism 3.

[0143] In addition, for example, the first pressure sensor 17 may be disposed on the input line 12 at a position downstream of the first liquid sensor 15 and upstream of the first mechanism 2 (in other words, at an upstream point relative to the first mechanism 2). The first pressure sensor 17 may be configured to detect the pressure of the sample preparation system 1 at the position where the first pressure sensor 17 is disposed. Preferably, the first pressure sensor 17 may be disposed downstream of the pump 9 and upstream of the first mechanism 3. In some exemplary embodiments, the first pressure sensor 17 may be disposed downstream of the pump 9 and the first liquid sensor 15 and upstream of the first mechanism 9. Thus, the flow of the fluid to the first mechanism may be easily controlled.

[0144] In addition, for example, the second pressure sensor 18 may be disposed on the fluid path at a position downstream of the first mechanism 2 (in other words, at a downstream point of the first mechanism 2) and upstream of the second mechanism 3. The second pressure sensor 18 may be configured to detect the pressure of the sample preparation system 1 at the position where the second pressure sensor 18 is disposed. Preferably, the second pressure sensor may be disposed on the first line 6, upstream of the first valve 4. According to this configuration, based on the measurement result of the second pressure sensor 18, the first valve 4 and the second valve 5 may be switched to guide the fluid through the second line 7 via the second mechanism 3 or through the third line 8 to bypass the second mechanism 8.

[0145] In addition, for example, the target substance detection sensor 21 may be disposed on the fourth line 19 at a position downstream of the second valve 5 and upstream of the output valve 20. The target substance detection sensor 21 may be configured to detect a target substance within the fluid path at a position where the target substance detection sensor 21 is disposed. According to this configuration, the target substance emerging from the first mechanism 2 and / or the second mechanism 3 may be easily detected. According to the detection result of the target substance detection sensor 21, the fluid may be directed to the output cup 23 or the waste container. Specifically, in the case where the target substance detection sensor 21 detects the target substance, the output valve 20 may be switched to direct the target substance or the fluid containing the target substance to the output cup 23. In the case where the target substance detection sensor 21 does not detect the target substance, the output valve 20 may be switched to direct the fluid to the waste container. In some exemplary embodiments, the target substance detection sensor 21 may be an ultraviolet sensor.

[0146] Figure 2 A side view of components of an exemplary sample preparation system is shown. Specifically, Figure 2 (a) and Figure 2 (b) shows an input stack 11, which holds a plurality of filters (e.g., clarifying filters) as first consumables 2a, a filter processing device 27, and a waste tank 26. The filter processing device 27 can be connected to the first mechanism 2 (e.g., Figure 1 ) and input stack 11. Filter processing device 27 can be configured to receive a first consumable 2a disposed on a fluid path (e.g., from first mechanism 2) and provide first consumable 2a on the fluid path (e.g., supported by first mechanism 2). Filter processing device 27 can operate in an automated manner, e.g., without manual intervention.

[0147] Specifically, the filter processing device 27 can be connected to the input stack 11, and can be configured to receive the first consumable 2a from the first mechanism 2, and provide the received first consumable 2a to the waste bin 26. In addition, the filter processing device 27 can be configured to receive the first consumable 2a from the input stack, and automatically provide the received first consumable 2a to the first mechanism 2.

[0148] In some exemplary embodiments, filter treatment device 27 may be an index wheel.

[0149] Figure 3 An exemplary filter treatment device in the form of an indexing wheel is shown. Figure 3 The filter processing device 27 in FIG. 1 has an opening 28 in the plane direction thereof at the first position of the index wheel, and the opening 28 conforms to the shape of the filter as the first consumable product 2 a. Figure 3The filter treatment device 27 shown in FIG. 1 also has a hole 29 extending from the first surface of the index wheel to the second surface of the index wheel in the plane direction of the index wheel at the second position of the index wheel. The first position where the opening 28 on the index wheel is located and the second position where the hole 29 on the index wheel is located may be diametrically opposite to each other. Therefore, the filter treatment device 27 in the form of an index wheel may have a substantially crescent shape with a concave and convex area defined by two arcs.

[0150] The filter treatment device 27 in the form of an indexing wheel is rotatable so that the first opening of the hole 29 on the first surface of the indexing wheel is connected to the input line 12 (see Figure 1 ), and the second opening of the hole 29 on the second surface of the indexing wheel is connected to the first line 6 (see Figure 1 ). Thus, in situations where the fluid needs to flow through the first mechanism 2 without passing through the filter, such as when the sample preparation system 1 performs only purification without clarification, when flushing the input line 12 upstream of the first mechanism 2, when cleaning the sample preparation system 1, etc., the hole 29 on the filter handling device 27 can provide fluid communication between the input line 12 and the first line 6.

[0151] The filter handling device 27 in the form of an indexing wheel can be rotated so that the first consumable 2a can be received from the input stack 11 and provided to the first mechanism 2. In addition, the filter handling device 27 in the form of an indexing wheel can be rotated to receive the first consumable 2a from the first mechanism and provide it to the waste bin 26.

[0152] Use the reference above Figure 2 and Figure 3 The filter processing device 27 and the input stack 11 can automatically load the filter as the first consumable 2a onto the first mechanism 2 (e.g., the first filter holder) of the sample preparation system 1 and eject it from the first mechanism 2 of the sample preparation system 1. In other words, by using the filter processing device 27, new (e.g., unused) first consumables 2a can be easily provided to the first mechanism 2, and used first consumables 2a can be easily and automatically removed.

[0153] Figure 4 An exemplary pipetting robot (top) and an exemplary pipette washing station (bottom) that can be used in the sample preparation system 1 are shown. For example, the sample preparation system 1 may include a pipetting robot 30 configured to transfer a fluid such as a sample fluid from at least one input container (not shown) to an input cup 13 (see Figure 1 ). The pipetting robot 30 may include a pipette tip 31 connected to a flow-through pH electrode 32 and a fluid input valve 33. The fluid input valve 33 may be configured to provide, for example, water, sodium hydroxide, and / or a pH neutralizing buffer to the pipette tip.

[0154] The pipetting robot 30 may also include a pipette liquid sensor 34 disposed on a pipette robot line 35 that provides fluid communication between the pipette tip 31, the flow-through pH electrode 32, and the fluid input valve 33. The pipette liquid sensor 34 may be configured to detect the presence of liquid at its location. In addition, the pipetting robot 30 may include a syringe 36 connected to the flow-through pH electrode 32. The pipette wash station 37 may be configured to receive the pipette tip 31 of the pipetting robot 30. The pipette wash station 37 may have a wall 38 that surrounds the pipette tip 31 of the pipetting robot 30 when the pipetting robot 30 is disposed therein.

[0155] In addition, the pipette washing station 37 may have an outlet 39 at its bottom, through which a fluid may flow out. Specifically, the liquid may be provided by at least one fluid input valve 33 of the pipetting robot 30, and may be used to wash the pipette tip 31 when the pipetting robot 30 is disposed in the pipette washing station 37. The outlet 39 may be connected to a waste container (not shown), to which the liquid may be pumped using a tip washing waste pump 40. Figure 4 Furthermore, a storage container 41 for storing, for example, process liquid, an input container 42 and an output container 43 which can be arranged next to the pipette washing station 37 are shown.

[0156] In some exemplary embodiments, one input container may have a volume of 2 ml to 20 ml. The input container is not particularly limited, and may be selected from, for example, a culture container, a rotating tube, and a multi-well plate.

[0157] The type of input container is not particularly limited by using the pipetting robot 30. Therefore, the pipetting robot 30 can provide flexibility in selecting the input container, so that its selection can only depend on the fluid to be processed (eg, the sample fluid to be prepared).

[0158] In addition to or as an alternative to the pipetting robot 30 configured to transfer fluid from at least one input container (not shown) to the input cup 13 as described above, the sample preparation system 1 may further include a pipetting robot 30 configured to transfer fluid from the output cup 23 (see Figure 1 ) is transferred to at least one output container (not shown). As described above, the pipetting robot 30 configured to transfer fluid from the output cup 23 to at least one output container can be the same as the pipetting robot 30 configured to transfer fluid from at least one input container (not shown) to the input cup 13.

[0159] In some exemplary embodiments, an output container may have a volume of 2 ml to 80 ml. The output container is not particularly limited, and for example, may be selected from a 15 ml centrifuge tube, a 50 ml centrifuge tube, and a multi-well plate. By using the liquid transfer robot 30, the type of the output container is not particularly limited. Therefore, the liquid transfer robot 30 can provide flexibility in selecting the output container.

[0160] Controls

[0161] Figure 5 A schematic diagram illustrating the flow of control signals and sensor signals between an exemplary control device and an exemplary sample preparation system is shown. Figure 5 In the specific example, Figure 1 The sample preparation system 1 shown in FIG. 1 communicates with a control device 50. Note that in Figure 5 In order to facilitate understanding of the flow of signals, the input stack 11 of the sample preparation system 1 is not shown (see Figure 1 ),but Figure 5 The sample preparation system 1 shown in FIG. 1 also includes Figure 1 The input stack in 11.

[0162] like Figure 5 As shown, the control device 50 may include a processor 502 and a storage medium 504 in communication with the processor 502. The processor 502 may be configured to execute a control process to control a sample preparation system, such as the exemplary sample preparation system 1. For example, the processor 502 may be configured to communicate with various sensors provided in the sample preparation system 1 to obtain system information from the sensors. In addition, for example, the processor 502 may be configured to communicate with components included in the sample preparation system 1 to send control signals to these components. The processor 502 may communicate with the sensors and components via one or more wired and / or wireless networks. The processor 502 may also obtain information required for executing the control process from the storage medium 504 (e.g., one or more pieces of system information other than the information obtainable from the sensor, one or more operating parameter values ​​of the control process, etc.).

[0163] like Figure 5 As shown, the control device 50 may receive system information from the first liquid sensor 15, the pump 9 (e.g., a sensor (not shown) provided on the pump 9 to measure the rotation speed of the pump 9), the first pressure sensor 17, the second pressure sensor 18, the second liquid sensor 16, and / or the target substance detection sensor 21. The system information from the respective sensors may include information indicating the values ​​measured by the respective sensors.

[0164] The processor 502 can process the system information received from the various sensors to control the sample preparation system 1. For example, the processor 502 can determine how at least one component of the sample preparation system 1 should operate based on the processing system information, generate at least one control signal to instruct the at least one component to operate in the determined manner, and then output the generated (multiple) control signals to the at least one component. In some exemplary embodiments, the processor 502 can be configured to function as a PID controller (proportional-integral-derivative controller).

[0165] like Figure 5 As shown, the control device 50 can output control signals to the input sample valve 14, the process fluid input valve 24, the pump 9, the first valve 4, the second valve 5, the output valve 20 and / or the waste pump 25. In addition, although Figure 5 27 (see FIG. Figure 2 and Figure 3 ) and / or to the pipetting robot 30 (see Figure 4 ) output control signal.

[0166] The storage medium 504 may be configured to store information required by the processor 502 to execute a control process.

[0167] Details of the control process executed by the processor 502 of the control device 50 will be described below.

[0168] It is worth noting that although Figure 5 The control device 50 is shown as having a single processor 502, but in some exemplary embodiments, the control device 50 may have more than one processor 502. Figure 5 The control device 50 is shown as a separate device from the sample preparation system 1 , but in some exemplary embodiments, the control device 50 may be integrated into the sample preparation system 1 as a component of the sample preparation system 1 .

[0169] Sample preparation process

[0170] As described above, a sample preparation system can perform one or more unit operations on a sample, such as clarification and cleanup.

[0171] exist Figure 1 In a specific example, the sample preparation system 1 can perform clarification and / or cleanup.

[0172] a) Clarification process

[0173] The clarification process may be understood as a process of clarifying a sample fluid by passing the sample fluid through a clarification filter (eg, first consumable 2a) supported by a first filter holder (eg, first mechanism 2) to provide a clarified sample fluid.

[0174] A typical example of a clarification process performed by the sample preparation system 1 is provided below.

[0175] At the beginning of the exemplary clarification process (a), a clarification filter can be provided to the first mechanism 2 (hereinafter referred to as "step (c1)"), wherein the clarification filter is new, in other words, unused. In the step (c1), preferably, the clarification filter is provided from an input pile by a consumables processing device.

[0176] In some cases, the clarifying filter may already be connected to the first mechanism 2 at the beginning of the clarifying process (a). In any case, it may be necessary to replace the clarifying filter during the clarifying process (a) to avoid clogging of the clarifying filter and product loss. In some exemplary embodiments, the clarifying filter can be automatically ejected from the first mechanism 2 and automatically replaced by a new clarifying filter.

[0177] Preferably, based on the measured backpressure of the clarification filter measured by the first pressure sensor 17, or based on the pressure difference between the first pressure sensor 17 and the second pressure sensor 18 and the pumping speed, a decision can be made to automatically eject the clarification filter from the first mechanism and automatically replace it with a new clarification filter. Figure 7 The exemplary process shown in describes the details of how such a determination is made.

[0178] Then, the clarifying filter is preferably clamped so that the upper and lower surfaces of the clarifying filter are supported against the internal pressure during filtration (ie, "step (c2)").

[0179] In addition, before the sample to be clarified is pumped to the clarification filter, the sample preparation system 1 and the clarification filter can be subjected to an air pressure test (i.e., "step (c3)"). Specifically, in step (c3), the first valve and the second valve are set to close the flow path, and the pump 9 pumps air into the sample preparation system to reach a preset pressure. In some cases, the preset pressure is 0.1 bar to 4 bar, preferably 0.5 bar to 1 bar. The pressure is then monitored for a few seconds. At the end of the air pressure test, the pressure is released by setting the first valve, the second valve, and the output valve so that the pressure is released into the waste container via the third line.

[0180] After the optional air pressure test, the sample to be clarified can be provided to the input cup 13 of the sample preparation system 1 (i.e., "step (c4) a"). Alternatively, before any of steps (c1) to (c3), the sample to be clarified can also be provided to the input cup 13 of the sample preparation system 1 (i.e., "step (c4) b"). Preferably, the pipetting robot 30 can provide the sample to be clarified to the input cup 13 by transferring the sample to be clarified from at least one input container to the input cup 13 of the sample preparation system 1.

[0181] Then, the sample to be clarified can be pumped from the input cup 13 to the clarifying filter (i.e., "step (c5)"). In some cases, in the step (c5), the sample to be clarified passes through at least the input sample valve 14, the first liquid sensor 15, and the first pressure sensor 17 on the way from the input cup 13 to the clarifying filter.

[0182] Furthermore, the sample is clarified by passing the sample through a clarification filter connected to the first mechanism 2 (hereinafter referred to as "step (c6)").

[0183] Then, the clarified sample can be guided to the output cup 23 (hereinafter referred to as "step (c7)"). In some cases (for example, when the clarified sample does not need to be purified), in the step (c7), the clarified sample passes through at least the second pressure sensor 18, the second liquid sensor 16, the third line 8, the target substance detection sensor 19, and the output valve 20 from the downstream side of the clarifying filter to reach the output cup 23. In other cases (for example, when the clarified sample needs to be purified), in the step (c7), the clarified sample passes through at least the second pressure sensor 18, the second liquid sensor 16, the second line 3, the second consumable 3a, the target substance detection sensor 19, and the output valve 20.

[0184] When the input cup 13 is empty, the first liquid sensor 15 can detect that the sample to be clarified has been used up (i.e., "step (c8)"). Specifically, the first liquid sensor can detect whether the sample to be clarified previously provided to the input cup 13 has passed the position where the first liquid sensor 15 is arranged.

[0185] After step (c8), a flushing step (i.e., "step (c9)") may be automatically performed. Specifically, a flushing liquid (such as PBS) may be provided to the sample preparation system 1 through one of the process fluid input valves 24 disposed upstream of the first mechanism 2. Thus, the sample to be clarified still present upstream of the first mechanism 2 may be directed to the first mechanism 2, and the sample in the clarifying filter may be flushed through the clarifying filter. Preferably, the flushing liquid that has passed through the clarifying filter containing the clarified sample is directed to the output cup 23.

[0186] After step (c8) and / or step (c9), it is preferred to perform a step of pumping air (i.e., "step (c10)"). Specifically, air can be provided to the sample preparation system 1 through one of the process fluid input valves 24 arranged upstream of the first mechanism 2. The air passes through the clarifying filter to push the sample to be clarified or the flushing liquid still present on the upper flow field of the clarifying filter, as well as the partially clarified sample or flushing liquid still contained in the clarifying filter. The clarified sample thus produced can be directed to the output cup 23.

[0187] By applying step (c10), the product recovery rate can be improved. The air pressure used can be in the range of, for example, 0.5 bar to 2 bar. Thereby, the air pressure can be lower than the bubble point of the clarifying filter, so that the generation of foam can be avoided. Typically, the bubble point of the clarifying filter is greater than 3 bar. After a waiting time, for example from 0 seconds to 5 seconds, the air pressure is released by reversing the pump 9. The measurement of the bubble point is well known to the technician. For example, the bubble point can be measured according to ISO 2942 or ASTM F316-03.

[0188] Then, the clarified filter can be ejected from the first mechanism 2 (i.e., "step (c11)"). In the case where the first mechanism 2 is a first filter holder and the clarified filter is clamped by the first clamping member 10a and the second clamping member 10b, the clarified filter is released before being ejected. The ejected clarified filter can be received by the filter processing device 27 and provided to the waste tank 26 (for example, see Figure 2 ).

[0189] Furthermore, in some cases, the connection mechanism (e.g., Figure 3 The hole 29 shown in FIG. 2 can connect the input line 12 and the first line 6 to provide fluid communication between the input line 12 and the first line 6, thereby closing the liquid path (i.e., "step (c12)"). For example, this can be achieved by using a dividing wheel as a filter processing device and rotating the dividing wheel to a second position where the dividing wheel is positioned with a through-fluid channel, which can then be connected to the input line 12 and the first line 6.

[0190] Then, the clarified sample and / or the washing liquid containing the target substance present downstream of the first mechanism can be guided to the output cup 23 by pumping air (ie, "step (c13)").

[0191] In some cases, the output sample present in the output cup may be transferred to at least one output container (ie, “step (c14)”). For example, this step may be performed by the pipetting robot 30 .

[0192] Optionally, the sample preparation system 1 can then be cleaned by pumping a cleaning liquid such as a buffer, sodium hydroxide and / or water through the process fluid input valve 24 disposed upstream of the first mechanism 2 to the output cup 23 through the sample preparation system 1, and then pumping it in reverse from the output cup 23 to the input cup 13 (i.e., "step (c15)"). The resulting liquid is then directed to a waste container by using a waste pump 25.

[0193] b) Purification process

[0194] The purification process may be understood as a process of passing the sample fluid through a purification filter or a purification chromatography column (eg, the second consumable 3 a ) connected to the second mechanism 3 to provide a purified sample fluid.

[0195] In some exemplary embodiments, the clarification process described above may be followed by a purification process. However, in some cases, the purification process may be performed without performing a clarification process, in which case the clarification filter is not disposed on the filter holder (e.g., the first mechanism 2), and the fluid may be allowed to flow from the input line 12 through the aperture 29 of the filter treatment device 27 (see Figure 1 and Figure 3 ) without passing through the clarifying filter to flow to the first line 6.

[0196] From the input line 12 through the aperture 29 of the filter treatment device 27 without passing through the clarifying filter

[0197] Control Process

[0198] The clarification process described above can be driven at a pumping flow rate with a maximum pressure difference (also referred to as "dP") across the clarification filter (e.g., the first consumable 2a) to maintain the integrity of the cells. When the maximum pressure difference is reached, the control device 50 can then control the pump 9 to decelerate to keep the pressure difference constant. When the clarification process is controlled to the pressure difference by slowing down the flow rate (e.g., by reducing the rotation speed of the pump 9), the clarification process becomes very slow.

[0199] Once the maximum differential pressure is reached, the clarification process may produce a reduction in return and a process stop point must be determined, such as minimum flow rate, maximum process time. It may be desirable to minimize DNA and host cell proteins (HCP) in the output sample. This can be achieved by keeping the differential pressure as low as possible.

[0200] To maximize recovery, it may be necessary to flush the clarified product. An ideal balance for maximum efficiency may be to time the switch from the input culture to the flush buffer so that when the flush is complete, the maximum pressure differential is just reached, but the control device 50 does not need to reduce the pump speed (e.g., the rotational speed of the pump 9). In this case, the clarification process may be run at maximum speed for as long as possible. This can be technically challenging because fouling of the clarification filter can be non-linear and dependent on the "filterability" of the input culture.

[0201] The control process performed by the control device 50 according to the present disclosure can achieve or (at least come close to achieving) such clarification optimization. The control process performed by the control device 50 according to the present disclosure can also avoid the worst case of filter plugging, which may reduce time, product recovery, and may require further intervention to overcome.

[0202] Figure 6 A graph showing exemplary recorded online data obtained by running the exemplary sample preparation system 1 without a control process according to the present disclosure is shown. Figure 6 An example of the effect of waiting to reach a maximum differential pressure limit of 1000 mbar is shown. Figure 6 In the example shown in FIG. 1 , when the pressure difference is below the limit value of 1000 mbar, the control device 50 controls the pump 9 of the sample preparation system 1 to keep the sample fluid flowing into the flow path toward the clarification filter, and when the pressure difference reaches the limit value of 1000 mbar, the control device 50 reduces the rotation speed of the pump 9 (e.g., the flow rate of the pump).

[0203] like Figure 6 As shown, the pump flow rate (at Figure 6 ) slows down processing time and prevents the flushing buffer from easily passing through the filter (e.g., see Figure 6 This may reduce product recovery, as it is not possible to completely flush the filter, so product will remain in the filter. In addition, this may increase cell lysis (as indicated by LDH (lactate dehydrogenase)) and HCP contamination in the output.

[0204] Figure 7 1 shows a flow chart of an exemplary process for controlling a sample preparation system. More specifically, when the sample preparation system 1 performs the clarification process as described above, the following steps may be performed: Figure 7 The sample preparation system 1 is controlled by the exemplary process shown in FIG.

[0205] Figure 7The exemplary process shown in FIG. 5 can be executed by the processor 502 of the control device 50. When an instruction to start the exemplary process is received from a user through an input device (not shown), the process can be started. Figure 7 Example process shown. For example, the instructions from the user can include instructions to instruct the sample preparation system to begin clarifying the sample fluid.

[0206] It should be noted that Figure 7 It will be apparent from the description of the exemplary process shown in FIG. 1 that when the processor 502 performs the Figure 7 When the sample preparation system 1 is controlled by the exemplary process shown in , the clarification process performed at the sample preparation system 1 is not completely the same as the typical example of the clarification process described above. Specifically, for example, the rinsing step (c9) and / or the air pumping step (c10) may be performed under conditions different from the conditions under which it is detected that the sample to be clarified has been used up (step (c8)).

[0207] when Figure 7 When the exemplary process shown in FIG. 1 starts, at step S10, the processor 502 may receive one or more operating parameters of the exemplary process. The one or more operating parameters may include at least a specified maximum pressure difference. The specified maximum pressure difference may be input by a user using an input device (not shown) connected or in communication with the processor 502.

[0208] In some exemplary embodiments, the one or more operating parameters may further include a specified time period Δt (expressed in time units (e.g., seconds, minutes, etc.), or expressed by a change in the amount (e.g., volume) of fluid introduced into the fluid path), which is used to determine a regression function as described in detail below with respect to step S16. In some exemplary embodiments, the one or more operating parameters may further include a specified stop condition (e.g., a first specified condition) for determining whether to stop introducing the sample fluid into the fluid path of the sample preparation system 1, as described below with respect to step S18.

[0209] The specified time period Δt and / or the specified stop condition may also be input by the user using an input device.

[0210] Optionally, the one or more operating parameters may further include one or more of the following: cell density of the sample fluid, turbidity of the sample fluid, particle size distribution of the sample fluid, optical density of the sample fluid, filter resistance index, filter surface area. The values ​​of these further operating parameters may be input by a user using an input device. After step S10, the exemplary process may continue to step S12.

[0211] In step S12, the processor 502 may set the position of the valve and the flow rate of the pump to start the clarification process. For example, the processor 502 may generate a control signal to set the process fluid input valve 24 so as to prevent various types of process fluids from flowing into the fluid path, and output the generated control signal to each process fluid input valve 24. In addition, the processor 502 may generate a control signal to set the input sample valve 14 so as to allow the sample fluid to flow from the input cup 13 toward the pump 9 and the first mechanism 2, and output the generated control signal to the input sample valve 14. In addition, the processor 502 may generate a control signal to instruct the pump 9 to start pumping the fluid at a specific rotation speed (e.g., a default rotation speed according to the type of sample fluid, a user-specified rotation speed, etc.), and output the generated control signal to the pump 9.

[0212] In addition, for example, the processor 502 can generate a control signal to set the first valve 4, the second valve 5 and / or the output valve 20 to a position suitable for the desired flow of the clarified sample fluid, and output the generated control signal to the first valve 4, the second valve 5 and / or the output valve 20. For example, in the case where the clarified sample fluid is to be subjected to a purification process, the first valve 4 is set to allow the clarified sample fluid to flow toward the second mechanism 3.

[0213] In addition, for example, when the clarified sample fluid is collected in the output cup 23 without undergoing a purification process, the first valve 4, the second valve 5, and the output valve 20 are set to allow the clarified sample fluid to flow toward the output cup 23 through the third line 8 and the output line 22. In summary, the processor 502 can control the sample preparation system 1 to perform steps (c5), (c6), and (c7) of the exemplary clarification process described above. After step S12, the exemplary process can proceed to step S14.

[0214] In step S14, the processor 502 may monitor sensors disposed on the sample preparation system 1 (e.g., when the sample preparation system 1 performs steps (c5), (c6), and (c7) of the exemplary clarification process described above). For example, the processor 502 may receive system information indicating at least the amount of sample fluid introduced into the fluid path (e.g., including at least the input line 12 and the first line 6), the upstream pressure at the first pressure sensor 17, and the downstream pressure at the second pressure sensor 18.

[0215] For example, the amount of sample fluid that has been introduced into the fluid path can be obtained from a sensor (not shown) on the pump 9 to measure the rotation speed of the pump 9. For example, the amount of sample fluid can be calculated using the rotation speed of the pump 9 and the time elapsed since the start of the sample preparation process performed by the sample preparation system 1. More specifically, for example, when the rotation speed of the pump 9 is expressed as the amount of fluid pumped by the pump 9 per unit time (e.g., ml / min), the amount of sample fluid that has been introduced into the fluid path can be the product of the average rotation speed of the pump 9 and the time elapsed since the start of the sample preparation process. In addition, in some aspects, the amount of sample fluid that has been introduced into the fluid path since the start of the sample preparation process may be proportional to the amount of rotation of the pump 9 (e.g., the number of rotations). Therefore, if the amount of fluid that can be pumped per rotation of the pump 9 is known, the amount of sample fluid can be obtained by calculating the amount of rotation of the pump 9 since the start of the sample preparation process based on the rotation speed of the pump 9 (e.g., expressed in rpm) and the time elapsed.

[0216] In some exemplary embodiments, a rotation speed sensor is not necessarily provided on the pump 9. In these exemplary embodiments, a calibration value of the rotation of the pump 9 (for example, driven by a DC motor or a stepper motor) can be obtained from the storage medium 504, and the obtained calibration value of the rotation of the pump 9 can be used to calculate the amount of the sample fluid.

[0217] Furthermore, in some exemplary embodiments, the atmospheric pressure stored in the storage medium 504 may be obtained as the downstream pressure instead of obtaining the downstream pressure from the second pressure sensor 18 .

[0218] During the monitoring period of step S14, the processor 502 may repeatedly receive system information (particularly, one or more values ​​that may vary over time, such as the amount of fluid that has been introduced into the fluid path, the upstream pressure, etc.) within a specified time interval (e.g., 500 milliseconds, but may be longer or shorter depending on processing capabilities). In the case where the system information includes one or more values ​​that do not vary over time (e.g., atmospheric pressure as downstream pressure, etc.), the processor 502 does not need to repeatedly receive the value(s), but receiving at least once may be sufficient. After step S14, the exemplary process may continue to step S16.

[0219] In step S16, the processor 502 may determine a regression function to infer when the purification filter will become clogged. For example, it may be assumed that at different time points t within a specified time period Δt i -Δt,......,t i The pressure difference dP_t across the clarification filter obtained based on the upstream pressure and the downstream pressure i -Δt, ..., dP_t iis the value of the dependent variable y of the regression function, and at different time points t within the specified time period Δt i -Δt,......,t i The amount of sample fluid introduced into the fluid path obtained at Vin_t i -Δt, ..., Vin_t i is the value of the independent variable x of the regression function, thereby determining the regression function. Therefore, the current time point t obtained (in step S14) can be used current The regression function is determined by the system information of the previous specified time period Δt. As mentioned above, the current time point t current It can be represented by the amount of fluid that has been introduced into the fluid path since the sample preparation system 1 started to perform the sample preparation process. current It may be expressed in units of time (eg, t seconds or minutes from the start of the sample preparation process).

[0220] The specified time period Δt used in step S16 can vary depending on the sample preparation process performed by the sample preparation system 1. In some cases, the specified time period Δt may be as short as the monitoring interval (step S14), for example 500 milliseconds. In other cases, the specified time period Δt may be as long as the entire duration of the sample preparation process, in other words, from the start of sample preparation until the current time point. In some exemplary embodiments, the specified time period Δt may be the time period for 1.0 ml of fluid to be introduced into the fluid path or 10 seconds.

[0221] In some exemplary embodiments, the specified time period Δt may be immediately adjacent to the current time point t current Here, "immediately before" may mean a time period up to a time point of a single time interval (for receiving system information) before the current time point. For example, in the case where the time interval for receiving system information during the monitoring step S14 is 500 milliseconds and the specified time period is 10 seconds, immediately before the current time point t current The previous specified time period Δt can be from t current -10.5 seconds from start to t current -0.5 second time period.

[0222] In some other exemplary embodiments, the specified time period Δt does not necessarily immediately follow the current time point t current For example, a specified time period Δt can represent the period up to the current time point t current The time period is preferably within a certain fraction (eg, 1 / 10) of the expected total time of the sample preparation process (or the total amount of sample fluid).

[0223] In some exemplary embodiments, the regression function may be a linear regression function as follows:

[0224] y=ax+c (1),

[0225] Wherein, x and y may be the independent variable and the dependent variable as described above, respectively, and a and c may be coefficients of the regression function. By monitoring the system information in step S14, paired xy values ​​during a specified time period may be obtained.

[0226] More specifically, the amount of sample fluid that has been introduced into the fluid path (e.g., x value) and the pressure difference across the clarification filter (e.g., y value, which can be determined by calculating the difference between the downstream pressure from the second pressure sensor 18 and the upstream pressure from the first pressure sensor 17) can be obtained in pairs during a specified time period. The coefficients a and b of the regression function (1) can be determined using the pairs of xy values ​​obtained during the specified time period.

[0227] In some further exemplary embodiments, the regression function may have a form different from the above-mentioned linear regression function. For example, one of the following regression functions may be used as the regression function in step S16:

[0228] y=ax b +c (2),

[0229] y=ae bx +c (3),

[0230] Wherein, x and y may be the independent variable and the dependent variable as described above, respectively, and a, b and c may be the coefficients of the regression function. Similarly, in the case where function (2) or function (3) is used as the regression function in step S16, the coefficients a, b and c may be determined using the paired xy values ​​obtained during the specified time period as described above.

[0231] In exemplary embodiments where one or more further operating parameters are obtained (eg, one or more of the following: cell density, turbidity, particle size distribution, optical density, filter resistance index, filter surface area), these further operating parameters may also be used to determine the regression function.

[0232] For example, further operating parameters may be used to determine the value(s) of the coefficient(s) included in the regression function, e.g., coefficients a, b, and / or c in the above regression functions (1), (2), and (3). In addition, for example, operating parameters may be further used to determine or adjust a time period specified during the system information used to determine the regression function.

[0233] More specifically, for example, the processor 502 can use an equation to determine, for each of one or more further operating parameters, an amount of clogging as a function of one of the one or more parameters, wherein the clogging amount indicates an amount of sample fluid that, when introduced into at least one consumable, can cause at least one consumable to block the flow of the sample fluid.

[0234] Additionally, for example, processor 502 may determine, for each of the one or more further operating parameters, a coefficient indicating a ratio between:

[0235] the amount of sample fluid that has been introduced into the fluid path at the current point in time, or the total amount of sample fluid to be introduced into the fluid path, and

[0236] Use the generated equation to obtain the predicted blockage amount.

[0237] The processor 502 may then determine a regression function using the coefficients determined for each of the one or more further operating parameters.

[0238] To determine the regression function, for example, processor 502 may determine a sensitivity factor using coefficients determined for each of the one or more further operating parameters, and select one type of regression function from among multiple types of regression functions to use as the regression function based on the sensitivity factor.

[0239] In a specific example, the sensitivity factor can be calculated as follows:

[0240] Sensitivity factor = α 1 ×α 2 ×…×α N (4)

[0241] where N may be the number of further operating parameters used, and α i (i=1, 2, ..., N) may be a coefficient determined for further operating parameter i by the following calculation:

[0242]

[0243] Among them, V input V may be the volume of the sample fluid that has been introduced into the fluid path of the sample preparation system 1 at the current point in time, and V predicted_i It may be the predicted occlusion volume obtained using the equation generated for further manipulation of parameter i.

[0244] If the coefficient α i is equal to 1, then the volume of the sample fluid V input may be equal to the predicted blockage volume V predicted_iIf the coefficient α i is less than 1, then the volume of the sample fluid V input May be smaller than the predicted clogging volume V predicted_i If the coefficient α i If V is greater than 1, then the volume of the sample fluid V input May be larger than the predicted clogging volume V predicted_i .

[0245] The number N of further operating parameters to be used may be specified by a user, for example using an input device (not shown) in communication with processor 502 .

[0246] In some exemplary embodiments, when the sensitivity factor determined as described above is greater than a specified sensitivity threshold, processor 502 may select a more sensitive (in other words, responsive) regression function among multiple types of regression functions. On the other hand, when the sensitivity factor is equal to or less than the specified sensitivity threshold, processor 502 may select a less sensitive (in other words, responsive) regression function among multiple types of regression functions.

[0247] For example, in the case where the multiple types of regression functions include regression functions (1), (2) and (3) as described above, the linear regression function (1) may be the least sensitive of the three. Since which of the regression functions (2) and (3) is more sensitive may depend on the values ​​of coefficients a, b and c, in the case where a more sensitive regression function is selected (e.g., the sensitivity factor is greater than a specified sensitivity threshold), one or more of the coefficients a, b and c may be set to different values, and a more sensitive regression function having a specific value of coefficients a, b and / or c may be selected. The specified sensitivity threshold may be predetermined using test data obtained from an experiment.

[0248] In addition, the sensitivity factor can be used to determine and / or adjust the specified time period for which the system information used to determine the regression function is used. For example, for a lower sensitivity factor, the specified time period can be set to be longer than the specified time period set for a higher sensitivity factor.

[0249] After step S16, the exemplary process may continue to step S18.

[0250] In step S18, the processor 502 may determine whether the specified stop condition is satisfied. For example, when the value indicating the predicted congestion amount Vpb is equal to the value at the current time point t current The amount of sample fluid that has been introduced into the fluid path Vin_t current When the corresponding condition is satisfied, it can be determined that the specified stop condition is satisfied. The predicted clogging amount Vpb can be the value of the independent variable x of the regression function when the value of the dependent variable y is the specified maximum pressure difference.

[0251] The predicted clogging amount Vpb can be understood as the predicted amount of sample fluid that will be put into the filter when the pressure difference across the filter reaches the specified maximum pressure difference. The predicted clogging amount can also be called the predicted filter clogging amount, or, when the amount is expressed in volume, the predicted filter clogging volume. In addition, at the current time point t current The amount of sample fluid that has been introduced into the fluid path Vin_t current It may also be referred to as the current sample amount, or, if the amount is expressed in terms of volume, the current sample volume.

[0252] In some exemplary embodiments, the processor 502 may determine that a specified stop condition is satisfied when the difference between the predicted filter blockage amount and the current sample amount (e.g., (predicted filter blockage amount) - (current sample amount)) is equal to or less than a specified threshold value (e.g., 2 ml). The processor 502 may determine that a specified stop condition is not satisfied when the difference between the predicted filter blockage amount and the current sample amount is greater than a specified threshold value. The specified threshold value may be related to the input volume of the sample preparation system, which may be determined by the volume of the conduit(s) between the input valve 14 and the clarification filter (e.g., filter 2a).

[0253] The specified threshold may have been received by the processor 502 in step S10. In the exemplary embodiment using (multiple) further operating parameters as described above, the further operating parameters may be used to adjust the specified threshold. Alternatively or additionally, the specified threshold may be adjusted using system information obtained relative to a specified time period Δt for determining the regression function in step S16. For example, if the predicted filter blockage volume Vpb obtained from the regression function decreases as the iteration of step S16 proceeds, the specified threshold may be increased. Furthermore, for example, if the predicted filter blockage volume Vpb obtained from the regression function increases as the iteration of step S16 proceeds, the specified threshold may be reduced. It is to be noted here that the predicted filter blockage volume Vpb obtained from the regression function may depend on system information indicating an upstream pressure and a downstream pressure.

[0254] If the processor 502 determines that the specified stop condition is not satisfied (step S18: No), then Figure 7The exemplary process may return to step S14. In this case, while the processor 502 controls the sample preparation system 1 to continue introducing the sample fluid into the fluid path of the sample preparation system 1, the step S14, the regression function determined in step S16, and the determination of whether the specified stop condition is met in step S18 will be repeatedly monitored. It is worth noting that the regression function determined in step S16 may be different from the regression function determined in different iterations of step S14, step S16, and step S18, because the system information received for different time periods can be used to determine the regression function. Specifically, since the specified time period Δt used in step S16 may move forward over time, the system information used in step S16 may include different information fragments in different iterations. Therefore, the regression function can be updated in real time.

[0255] When the processor 502 determines that the specified stop condition is satisfied (yes at step S18 ), the exemplary process may continue to step S20 .

[0256] In step S20, the processor 502 may control the sample preparation system 1 to stop introducing the sample fluid into the fluid path of the sample preparation system 1. For example, the processor 502 may generate a control signal to set the input sample valve 14 to a closed state in which the sample fluid is blocked from flowing toward the filter in the input line 12, and output the generated control signal to the input sample valve 14. In addition, for example, the processor 502 may generate a control signal to instruct the pump 9 to stop moving the sample fluid in the input line 12, and output the generated control signal to the pump 9. After step S20, the exemplary process may proceed to step S22 or step S24.

[0257] In optional step S22, the processor 502 can control the sample preparation system 1 to pump the flushing liquid through the filter (e.g., the flushing step (c9) in the above exemplary clarification process). For example, the processor 502 can generate a control signal to set one of the process fluid input valves 24 corresponding to the flushing liquid source to an open state to allow the flushing liquid to flow toward the filter in the fluid path, and output the generated control signal to the one of the process fluid input valves 24.

[0258] In addition, for example, the processor 502 can generate a control signal to instruct the pump 9 to move the fluid in the input line 12 (e.g., the flushing liquid and any remaining sample fluid) toward the filter, and output the generated control signal to the pump 9. In step S22, the sample fluid remaining in the input line 12 and / or in the filter can pass through the filter together with the flushing liquid. In addition, the processor 502 can set one of the process fluid input valves 24 to a closed state in which the flushing liquid is prevented from flowing into the input line 12 at the end of the flushing step S22 (e.g., after a period of time). After step S22, the exemplary process can proceed to step S24.

[0259] It should be noted that step S22 is an optional step and may be skipped in some exemplary embodiments.

[0260] In step S24, the processor 502 may control the sample preparation system 1 to flush air through the filter (e.g., the air pumping step (c10) in the exemplary clarification process described above). For example, the processor 502 may generate a control signal to set one of the process fluid input valves 24 corresponding to the air source to an open state to allow air to flow toward the filter in the fluid path (e.g., the input line 12), and output the generated control signal to the one of the process fluid input valves 24.

[0261] In addition, for example, the processor 502 can generate a control signal to instruct the pump 9 to move the fluid in the input line 12 (e.g., air and any remaining flushing liquid and / or any remaining sample fluid) toward the filter, and output the generated control signal to the pump 9. In step S24, the sample fluid and / or flushing liquid remaining in the input line 12 and / or in the filter can pass through the filter together with the air. In addition, the processor 502 can set one of the process fluid input valves 24 to a closed state to prevent air from flowing into the input line 12 at the end of the air flushing step S22 (e.g., after a certain time). After step S24, the exemplary process can continue to step S26.

[0262] In step S26, the processor 502 may control the sample preparation system 1 to eject the filter (e.g., step (c11) of the exemplary clarification process described above). For example, the processor 502 may control the filter processing device 27 (e.g., see FIG. Figure 2 and Figure 3 ) to remove the filter from the first mechanism 2. More specifically, the processor 502 can generate and output a control signal to the filter handling device 27 to remove the filter from the first mechanism 2 by receiving the filter. Therefore, the filter can be automatically removed from the fluid path of the sample preparation system 1. After step S26, the exemplary process can proceed to step S28.

[0263] In step S28, the processor 502 may determine whether to set another filter (e.g., a new, unused filter) on the fluid path (e.g., in the first mechanism 2). For example, if a specified exchange condition (e.g., a second specified condition) is met, the processor 502 may determine to set another filter, and if the specified exchange condition is not met, the processor 502 may determine not to set another filter. The specified exchange condition may include a condition on the amount of remaining sample fluid to be processed by the sample preparation system 1. For example, a threshold value for the amount of remaining sample fluid may be specified (e.g., by a user), and if the amount of remaining sample fluid is above the threshold value, it is determined that the specified exchange condition is met.

[0264] If processor 502 determines to set another filter (yes at step S28 ), the exemplary process may proceed to step S30 .

[0265] In step S30, the processor 502 can control the sample preparation system 1 to set a new filter (e.g., an unused filter) on the fluid path (e.g., in the first mechanism 2). For example, the processor 502 can generate a control signal and output the control signal to the filter processing device 27 to set the new filter in the first mechanism 2. After step S30, the exemplary process can return to step S12.

[0266] In the event that the processor determines not to set another filter (NO at step S28), then the exemplary process may end.

[0267] exist Figure 7 After or in parallel with the exemplary process shown in , the processor 502 may execute further (multiple) control processes to control the sample preparation system 1 to perform a purification process using a second mechanism 3a (e.g., a purification filter or a purification chromatographic column) to direct the fluid from the first mechanism 2 or the second mechanism 3 to the output cup 23 or the waste container to clean the sample preparation system 1, etc.

[0268] Experimental Results

[0269] Figure 8 A graph showing exemplary recorded online data obtained by running an exemplary sample preparation system controlled by a control process according to the present disclosure. Figure 8 In the example shown, the control device 50 uses the above-mentioned linear regression function (1) to perform a calculation for a specified time period of 10 seconds or a change in the volume of the fluid introduced into the fluid path of 2 ml. Figure 7 The exemplary process shown in FIG. Figure 8As shown, the filter stops processing culture at 650 mbar so that the limit of 1000 mbar is not reached before all the flushing liquid has flowed out. During the flushing period, the pressure difference ( Figure 8 Calculated_dP_Clear_Pressure) increased to 800 mbar without clogging the filter, and the flow rate ( Figure 8 The "Liquid Controller Pump Instantaneous Speed" in the Controller is maintained at the set point.

[0270] Fig. 9 The control process of the present invention predicts the blocked volume of the filter disposed on the fluid path of the sample preparation system, the volume pumped through the sample input valve 14, and the pressure difference across the filter, wherein the control device 50 uses the above-mentioned linear regression function (1) to perform a calculation at a specified time period of 10 seconds or when the volume of the fluid introduced into the fluid path changes by 2 ml. Figure 7 The maximum pressure difference is 1000 mbar. Fig. 9 In the example of , the difference between the predicted filter blockage volume and the current sample volume does not reach the specified threshold. In other words, the sample fluid has been used up and filter blockage has not occurred.

[0271] Fig.10 Another exemplary graph shows the predicted blocked volume of a filter disposed on a fluid path of a sample preparation system, the volume pumped through the input sample valve 14, and the pressure difference across the filter during the control process according to the present disclosure, wherein the control device 50 performs the linear regression function (1) described above. Figure 7 The maximum pressure difference is set to 1000 mbar. Fig.10 As shown, the difference between the actual input sample volume (expressed as "Volume pumped through the valve - Input") and the predicted filter plugging volume (expressed as Predicted_Plugging_Volume) tends to be smaller than the value at the beginning of the process. Therefore, the difference meets the specified threshold, and the sample preparation system is controlled to stop the sample fluid from flowing into the fluid path.

[0272] Fig.10 Further shown are two exemplary time periods t i -Δt to t i and t j -Δt to t j , these two time periods can be used in Figure 7 The regression function is determined in two different iterations of steps S14, S16 and S18 in the exemplary process of i -Δt to t i The pressure difference dP_t obtained within i -Δt,…,dP_t i and input volume Vin_t i-Δt,…,Vin_t i Can be used to determine the time point t i (or later than time point t i In addition, at time point t i (or at time t i The regression function determined at the time point after t can be used to calculate i The predicted blockage volume Vpb_t at i (or at time t i Similarly, for example, at time period t j -Δt to t j The pressure difference dP_t obtained within j -Δt, ..., dP_t j and input volume Vin_t j -Δt, ..., Vin_t j Can be used to determine at time point t j (or later than time point t j In addition, at time point t j (or later than time point t j The regression function determined at the time point t can be used to calculate j The predicted congestion amount Vpb_t at j (or later than time point t j The predicted congestion amount Vpb at the time point.

[0273] exist Fig.10 In the specific example, at time point t j Satisfy the specified stop condition (see Figure 7 Step S18). Therefore, at time point t j Afterwards, as the sample preparation system 1 is controlled to stop introducing the sample fluid into the fluid path, the pressure difference dP decreases. j Afterwards, since the control pump 9 releases the pressure difference, the input sample volume Vin also decreases slightly.

[0274] Variants

[0275] In the above exemplary embodiments, Figure 1 As shown, the sample preparation system 1 is controlled by a control device 50 .

[0276] In more exemplary embodiments, the control device 50 may control Figure 1The examples shown are sample preparation systems of different configurations. For example, the sample preparation system to be controlled may include a unit configured to perform clarification, but not a unit configured to perform purification.

[0277] In addition, in some exemplary embodiments, the sample preparation system to be controlled can be configured to perform other filtering operations in addition to the clarification process. In this case, the filter provided on the fluid path is not a clarification filter, but a filter for different filtering operations. For example, the sample preparation system can use filters (such as syringe filters, ultrafiltration filters, membrane filters, glass and quartz microfiber filters, syringeless filters, filter paper, hollow fiber filters, etc.) to perform any biological filtration process of biomolecules. In addition, for example, in the case of using a membrane filter, the filter can have different molecular weight cutoffs (MWCO) according to the purpose of the filtering operation, for example, 1kDa, 5kDa, 10kDa, 30kDa, 50kDa, 100kDa, 300kDa, 500kDa, 0.2μM.

[0278] Furthermore, in some exemplary embodiments, the sample preparation system to be controlled may include more than one serial arrangement of the first mechanism 2 and the second mechanism 3, in other words, more than one serial arrangement of units for different unit operations (e.g., clarification and purification). In particular, each of these serial arrangements may have the same characteristics as described above with respect to Figure 1 The same configuration as the serial arrangement of the sample preparation system 1 shown in FIG. If there is more than one serial arrangement in the sample preparation system, the serial arrangements may be arranged in parallel with each other, and each of the serial arrangements may have its own input cup and output cup to allow independent operation. In addition, the control device 50 may execute in parallel for each of the serial arrangements. Figure 7 An exemplary process is shown in .

[0279] In addition, in the above-mentioned exemplary embodiments, the sample preparation system to be controlled includes an input sample valve that allows or prevents a sample fluid from flowing into or out of a fluid path of the sample preparation system. In further exemplary embodiments, allowing or preventing a sample fluid from flowing into or out of a fluid path can be achieved by controlling only a pump on the fluid path without using a valve. In these further exemplary embodiments, a dedicated pump can be provided on each of the input fluid lines (e.g., for sample fluids and for different types of process fluids) without using a valve. The input fluid lines can be connected together downstream of the pump to form a single downstream fluid line, and a liquid sensor can be provided on the single downstream line. By activating the corresponding pump and deactivating the other pumps, the fluid to be pumped into the fluid path of the sample preparation system can be selected.

[0280] In addition, in the above exemplary embodiments, regression functions (1), (2) and / or (3) may be used. In further exemplary embodiments, an improved prediction model for predicting the amount of filter clogging may be used. For example, the prediction model may be improved by identifying repeated samples and enabling machine learning (e.g., neural networks, fuzzy logic) so that the prediction model is improved from sample to sample. The model may also be improved in its predictive ability by incorporating complex filter clogging formulas (e.g., cake adsorption models, etc.).

[0281] Furthermore, the predictive model can take into account all tubing lengths and dead volumes of the sample preparation system (including the dead volume of the clarification filter), which can allow the predictive model to be implemented with different systems and different filters.

[0282] Furthermore, in some exemplary embodiments, predicted filter blocking data may be generated across multiple platforms, filters, and scales, thereby enabling a fully automated scaling software platform for filtering.

[0283] Hardware Configuration

[0284] Fig.11 An example hardware configuration of a computer is shown, which can be used to implement at least part of the above system. For example, Figure 5 At least part of the control device 50 shown in FIG. Fig.11 The computer 7 shown in FIG. Fig.11 The computer 7 shown includes a central processing unit (CPU) 70, a system memory 72, a network interface 74, a hard disk drive (HDD) interface 76, an external disk drive interface 78, and an input / output (I / O) interface 80. These components of the computer are connected to each other through a system bus 82. The CPU 70 can perform arithmetic, logic, and / or control operations by accessing the system memory 72. The system memory 72 can store information and / or instructions for use in conjunction with the CPU 70. The system memory 72 can include volatile and non-volatile memory, such as a random access memory (RAM) 720 and a read-only memory (ROM) 722. A basic input / output system (BIOS) containing routines that help transfer information between elements within the computer 7 (e.g., during startup) can be stored in the ROM 722. The system bus 82 can be any of several bus structures, including a memory bus or memory controller, a peripheral bus, and a local bus using any of a variety of bus architectures.

[0285] The computer may include a network interface 74 for communicating with other computers and / or devices over a network.

[0286] In addition, the computer may include a hard disk drive (HDD) 84 for reading and writing to a hard disk (not shown), and an external disk drive 86 for reading or writing to a removable disk (not shown). The removable disk may be a disk of a disk drive or an optical disk of an optical disk drive, such as a CD ROM. The HDD 84 and the external disk drive 86 are connected to the system bus 82 via the HDD interface 76 and the external disk drive interface 78, respectively. The drive and its associated computer-readable medium provide non-volatile storage of computer-readable instructions, data structures, program modules and other data for the general-purpose computer. The data structure may include relevant data for implementing the example methods described herein and variations thereof. The relevant data may be organized in a database, such as a relational database or an object database.

[0287] Although the example environment described herein uses a hard disk (not shown) and an external disk (not shown), those skilled in the art will appreciate that other types of computer-readable media capable of storing data accessible by a computer, such as magnetic tape cassettes, flash memory cards, digital video disks, random access memory, read-only memory, etc., may also be used in the example operating environment.

[0288] A number of program modules may be stored in the hard disk, external disk, ROM 722 or RAM 720, including an operating system (not shown), one or more application programs 7202, other program modules (not shown) and program data 7204. The application program may include at least part of the functionality described above.

[0289] The computer 7 can be connected to an input device 92 (e.g., a mouse and / or a keyboard) and a display device 94 (e.g., a liquid crystal display) via corresponding I / O interfaces 80a and 80b and a system bus 82. In the case where the computer 7 is implemented as a tablet computer, for example, a touch panel that displays information and receives input can be connected to the computer 7 via corresponding I / O interfaces and the system bus 82. In addition, in some examples, although Fig.11 Not shown in the figure, the computer 7 may be further connected to a printer and / or an imaging device such as a camera via corresponding I / O interfaces and the system bus 82.

[0290] As use Fig.11 In addition or alternatively to the implementation of the computer 7 shown in , some or all of the functions of the exemplary embodiments described herein may be implemented as one or more hardware circuits. Examples of such hardware circuits may include, but are not limited to: large-scale integrated circuits (LSI), reduced instruction set circuits (RISC), application-specific integrated circuits (ASICs), and field programmable gate arrays (FPGAs).

[0291] Other aspects

[0292] The following clauses provide further aspects of the present disclosure:

[0293] Clause 1. A sample preparation system comprising:

[0294] a serial arrangement of a first mechanism configured to be connected to a first consumable and a second mechanism configured to be connected to a second consumable;

[0295] a first valve disposed between the first mechanism and the second mechanism;

[0296] a second valve disposed downstream of the second mechanism;

[0297] a first line providing fluid communication between the first mechanism and the first valve;

[0298] a second line providing fluid communication between the first valve and the second valve via the second mechanism;

[0299] a third line providing fluid communication directly between the first valve and the second valve, configured to bypass the second mechanism; and

[0300] A pump is configured to move fluid within the sample preparation system.

[0301] Clause 2. A sample preparation system according to clause 1,

[0302] Wherein, the first mechanism is configured to be connected to the first consumable and to support the first consumable.

[0303] Clause 3. A sample preparation system according to clause 1 or 2,

[0304] Wherein, the second mechanism is configured to be connected to the second consumable and to support the second consumable.

[0305] Clause 4. A sample preparation system according to any one of clauses 1 to 3,

[0306] Wherein, the first consumable is a first filter.

[0307] Clause 5. A sample preparation system according to any one of clauses 1 to 4,

[0308] Wherein, the second consumable is a second filter or a chromatographic column.

[0309] Clause 6. A sample preparation system according to any one of clauses 1 to 5,

[0310] Wherein, the first mechanism is a first filter support.

[0311] Clause 7. A sample preparation system according to any one of clauses 1 to 6, further comprising:

[0312] A consumables handling device is connected to the first mechanism, and is configured to provide a first consumable to the first mechanism and receive a first consumable from the first mechanism.

[0313] Clause 8. A sample preparation system according to clause 7,

[0314] further comprising an input line providing fluid communication between an input cup disposed upstream of the first mechanism and the first mechanism,

[0315] Wherein, the consumables processing device includes a connection mechanism, and the connection mechanism is configured to connect the input line and the first line to provide fluid communication between the input line and the first line.

[0316] Clause 9. A sample preparation system according to clause 8,

[0317] Also included is an input sample valve located on the input line downstream of the input cup and upstream of the first mechanism.

[0318] Clause 10. A sample preparation system according to any one of clauses 1 to 9,

[0319] It also includes a target substance detection sensor, which is arranged downstream of the second mechanism and is configured to detect a target substance.

[0320] Clause 11. A method for preparing a sample using a sample preparation system according to any one of clauses 1 to 10,

[0321] The method comprises at least one of the following steps:

[0322] (i) clarifying the sample by passing the sample through a first consumable connected to a first mechanism to provide a clarified sample, wherein the first consumable is a clarification filter, and

[0323] (ii) purifying the sample by passing the sample through a second consumable connected to a second mechanism to provide a purified sample, wherein the second consumable is a purification filter or a purification chromatography column.

[0324] Clause 12. A method for preparing a sample according to clause 11,

[0325] Wherein, the method comprises steps (i) and (ii), and step (i) is performed before step (ii), wherein the clarified sample immediately flows from the clarification filter into the purification filter or the purification chromatographic column.

[0326] Clause 13. A method for preparing a sample according to clause 12,

[0327] The method further comprises the following steps performed in the following order between step (i) and step (ii):

[0328] (a) ejecting the clarification filter,

[0329] (b) providing a flow path within the first mechanism, the flow path connecting a line upstream of the first mechanism and the first line of the sample preparation system, and

[0330] (c) removing sample from a line upstream of the first mechanism by directing the sample through the flow path, the first line, and the third line of the sample preparation system.

[0331] Clause 14. A method for preparing a sample according to any one of clauses 11 to 13,

[0332] wherein the sample is a cell culture containing protein,

[0333] The clarification filter is a cell culture clarification filter, and

[0334] The purification filter is a protein purification filter or a protein purification chromatography column.

[0335] Clause 15. A method for preparing a sample according to any one of clauses 11 to 14,

[0336] Wherein, in step (i), the clarifying filter is automatically ejected from the first mechanism and automatically replaced by a new clarifying filter.

Claims

1. A computer-implemented method for controlling a sample preparation system (1) for preparing a chemical sample, a pharmaceutical sample and / or a biotechnological sample, the sample preparation system (1) comprising a fluid path and at least one consumable (2a) such as a filter arranged on the fluid path, the method comprising: controlling the sample preparation system (1) so that a sample fluid including a target substance flows through the at least one consumable (2a) in the fluid path, wherein the sample fluid is allowed to sequentially pass through an upstream point in the fluid path, the at least one consumable (2a), and a downstream point in the fluid path; Obtain (S14) system information indicating at least the following: an amount of the sample fluid that has been introduced into the fluid path; the upstream pressure at the upstream point; and a downstream pressure at the downstream point; Use relative to the current time point (t current ), determining (S16) a regression function, wherein the regression function is determined by assuming the following conditions: At different time points (t i -Δt,…,t i ), a pressure difference (dP_t) across the at least one consumable (2a) obtained based on the upstream pressure and the downstream pressure i -Δt,…,dP_t i ) is the value of the dependent variable (y) of the regression function, and At different time points (t i -Δt,......,t i ) obtained by introducing the sample fluid into the fluid path (Vin_t i -Δt, ..., Vin_t i ) is the value of the independent variable (x) of the regression function; Determine (S18) whether a first specified condition is satisfied, wherein when the value indicating the predicted congestion amount (Vpb) is equal to the value at the current time point (t current ) has been introduced into the fluid path (Vin_t current ), determining that the first specified condition is satisfied when the value of the dependent variable (y) is the specified maximum pressure difference, wherein the predicted blockage amount (Vpb) is the value of the independent variable (x) of the regression function; When the first specified condition is satisfied, controlling (S20) the sample preparation system (1) to stop introducing the sample fluid into the fluid path; If the first specified condition is not met, controlling the sample preparation system (1) to continue introducing the sample fluid into the fluid path, and The steps of obtaining (S14) system information, determining (S16) a regression function, and determining (S18) whether the first specified condition is satisfied are repeated.

2. The method according to claim 1, further comprising: In the event that the first specified condition is met, the sample preparation system (1) is further controlled so that a flushing liquid flows through the at least one consumable (2a) within the fluid path.

3. The method according to claim 1 or 2, further comprising: In the event that the first specified condition is met, the sample preparation system (1) is further controlled so that air flows through the at least one consumable (2a) within the fluid path.

4. The method according to any one of the preceding claims, further comprising: In the event that the first specified condition is met, the sample preparation system (1) is further controlled to remove the at least one consumable (2a) from the fluid path.

5. The method according to claim 4, further comprising: After controlling the sample preparation system (1) to remove the at least one consumable (2a) from the fluid path, controlling the sample preparation system (1) to provide a new consumable (2a) on the fluid path.

6. The method according to claim 5, wherein: When a second specified condition is met, controlling the sample preparation system (1) to provide new consumables on the fluid path; as well as Therein, the second specified condition can include a condition regarding the amount of remaining sample fluid to be processed by the sample preparation system (1).

7. The method according to claim 5 or 6, wherein: The at least one consumable (2a) is a filter; The sample preparation system (1) further comprises a filter processing device (27), wherein the filter processing device (27) is configured as follows: receiving the at least one consumable (2a) disposed on the fluid path; and providing the at least one consumable (2a) on the fluid path; Wherein, controlling the sample preparation system (1) to remove the at least one consumable (2a) from the fluid path comprises: outputting a control signal to the filter processing device (27) to remove the at least one consumable (2a) from the fluid path by receiving the at least one consumable (2a); and Wherein, controlling the sample preparation system (1) to provide new consumables (2a) on the fluid path includes: outputting a control signal to the filter processing device (27) to provide new consumables (2a) on the fluid path.

8. A method according to any one of the preceding claims, wherein: The sample preparation system (1) further comprises a pump (9), wherein the pump (9) is configured to move the fluid within the fluid path; Wherein, controlling the sample preparation system (1) so that the sample fluid flows through the at least one consumable (2a) in the fluid path comprises: outputting a control signal to the pump (9) so that the sample fluid in the fluid path moves toward the at least one consumable (2a); and Wherein, controlling the sample preparation system (1) to stop introducing the sample fluid into the fluid path comprises: outputting a control signal to the pump (9) to stop moving the sample fluid in the fluid path.

9. A method according to any one of the preceding claims, wherein: The sample preparation system (1) further comprises a valve (14), wherein the valve (14) is configured to switch between at least the following states: an open state, wherein the sample fluid is allowed to flow within the fluid path towards the at least one consumable (2a); or a closed state, wherein the sample fluid is prevented from flowing within the fluid path toward the at least one consumable (2a); as well as Wherein, controlling the sample preparation system (1) so that the sample fluid flows through the at least one consumable (2a) in the fluid path comprises: outputting a control signal to the valve (14) to set the valve (14) to the open state; and Wherein, controlling the sample preparation system (1) to stop introducing the sample fluid into the fluid path comprises: outputting a control signal to the valve (14) to set the valve (14) to the closed state.

10. A method according to any one of the preceding claims, wherein: Determining the regression function includes: obtaining one or more values ​​of one or more parameters associated with the sample fluid and / or the sample preparation system (1); generating, for each of the one or more parameters, an equation to determine a blockage amount as a function of one of the one or more parameters, the blockage amount indicating an amount of the sample fluid that can cause the at least one consumable (2a) to block the flow of the sample fluid when the sample fluid is introduced into the at least one consumable (2a); For each of the one or more parameters, a coefficient is determined that indicates a ratio between: At the current time point (t current ) the amount of the sample fluid that has been introduced into the fluid path (Vin_t current ) or the total amount of the sample fluid to be introduced into the fluid path, and The amount of blockage obtained using the generated equation; and determining the regression function using the coefficients determined for each of the one or more parameters; and The one or more parameters may include one or more of the following: a cell density of the sample fluid; turbidity of the sample fluid; a particle size distribution of the sample fluid; The optical density of the sample fluid; a filter resistance index, wherein the at least one consumable is a filter; A filtration surface area, wherein the at least one consumable is a filter.

11. The method according to claim 10, wherein: Determining the regression function using the coefficients determined for each of the one or more parameters includes: determining a sensitivity factor using the coefficients determined for each of the one or more parameters; and Based on the sensitivity factor, one type of regression function is selected from a plurality of types of regression functions to be used as the regression function.

12. A method according to any one of the preceding claims, wherein: The sample preparation system (1) is used to prepare a sample, wherein the sample is a cell culture including a protein; as well as Wherein, the sample fluid is the cell culture, and the protein included in the cell culture is the target substance.

13. A computer program product comprising computer readable instructions which, when loaded and executed on a suitable system, cause the system to perform a method according to any one of the preceding claims.

14. A control device (50), comprising: A processor (502) configured to execute the method according to any one of claims 1 to 12; as well as A storage medium (504) is in communication with the processor.

15. A system comprising: A sample preparation system (1), comprising: Fluid paths, and at least one consumable (2a), such as a filter, disposed on the fluid path; and A control device (50) according to claim 14.

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