Method for operating a chromatography device

Abstract

The present invention relates to a method for purifying a chromatographic column comprising: I ) group, exit port (P O ) group, column import (CP I ) group, and column out port (CP O 1. A method for operating a chromatography device (1) in a bioprocessing facility (2) having a valve cassette (13) having a port (CP I , C.P. O ) communicates with an assigned internal liquid line (14), and the valve switching cassette (13) includes a liquid pumping device (15) assigned to the valve switching cassette (13) and at least one switchable valve unit (n x,y ) and an electronic process controller (16) for controlling the liquid pumping device (15) to selectively interconnect the internal liquid lines (14) to carry out the chromatographic process. x,y A first liquid stream (17) of concentrated buffer is introduced into a first inlet port (P I ) into the first internal liquid line (14); a second liquid stream of diluent (18) is introduced into the second inlet port (P I ) into the second internal liquid line (14) via the valve unit (n) so as to combine the first liquid stream (17) and the second liquid stream (18) at a combining position (20) of the valve switching cassette (13) to create a third liquid stream (19) in the dilution process. x,y It is proposed that an array of ) be switched.

Description

[Technical field]

[0001] The invention relates to a method for operating a chromatography device of a bioprocessing installation according to the general part of claim 1, a chromatography device for performing the method according to claim 17, an electronic process control device for a chromatography device according to claim 18, a computer program product for the electronic process control device according to claim 20 and a computer-readable storage medium according to claim 21 on which the computer program product is stored. [Background technology]

[0002] The expression "bioprocess" currently refers to any kind of biotechnological process, in particular a biopharmaceutical process. The operation of a chromatography apparatus having a number of chromatography columns connected to a valved cassette, preferably for carrying out a multicolumn simulated moving bed (SMB) chromatography process, can be part of such a bioprocess.

[0003] The method in question may be applied in various fields of biotechnology. High cost efficiency and increased flexibility in this field have been driven by the growing demand for biopharmaceuticals. Cost efficiency is related not only to the cost of materials but also to the cost of production, which depends among other things on the manufacturing floor space required. Flexibility should be understood in a broad sense, with reference to the operating scale of the bioprocessing facility, as well as the operating mode itself, such as flexibility with respect to the type and volume of buffers used. In commercial manufacturing, floor space is generally limited and expensive. However, chromatography processes require large amounts of buffers, which is especially true for SMB chromatography processes, since they involve the control of a large number of chromatography columns and process cycles. Therefore, it is particularly important to limit the size and number of manufacturing vessels, such as buffer vessels or buffer preparation systems, for bioprocessing at the manufacturing site, especially for SMB chromatography processes.

[0004] In downstream processes, it is the capture step that limits the throughput of the facility, since affinity resins are often not used to their full binding capacity to avoid the breakthrough of expensive bioproducts. In addition, affinity resins are themselves expensive products. Therefore, there is a strong need to optimize the utilization of capture resins, which is why SMB chromatography has become the subject of increasing interest. This interest is based on the fact that SMB chromatography offers lower production costs by requiring less chromatography column volume, less chromatographic separation medium (resin as "stationary phase"), using less energy, and requiring much fewer manual steps, thus reducing the burden on the user. Alternatively, SMB chromatography offers a higher throughput for a given amount of resin compared to other chromatography methods.

[0005] At industrial scale, SMB chromatography processes are operated continuously, which requires less resin and buffer per chromatography column compared to batch chromatography, although continuous operation may increase the overall buffer volume required. Finally, at industrial scale, SMB chromatography is used to improve the economics of bioprocessing. The method in question relies on the use of small amounts of concentrated buffer that are combined and therefore diluted on the skid without the need for a separate in-line combining system.

[0006] The terms "confluence" and "dilution" as used herein refer to the process of reducing (diluting) the concentration of a solute in a solution, preferably a concentrated buffer, by mixing (confluence) the solution with a solvent, usually water.

[0007] A known method for operating a chromatography process, particularly a multi-column SMB chromatography process (WO2015117884) comprises a first and at least a second chromatography column, a plurality of buffer vessels, and an additional in-line merging system having an inlet and an outlet. However, the additional in-line merging system requires additional manufacturing floor space, resulting in increased material costs and increased structural complexity, as well as increased maintenance costs.

[0008] Another known method (EP 1 775 001 A1), which is the starting point of the present invention, relies on a valve changer cassette for operating a chromatography process, in particular a multi-column SMB chromatography process, having ports and liquid lines grouped together in a compact manifold. Using these ports, it is possible to introduce multiple liquid streams into the valve changer cassette, which are then guided through the valve changer cassette via said liquid lines. The valve changer cassette comprises an array of switchable valve units for selectively interconnecting a first set of internal liquid lines with a second set of internal liquid lines via transfer lines. A large number of conduits are machined into the manifold to create these first and second sets of internal liquid lines, arranged in rows and columns. With the known valve changer cassette, the first and second sets of internal liquid lines can be selectively interconnected in a very flexible manner. However, the known valve changer cassette has limited efficiency in terms of manufacturing costs as well as use of manufacturing floor space. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2015117884 Brochure [Patent Document 2] European Patent Publication No. 1775001 Summary of the Invention [Problem to be solved by the invention]

[0010] It is therefore an object of the present invention to provide a method of operating a chromatography process that increases cost efficiency by reducing the manufacturing floor space required with as little labor as possible. [Means for solving the problem]

[0011] The above problem is solved by a method for operating a chromatography process according to the general part of claim 1 having the features of the characterizing part of claim 1.

[0012] The general concept underlying the present invention is based on the finding that the required manufacturing floor space, as well as the required buffer volume, can be reduced by mixing a small amount of concentrated buffer with a diluent in a valve switching cassette (in-line). This creates a diluted working buffer that can be immediately used in current chromatography processes, especially SMB chromatography processes, without the need for multiple large-volume buffer containers. Therefore, in order to reduce the required manufacturing floor space of bioprocesses, especially multi-column SMB chromatography processes, it is proposed to use a valve switching cassette for selectively interconnecting components of a bioprocess on the one hand, and for in-line merging on a skid on the other hand, without the need for a separate in-line merging system.

[0013] In detail, it is proposed that a first liquid stream of concentrated buffer solution is introduced into a first internal liquid line via a first inlet port, a second liquid stream of diluent is introduced into a second internal liquid line via a second inlet port, and in the dilution process, the array of valve units is switched to create a third liquid stream by merging the first and second liquid streams at a merging position of the valve switching cassette.

[0014] As mentioned above, the third liquid stream is located at least partially within the valve switching cassette, and preferably also external to the valve switching cassette.

[0015] The term "buffer" refers to any aqueous or non-aqueous solution used in a chromatographic step of a chromatographic process, in particular equilibration, loading, washing, elution, regeneration, and / or storage buffers. These buffers may be of the same or different composition.

[0016] The term "diluent" refers to any aqueous or non-aqueous solvent used as the main component in the preparation of chromatography buffers, such as water, particularly demineralized water, sterile filtered water, and / or deionized water.

[0017] Claims 2 and 3 are directed to preferred embodiments relating to selective and individual control of the switchable valve units and the pumps of the liquid pumping device by an electronic process control device. These measures are particularly advantageous since they solve the above-mentioned problem of achieving a desired target dilution ratio in the third liquid stream. This is of particular interest when using at least one chromatographic column, since it ensures that only a suitably diluted buffer with the desired predetermined properties is applied to the chromatographic column.

[0018] The preferred embodiment according to claims 4 and 5 refers to the presence of a first and a second set of internal liquid lines arranged in two planes of the valve switching cassette. The valve units are arranged to selectively interconnect the internal liquid lines of the first set with the internal liquid lines of the second set. This is achieved by fluid communication, in particular communication via transfer lines. This selective interconnection by the valve units offers great flexibility in terms of the selection of the respective potential flow paths.

[0019] Claim 6 defines a particularly preferred embodiment regarding the flow paths of the liquid streams. The first and second liquid streams each go to separate internal liquid lines before both liquid streams are introduced into one and the same internal liquid line by corresponding valve units, thereby providing a junction point. This is particularly advantageous as it provides a junction point internal to the valve switching cassette without the need for a separate external junction device.

[0020] A preferred embodiment according to claim 7 refers to the presence of an internal stream through one or more of the internal liquid lines and an external stream through one or more of the external liquid lines outside the valve switching cassette. This is particularly interesting as it achieves in-line merging without the need for a separate in-line merging device.

[0021] Claims 8 to 10 are directed to preferred embodiments regarding the required length of the third liquid stream, which is derived from the dilution model. The dilution model is particularly interesting since it serves as a rule system for deriving the minimum merging length and / or minimum merging time required to determine the length and / or diameter of the respective external liquid line. For this purpose, the dilution model takes into account, among others, chromatographic device parameters and rheological parameters. Compliance with these measures ensures a stable realization of the target dilution ratio at the end of the third liquid stream and ensures that only properly diluted buffer is directed onto at least one chromatographic column.

[0022] A preferred embodiment according to claim 11 refers to a human machine interface for inputting a target dilution ratio and / or outputting a minimum junction length. This provides an additional level of control and information to the user, since the user can freely input a target dilution ratio and / or receive advice regarding the required minimum junction length required to estimate the required length of one or more external liquid lines to achieve the target dilution ratio.

[0023] Claim 12 specifies that the chromatography process is preferably a multi-column chromatography (MCC) process, which creates an in-line merger that does not require a separate in-line merger device for multi-column SMB chromatography, which employs multiple chromatography columns and a complex system of respective valves.

[0024] A preferred embodiment according to claim 13 refers to a sensor device for providing sensor values. This provides the advantage that the actual dilution ratio of the third liquid stream can be verified at the measurement location by comparing the measured actual dilution ratio with a target dilution ratio. This is particularly advantageous since the actual dilution ratio is represented by these sensor values ​​and can be adjusted in case of emergency events such as pump failure. This also provides the advantage that the user can determine, prior to the bioprocess, the required minimum merging length or minimum merging time required to estimate the required length for at least one external liquid line.

[0025] Claims 14 to 16 provide a particularly preferred embodiment for bypassing at least one chromatographic column. After the sensor device detects a stable value of the dilution ratio, the electronic process control device switches the at least one chromatographic column from being bypassed to the external liquid line leading to the chromatographic column. This provides the great advantage that the not yet properly diluted buffer bypasses the at least one chromatographic column, thus increasing the separation performance and product recovery as well as the lifetime of all involved chromatographic columns.

[0026] According to the second independent teaching according to claim 17, a chromatography device for carrying out the proposed method is claimed as such. All explanations given with respect to the first teaching are fully applicable to this second teaching.

[0027] The third independent teaching according to claim 18 is directed to an electronic process control device. The electronic process control device is designed to execute the proposed method. According to claim 19, the electronic process control device comprises a data processing system for executing the proposed method. All explanations given with respect to the first and second teachings are fully applicable to this third teaching.

[0028] According to the fourth teaching according to claim 20 of equal importance, a computer program product for the proposed electronic process control device is claimed as such. The computer program product is configured to execute the proposed method. All explanations given with respect to the first, second and third teachings are fully applicable to this fourth teaching.

[0029] According to the fifth teaching according to claim 21, which is also of equal importance, a computer-readable storage medium having a computer program stored thereon is claimed as such. All explanations given with regard to the first to fourth teachings are fully applicable to this fifth teaching.

[0030] In the following, embodiments of the invention will be described with reference to the drawings, in which: [Brief description of the drawings]

[0031] [Figure 1] FIG. 1 shows a proposed chromatographic device with a valve switching cassette, in which the proposed method can be carried out. [Diagram 2] FIG. 2 illustrates a pump ratio and / or flow control according to FIG. 1. [Diagram 3] 2 shows the valve switching cassette according to FIG. 1 in a first exemplary mode of operation using a bypass line; [Figure 4] 2 shows the valve switching cassette according to FIG. 1 in a second exemplary mode of operation using a column line; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0032] The proposed method for operating a chromatography device 1 of a bioprocessing installation 2 for carrying out a chromatography process is preferably assigned to downstream processing.

[0033] The expression "chromatographic process" currently refers to any kind of biochemical purification process, in particular a biopharmaceutical purification process, employing at least one chromatographic column 3 to 10 for the separation of chemical compounds. The operation of a chromatographic apparatus 1 having multiple chromatographic columns 3 to 10 to perform a multi-column SMB process represents such a chromatographic process.

[0034] The term "downstream processing" includes all steps relating to the recovery and purification of biosynthetic products, particularly biopharmaceuticals, from natural sources such as animal or plant tissues or cell broths, including recycling of salvageable components and proper treatment and disposal of waste products. Such steps are preferably liquid / solid separation, capture, purification, and / or polishing steps.

[0035] Generally, cell culture is used for the production of biopharmaceuticals, especially proteins such as human insulin, growth factors, hormones, vaccines, or antibodies, antibody derivatives, or viral vectors such as lentiviral vectors and adeno-associated viral vectors. The products may also be non-biopharmaceuticals, such as enzymes for food processing, laundry detergent enzymes, biodegradable plastics, or biofuels. The focus of the present invention is on biopharmaceuticals, such as antibodies, viral vectors, and nucleic acids such as DNA and RNA.

[0036] As shown in Figures 1 to 4, the proposed method for operating a chromatography apparatus 1 of a bioprocessing facility 2 to perform a chromatography process employs a number of chromatography columns 3 to 10. The proposed method preferably employs at least four, more preferably at least six, here preferably eight, chromatography columns, each of which has a column inlet 11 and a column outlet 12. The chromatography apparatus also comprises a valve switching cassette 13. It is particularly noteworthy that the proposed method is easily adaptable to employ more than nine chromatography columns 3 to 10 simultaneously, due to the complex valve manifold provided by the valve switching cassette 13. According to a particularly preferred embodiment (not shown), the valve switching cassette 13 can employ up to sixteen chromatography columns 3 to 10 simultaneously.

[0037] A chromatography apparatus 1 having a number of chromatography columns 3 to 10 is operated in a chromatography cycle that includes chromatography steps such as equilibration, loading, washing, elution, regeneration, and storage steps.

[0038] The equilibration step represents the step where the system enters into equilibrium. In the chromatography apparatus 1, this refers to filling each chromatography column 3 to 10 with the respective buffer used in the subsequent bioproduct purification until its entire volume is occupied by the respective buffer.

[0039] The loading step refers to loading each of the chromatography columns 3 to 10 with product-containing supernatant in order to bind the product to at least one of the chromatography columns 3 to 10 and initiate the purification of the bioproduct.

[0040] The washing step refers to washing each of the chromatographic columns 3 to 10 with a buffer solution. This washing step typically serves to flush each of the chromatographic columns 3 to 10 to remove non-specifically bound compounds and separate them from the target product.

[0041] The elution step represents the extraction of one material from another, for example by elution with a solvent such as water, buffer, imidazole, etc. Here, this refers to the extraction of the bioproducts from each of the chromatographic columns 3 to 10 using aqueous solutions having pH and / or ionic gradients representing different salt concentrations and conductivities.

[0042] The regeneration step refers to a step of recovering separation material in order to restore the separation performance of at least one chromatographic column 3 to 10. In this particular context, it refers to the re-equilibration and / or washing of each chromatographic column 3 to 10, for example with a sodium hydroxide (NaOH) solution.

[0043] The storage step refers to flushing at least one of the chromatography columns 3 to 10 with, for example, an ethanol solution that keeps the separation material sterile. In this particular context, it refers to storage of the separation material of each of the chromatography columns 3 to 10, preferably in a 10% ethanol (EtOH) solution.

[0044] According to FIG. 1, the valve switching cassette 13 includes an inlet port P I Group of outlet port P O Group of columns, import CP I group, and column out port CP O Each port has a group of CP I , C.P. O communicate with assigned internal liquid lines 14 within the valve switching cassette 13.

[0045] The term “internal liquid lines” is used herein to refer to the entirety of all internal liquid lines 14 within the valve switching cassette 13 .

[0046] The term “port” refers to an interface for interconnecting components of the bioprocessing equipment 2 to their respective internal fluid lines 14 .

[0047] The expression "line" refers to any longitudinal volume capable of holding and directing a liquid between two points. A line in this sense may also include expandable and collapsible conduit structures.

[0048] The term “column in port” refers to an interface of the valve switching cassette 13 for interconnecting components of the bioprocessing equipment 2 to generate an output flow from the valve switching cassette 13 into at least one chromatography column 3 to 10.

[0049] The term “column out port” refers to an interface of the valve switching cassette 13 for interconnecting components of the bioprocessing equipment 2 to generate an output flow from the chromatography columns 3 to 10 into the valve switching cassette 13.

[0050] As shown in FIG. 1, the selectively interconnected components are preferably a chromatography device 1 as described above having a plurality of chromatography columns 3 to 10 for performing multi-column SMB chromatography, where an inlet port P I The groups are used as inlets for feed or buffers, etc. These are the respective column import CP I , selectively guided to the respective column inlet 11, passing through the respective chromatography column 3 to 10, leaving the chromatography column 3 to 10 via the column outlet 12, and exiting the column out port CP O re-enters the valve switching cassette 13 via

[0051] As shown in FIG. 1, the valve switching cassette 13 includes switchable valve units nx,y which are selectively interconnected with internal liquid lines 14 for carrying out a chromatographic process, particularly a multi-column SMB process.

[0052] The term "switchable" refers to the ability of a valve unit n to switch from an "open" state to a "closed" state or from a "closed" state to an "open" state. x,y In Fig. 3 and Fig. 4, the valve opening unit n x,y is indicated by a solid circle, and the closing valve unit n x,y are indicated by open circles.

[0053] The term "interconnect" should be understood to mean a fluid connection.

[0054] The chromatography device 1 also comprises a liquid pumping device 15 assigned to a valve switching cassette 13 and at least one switchable valve unit n x,y and an electronic process controller 16 for controlling the liquid pumping device 15.

[0055] In the present invention, a first liquid stream 17 of concentrated buffer solution is introduced into a first inlet port P I and a second liquid stream 18 of diluent is introduced into the first internal liquid line 14 via a second inlet port P. I In the dilution process, it is particularly essential that the liquid is introduced into the second internal liquid line 14 via the valve unit n x,y The array is switched to create a third liquid stream 19 by combining the first liquid stream 17 and the second liquid stream 18 at a combination location 20 in the valve switching cassette 13 .

[0056] As shown in Figs. 1 and 2, preferably here switchable valve units n x,y and liquid pumping device 15 is controlled by electronic process controller 16 such that a predetermined target dilution ratio of third liquid stream 19 is achieved, preferably at least at the end of third liquid stream 19.

[0057] Preferably here, as seen in Figures 1 and 2, the liquid pumping device 15 comprises a first pump 21 driving the first liquid stream 17 and a second pump 22 driving the second liquid stream 18. Both pumps 21, 22 are selectively controlled by the electronic process controller 16 to achieve a target dilution ratio in the third liquid stream 19. In general, the dilution ratio, and in particular the target dilution ratio, is the result of the pump speeds of the different pumps driving the liquids to merge. The individual flow rates of the first liquid stream 17 and the second liquid stream 18, including their ratio, therefore define the merge ratio in the third liquid stream 19.

[0058] The third liquid stream 19 comprises predetermined properties, preferably at the end point of the third liquid stream 19. These predetermined properties may be a desired final salt concentration (and therefore conductivity), a desired final pH, temperature, flow rate, etc. The end point of the third liquid stream 19 is defined either by the respective column inlet 11 (during the run process) or by the position of the sensor device 27 (verification process below).

[0059] Preferably, according to Figs. 1, 3 and 4, a first set of internal liquid lines L F and a second set of internal liquid lines L S are arranged in two preferably parallel planes of the valve switching cassette 13. x,y The first set of internal liquid lines L F and a second set of internal liquid lines L S are arranged to selectively interconnect

[0060] The term "selectively interconnect" refers to the first set of internal liquid lines L F one or more of the second set of internal liquid lines L S This means that the 10-bit 110-bit 120-bit 130-bit 140-bit 150-bit 160-bit 170-bit 180-bit 200-bit 210-bit 220-bit 230-bit 240-bit 250-bit 260-bit 270-bit 280-bit 290-bit 300-bit 310

[0061] Preferably, the valve unit n x,y These internal liquid lines L F , L S A first set of internal liquid lines L are connected to the first set of internal liquid lines L, preferably via transfer lines, so as to selectively interconnect the F and a second set of internal liquid lines L S These transfer lines are connected to the internal liquid line L F The first set of internal liquid lines L S are disposed orthogonal to the two preferably parallel planes of the second set.

[0062] The first liquid stream 17 and the second liquid stream 18 are preferably fed through separate first set of internal liquid lines L. F The first liquid stream 17 and the second liquid stream 18 then flow through a second set of identical internal liquid lines L S The two liquid streams 17, 18 are preferably introduced into the same second set of internal liquid lines L S This is because the second set of internal liquid lines L S provides a joining position 20, the corresponding valve unit n x,y The junction 20 defines the start of the third liquid stream 19.

[0063] Thus, according to FIGS. 3 and 4, the junction location 20 is internal to the valve switching cassette 13 and is connected to any second set of internal liquid lines L S Preferably, the junction location 20 is located in the first and second sets of internal liquid lines L S 13, the first and second liquid streams 17, 18 are coupled to a first L F The first liquid stream 17 and the second liquid stream 18 are preferably connected to an inlet port P I and enters the valve switching cassette 13 via the outlet port P Oor the first liquid stream 17 and the second liquid stream 18 are preferably directed to an outlet port P O and enters the valve switching cassette 13 via the inlet port P I This means that the valving cassette 13 is fluidly controllable in both possible fluid flow directions.

[0064] Preferably here, as seen in Fig. 4, the third liquid stream 19 includes an internal stream 23 through one or more of the internal liquid lines 14 in the valve switching cassette 13, and an external stream 24 through one or more of the external liquid lines 25, preferably outside the valve switching cassette 13. For clarity, as derived from Fig. 3, the third liquid stream 19 is determined by the second set L in order to determine the required minimum merging length or minimum merging time required to determine the length and / or diameter of at least one external liquid line prior to the bioprocessing. S Alternatively, the internal stream 23 may include only the internal stream 23 passing through the bypass line 30.

[0065] Generally, the external liquid line 25 is connected to each column inlet CP I to the respective column inlets 11. Here, preferably, the external liquid lines 25 are dual purpose. The external streams 24 flow through one or more of the external liquid lines 25 outside the valve switching cassette 13 and additionally serve to generate a defined minimum merging length and / or merging time required to establish a desired target dilution ratio in the third liquid stream 19.

[0066] According to FIG. 4, at least one external liquid line 25 is preferably connected to the column in-port CP of the valve switching cassette 13. Iand the column inlet 11 of at least one of the chromatography columns 3 to 10. During the running process of at least one of the chromatography columns 3 to 10, an end of the third liquid stream 19 is defined at the column inlet 11 of the respective chromatography column 3 to 10. Ultimately, the stream length of the third liquid stream 19 is defined by its beginning at the junction location 20 and its preferred end at the column inlet 11 of the respective chromatography column 3 to 10.

[0067] The term "running process" potentially defines any chromatographic step in a chromatographic process in which a liquid stream is directed through at least one chromatographic column 3 to 10, such as an equilibration, loading, washing, elution, regeneration, and / or storage step.

[0068] Preferably herein, as seen in Figures 3 and 4, the stream length of the third liquid stream 19 is longer than the minimum merging length.

[0069] The terms "minimum merging length" and "minimum merging time" are used herein to refer to the minimum distance and minimum time, respectively, that third liquid stream 19 must travel to steadily achieve the target dilution ratio.

[0070] Preferably, this minimum merging length has been derived, preferably by the electronic process controller 16 or a user, from the dilution model 26. Additionally or alternatively, the stream length of the third liquid stream 19 is longer than a length corresponding to a minimum merging time and flow rate of the pump of the liquid pumping device 15.

[0071] Preferably, according to FIG. 4, a minimum merge length and / or a minimum merge time is adhered to to ensure stable realization of the target dilution ratio at the end of the third liquid stream 19 .

[0072] The term "stable" as used herein means that the actual dilution ratio does not deviate from the target dilution ratio by more than a predetermined value, preferably by less than 10%, more preferably by less than 5%, and even more preferably by less than 3%.

[0073] Preferably, the dilution model 26 represents the interdependence between the minimum junction length on the one hand and the pump flow rate and / or the ratio of the pump flow rate to the target dilution ratio on the other hand. Additionally or alternatively, the dilution model 26 represents the interdependence between the minimum junction time on the one hand and the pump flow rate and / or the ratio of the pump flow rate to the target dilution ratio on the other hand.

[0074] The dilution model 26 should be understood as a system of rules for deriving the minimum merging length and / or minimum merging time required to determine the length and / or diameter of each external liquid line 25. These lengths and / or diameters of each external liquid line 25 allow the stable realization of the target dilution ratio in the external stream 24. The minimum merging length and / or minimum merging time depend inter alia on the flow rates of the first liquid stream 17 and the second liquid stream 18 (additionally or alternatively on the resulting flow rate of the third liquid stream 19) and from the ratio of the flow rates of the first liquid stream 17 and the second liquid stream 18. These flow rates and the ratio of the flow rates in turn depend on and are from the ratio of the flow rates of the corresponding pumps 21, 22, respectively.

[0075] The dilution model 26 preferably relies on statistical modeling or machine learning algorithms to determine the minimum merger length and / or minimum merger time. The machine learning mechanism is preferably based on a supervised or unsupervised neural network, which is more preferably a neural convolutional network (CNN).

[0076] Additionally or alternatively, the minimum merge length and / or minimum merge time can be derived by a series of experiments, preferably performed by a user. In the course of such a series of experiments, the individual minimum merge lengths and / or minimum merge times can be empirically determined by testing the interactions between the individual target dilution ratios, on the one hand, and the individual flow rates of the pumps and / or the ratio of the flow rates of the pumps as a function of space and time, as well as the liquid viscosity, pressure, density, and temperature to be merged, on the other hand. Preferably, all derived minimum merge lengths and / or minimum merge times are preferably stored in a look-up table and / or a cloud service instance.

[0077] This allows the required minimum merging length and / or minimum merging time to be easily checked, preferably by the electronic process control device 16 and / or by a user. For this reason, particularly preferably, the chromatography device 1 is designed without a sensor 28 providing a sensor value 29 of the third liquid stream 19, as this makes additional verification of the respective minimum merging length and / or minimum merging time by the user unnecessary.

[0078] Thus, in the dilution model 26, the electronic process controller 16 preferably determines the distance and / or time required for the third liquid stream 19 to cover the distance between its start and end, preferably the distance between the junction position 20 and the column inlet 11 of at least one chromatography column 3 to 10.

[0079] Preferably, and by way of example only, with a summary of the required times and respective flow rates, the electronic process controller 16 calculates the required volume of the external liquid line 25 required to provide the minimum merge time required for stable realization of the target dilution ratio in the external stream 24.

[0080] Alternatively, a second set of internal liquid lines L SFrom a summary of the required distances, respective flow rates, and diameters of the external stream 24, the electronic process controller 16 preferably calculates the required length and required diameter of the external liquid line 25 required to provide the minimum junction length required for stable realization of the target dilution ratio in the external stream 24.

[0081] Preferably, the dilution model 26 can be exchanged between two different operational instances or even within the very same operational instance. Also, the dilution model 26 is highly adaptable to different bioprocessing setups resulting in changes in flow paths, dilution ratios, tubing lengths, tubing diameters, flow rates, flow rate ratios, pump flow rates, and pump flow rate ratios. This adaptability makes the proposed method very flexible.

[0082] Preferably, the electronic process controller 16 comprises a human machine interface for inputting the target dilution ratio. Preferably, the user can preset the target dilution ratio in the electronic process controller 16 to be measured in the third liquid stream 19. According to this preset target dilution ratio, the electronic process controller 16 adjusts the pump flow rates and / or the ratio of the pump flow rates. Thus, a stable realization of the target dilution ratio at the end of the third liquid stream 19 means that the actual target dilution ratio does not deviate from the target dilution ratio by more than a predefined value.

[0083] Additionally or alternatively, the electronic process control device comprises a human machine interface for outputting the minimum junction length, in particular the length of each external liquid line 25 of the third liquid stream 19. Preferably, the user can then adjust the length of each external liquid 25 line accordingly, more preferably by installing disposable tubing with an appropriate minimum junction length or by cutting the disposable tubing under sterile conditions according to the outputted minimum junction length. In case of an emergency event such as a pump failure, when using the outputted minimum junction length, the stable realization of the target dilution ratio can be verified by the user, as will be explained later.

[0084] As can be seen in Figures 1 to 4, the chromatography process is also preferably a multi-column chromatography (MCC) process, in particular a simulated moving bed chromatography (SMB) process. During the chromatography process, a liquid such as a feed solution or a buffer is introduced through an inlet port P I It is preferable that the ion exchange polymer is introduced into one of the following:

[0085] Preferably, as seen in Figures 2 and 3, the chromatographic apparatus 1 comprises a sensor device 27 having at least one sensor 28 providing sensor values ​​29. These sensor values ​​29 are transmitted to the electronic process control device 16. The sensor 28 preferably provides as sensor value 29 the conductivity of the third liquid stream 19, thus representing the actual dilution ratio of the third liquid stream 19 at the measurement location. In addition, these sensor values ​​29 may represent other properties of the third liquid stream 19, preferably properties such as pH, temperature, or optical density.

[0086] The sensor device 27 can be used not only to adjust the dilution ratio in case of an emergency event, but also to determine the necessary minimum merging length or minimum merging time before the bioprocess, which is necessary for a stable realization of the target dilution ratio in the third liquid stream 19. This allows the length and diameter of the respective necessary external liquid line 25 to be derived. Preferably, the sensor device 27, in particular the measurement location, is located at the end of a bypass line 30, which will be discussed later. In order to determine the necessary minimum merging length or minimum merging time before the bioprocess or in case of a validation process, the end of the third liquid stream 19 is defined in at least one sensor 28 of the sensor device 27.

[0087] As mentioned above, in case of an emergency event, the stable realization of the target dilution ratio at the end of the third liquid stream 19 can be verified by the user. Here, preferably, the sensor 28 can be used to verify the stable realization of the target dilution ratio of the third liquid stream 19. For the verification, the actual dilution ratio of the third liquid stream 19 represented by the sensor value 29 is compared with the target dilution ratio. The verification is preferably achieved when the actual dilution ratio measured by the at least one sensor 28 in the third liquid stream 19 corresponds to the target dilution ratio, preferably when the actual dilution ratio deviates from the target dilution ratio by less than 10%, more preferably less than 5%, even more preferably less than 3%.

[0088] For such a validation process, the terms "minimum junction length" and "minimum junction time" refer to the distance and time covered by the third liquid stream 19 to flow from the junction location 20 to at least one sensor 28 providing a sensor value 29, preferably the conductivity of the third liquid stream 19. Preferably, the sensor 28 is connected to an outlet port P, as can be seen in FIG. O Preferably, the outlet port P O The distance between the third liquid stream 19 and the sensor 28 is taken into account by the dilution model when verifying the minimum junction length and minimum junction time in a validation process or pre-calibration step to first determine the minimum junction length or minimum junction time of the third liquid stream 19 prior to the bioprocessing.

[0089] In the event of an emergency event, the actual dilution ratio measured by at least one sensor 28 in the third liquid stream 19 does not correspond to the target dilution ratio. In this case, the electronic process controller 16 preferably adjusts the pump dilutions and / or pump flow rates until the measured sensor value 29 corresponds to the target dilution ratio, and more preferably until the measured sensor value 29 deviates from the target dilution ratio by less than 10%, more preferably less than 5%, and even more preferably less than 3%.

[0090] Preferably, the chromatography apparatus includes a bypass line 30 configured to provide an internal liquid line 14 such that the liquid stream bypasses at least one chromatography column 3 to 10. During the priming process, the third liquid stream 19 is guided through the bypass line 30. Thereby, during the chromatography process, the third liquid stream 19 not containing the target dilution ratio is guided through the corresponding valve unit (n x,y ) to bypass at least one of the chromatography columns 3 to 10 via one of the internal liquid lines 14.

[0091] The term "bypass line" herein refers potentially to any internal liquid line 14 that serves to bypass at least one chromatography column 3 to 10.

[0092] The term “prime process” is used herein to refer to the process in which the internal fluid line 14 fills with fluid, allowing the pump to propel fluid within the valve switching cassette 13 .

[0093] In the following, with reference to Figs. 3 and 4, two exemplary operating modes of applying the proposed method are described.

[0094] In a first mode of operation, as seen in FIG. 3, and by way of example only, a first liquid stream 17, preferably a liquid stream of concentrated buffer, and a second liquid stream 18, preferably a liquid stream of sterile water, are fed to corresponding inlet ports P I , where the corresponding inlet ports P at positions 3 and 4 I Here, preferably, both liquid streams 17, 18 are introduced into the valve switching cassette 13 via an eighth internal liquid line L S and both liquid streams 17, 18 cross over in the valve switching cassette 13. Here, preferably, the resulting third liquid stream 19 enters a bypass line 30 to bypass at least one chromatography column 3 to 10 and is then discarded in waste.

[0095] Such an operating mode can be used, for example, in case of an emergency event such as a pump failure, to verify the stable realization of the target dilution ratio with the help of the sensor device 27 after the emergency event has been cleared. Alternatively, as mentioned above, it can be used to determine the minimum merger time required to realize the target dilution ratio in the third liquid stream 19 and / or to determine the minimum merger length of the external liquid line 25 prior to such a bioprocess.

[0096] After such an emergency has been eliminated, the electronic process control device 16 switches from the bypass line 30 to the column line 31 as soon as the sensor device 27 detects a stable value of the actual dilution ratio at the end of the bypass line 30. The stable value is here preferably detected by the electronic process control device 16.

[0097] Corresponding valve unit n x,y During switching, in the second mode of operation, as seen in FIG. 4, the third liquid stream 19 enters column line 31 and leads to at least one of the chromatographic columns 3 through 10 .

[0098] The term “column line” herein refers potentially to any internal liquid line 14 or external liquid line 25 that can connect the third liquid stream 19 to each of the chromatography columns 3 to 10 .

[0099] According to a second teaching, a chromatography device 1 for carrying out the proposed method is claimed as such. Preferably, the components of the chromatography device 1 that are at least necessary for the intended function, in particular including at least the valve switching cassette 13 and the liquid pumping device 15, form a structural entity. Here preferably, the structural entity is designed as a preassembled unit. See all the descriptions given previously.

[0100] According to another independent teaching, an electronic process control device 16 of a chromatography device 1 for carrying out the proposed method is claimed as such. Again, reference is made to all the descriptions given previously.

[0101] The electronic process control device 16 includes at least one switchable valve unit n x,y and a liquid pumping device 15 designed to carry out the proposed method by controlling the liquid pumping device 15.

[0102] The electronic process controller 16 may be implemented as a central unit controlling all or at least most of the components of the bioprocessing facility 2. The electronic process controller 16 may also be implemented in a distributed structure comprising several distributed units. Preferably, the electronic process controller 16 comprises at least one microprocessor that is individually adjustable and / or programmable and / or capable of executing software. All the descriptions given previously are fully applicable to this teaching.

[0103] Preferably, the electronic process control device 16 comprises a data processing system for carrying out the above described methods, preferably comprising a local data storage device and a local processor unit.

[0104] Finally, independent teachings are directed to a computer program product for the electronic process control device 16, and to a computer readable storage medium on which the computer program product is preferably stored in a non-volatile manner. All descriptions given above are fully applicable to these teachings.

Claims

1. 1. A method of operating a chromatography device (1) of a bioprocessing facility (2) to perform a chromatography process, comprising: The chromatography device (1) comprises: a plurality of chromatography columns (3-10), each having a column inlet (11) and a column outlet (12); a valve switching cassette (13); The valve switching cassette (13) has an inlet port (P Ｉ ) group, outlet port (P Ｏ ) group, column import (CP Ｉ ) group, and column out port (CP Ｏ ) group, Each port (CP Ｉ , C.P. Ｏ ) communicates with an assigned internal liquid line (14) in said valve switching cassette (13); The valve switching cassette (13) includes switchable valve units (n) that selectively interconnect the internal liquid lines (14) to perform the chromatography process. ｘ，ｙ ) an array of The chromatography device (1) comprises a liquid pumping device (15) assigned to the valve switching cassette (13) and at least one of the switchable valve units (n ｘ，ｙ ) and an electronic process control device (16) for controlling said liquid pumping device (15), A first liquid stream (17) of concentrated buffer solution is introduced into a first inlet port (P Ｉ ) into the first internal liquid line (14), A second liquid stream of diluent (18) is introduced into a second inlet port (P Ｉ ) into a second internal liquid line (14), The valve unit (n) is configured to combine the first liquid stream (17) and the second liquid stream (18) at a combining position (20) of the valve switching cassette (13) to create a third liquid stream (19) during a dilution process. ｘ，ｙ ) array is switched A method characterized by:

2. The switchable valve unit (n ｘ，ｙ 2. The method of claim 1, wherein the third liquid stream (19) is supplied with a second liquid pumping device (15) and the second liquid pumping device (15) are controlled by the electronic process control device (16) to achieve a predetermined target dilution ratio of the third liquid stream (19), preferably at least at the end of the third liquid stream (19).

3. 3. The method of claim 1 or 2, wherein the liquid pumping device (15) comprises a first pump (21) driving the first liquid stream (17) and a second pump (22) driving the second liquid stream (18), both pumps (21, 22) being selectively controlled by the electronic process controller (16) to achieve the target dilution ratio of the third liquid stream (19).

4. The first set of internal liquid lines (L Ｆ ) and the second set of internal liquid lines (L Ｓ ) are arranged in two preferably parallel planes of the valve switching cassette (13), and the valve units (n ｘ，ｙ ) is the first set (L Ｆ ) internal liquid lines and the second set (L Ｓ 3. The method of claim 1, wherein the internal liquid lines of the first and second liquid supply pipes are arranged to selectively interconnect the internal liquid lines of the first and second liquid supply pipes.

5. The valve unit (n ｘ，ｙ ) are these internal liquid lines (L Ｆ , L Ｓ ), preferably via a transfer line, to selectively interconnect the first set (L Ｆ ) internal liquid lines and the second set (L Ｓ 5. The method of claim 4, wherein the fluid lines are each in communication with an internal fluid line of the fluid line.

6. The first liquid stream (17) and the second liquid stream (18) are Ｆ ) each traveling in a separate internal liquid line, The first liquid stream (17) and the second liquid stream (18) are Ｓ ) to provide said joining position (20). ｘ，ｙ ) by switching the second set (L Ｓ ) into one and the same internal liquid line, The junction (20) defines the beginning of the third liquid stream (19).

5. The method according to claim 4.

7. the third liquid stream (19) includes an internal stream (23) passing through one or more internal liquid lines (14) within the valve changer cassette (13), and an external stream (24) passing through one or more external liquid lines (25) preferably external to the valve changer cassette (13); During the running process of at least one of the chromatography columns (3-10), the end of the third liquid stream (19) is defined at the column inlet (11) of each of the chromatography columns (3-10).

3. The method according to claim 1 or 2.

8. the third liquid stream (19) has a stream length greater than the minimum joining length; the minimum junction length is preferably derived from a dilution model (26) by the electronic process controller (16); and / or The stream length of the third liquid stream (19) is greater than the length corresponding to the minimum merging time and flow rate of the pump of the liquid pumping device (15).

3. The method according to claim 1 or 2.

9. 9. The method according to claim 8, characterized in that compliance with the minimum joining length and / or the minimum joining time ensures stable realization of the target dilution ratio at the end of the third liquid stream (19).

10. the dilution model (26) expresses the interdependence between the minimum junction length on the one hand and the flow rate of the pump and / or the ratio of the flow rate of the pump to the target dilution ratio on the other hand; and / or The dilution model (26) represents the interdependence between the minimum merging time on the one hand and the flow rate of the pump and / or the ratio of the flow rate of the pump to the target dilution ratio on the other hand.

9. The method according to claim 8.

11. 3. The method according to claim 1 or 2, characterized in that the electronic process control device (16) comprises a human-machine interface for inputting the target dilution ratio and / or outputting the minimum joining length, in particular the length of each external liquid line (25) of the third liquid stream (19).

12. The chromatography process is a multi-column chromatography (MCC) process, in particular a simulated moving bed chromatography (SMB) process, preferably during the chromatography process, a liquid such as a feed solution or a buffer is introduced into the inlet port (P Ｉ 3. The method according to claim 1, wherein the nucleotide sequence is introduced into one of the following:

13. the chromatography device (1) comprises a sensor device (27) having at least one sensor (28) providing a sensor value (29) that is transmitted to the electronic process control device (16), the sensor value (29) representing the actual dilution ratio of the third liquid stream (19) at a measurement location; Preferably, said sensor (28) provides the conductivity of said third liquid stream (19) as a sensor value (29).

3. The method according to claim 1 or 2.

14. 3. The method according to claim 1 or 2, characterized in that the chromatography apparatus (1) comprises a bypass line (30) configured to provide an internal liquid line (14) through which a liquid stream bypasses at least one chromatography column (3-10), and in that during a priming process, the third liquid stream (19) is guided through the bypass line (30).

15. 15. The method according to claim 14, characterized in that during the running process of one of the chromatography columns (3-10), the third liquid stream (19) is guided through the bypass line (30) and subsequently through a column line (31) leading to the respective chromatography column (3-10).

16. 16. The method of claim 15, wherein the electronic process control device (16) switches from the bypass line (30) to the column line (31) after the sensor device (27) detects a stable value of the actual dilution ratio at the end of the bypass line (30).

17. Chromatography device (1) for carrying out the method according to claim 1.

18. An electronic process control device (16) for a chromatography device (1) according to claim 17.

19. 19. The electronic process control device (16) of claim 18, wherein the electronic process control device (16) comprises a data processing system for carrying out the method of claim 1.

20. A computer program product for an electronic process control device (16) according to claim 18.

21. A computer-readable storage medium on which the computer program product according to claim 20 is stored, preferably non-volatilely.

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