Method for dynamic in-line mixing

Abstract

1. A method for dynamic in-line mixing of a pressurized medium (1) comprising a liquid and at least one other liquid or solid component in a bioprocess assembly (3), the method comprising: mixing the liquid and the at least one other liquid or solid component in a predetermined volumetric ratio at an opening (4) to form a composite liquid stream (5); the bioprocess assembly (3) comprises a pump assembly (8) with a first pump (9), the first pump (9) being disposed in a conduit (7) of a conduit assembly (6); the first pump (9) being configured as a non-positive displacement pump (10), in particular a centrifugal pump, configured for dynamic in-line mixing of the medium (1); the first pump (9) having a liquid inlet (9a) forming a suction side of the pump during normal operation and a liquid outlet (9b) forming a discharge side of the pump during normal operation; and directing the medium (1) through the non-positive displacement pump (10) for dynamic in-line mixing. It is proposed that the non-positive displacement pump (10) be run in a reverse flow direction compared to normal operation for dynamic in-line mixing.

Description

[Technical Field]

[0001] The present invention relates to a method for dynamic in-line mixing according to the preamble of claim 1, a bioprocess assembly for dynamic in-line mixing according to claim 13, an electronic process controller of the proposed bioprocess assembly according to claim 15, a non-positive displacement pump for realizing the proposed method according to claim 17, a computer program for the proposed electronic process controller according to claim 18, and a computer readable storage medium for storing a computer program according to claim 19. [Background technology]

[0002] The methods for dynamic in-line mixing referred to herein are used in the context of mixing processes, particularly for mixing buffers and / or media in bioprocesses, thereby avoiding inconvenient storage times in intermediate vessels.

[0003] The term "bioprocess" as used herein refers to biotechnological and biopharmaceutical processes related to the production of therapeutic bioproducts, such as vaccines, biologics, components for cell or gene therapy, or non-therapeutic bioproducts, such as pigments, biofuels or nutrients. Such bioproducts may be produced by living cells, the cells themselves may be bioproducts, or they may be the result of cell-free manufacturing based on naturally occurring or non-naturally occurring cellular components.

[0004] In the biopharmaceutical industry, single-use technologies are currently making great strides. At the same time, there is a trend towards process intensification, which leads to the increasingly frequent implementation of continuous or semi-continuous process steps. This also applies to mixing processes in which two or more liquids are mixed together or solids (often in powder form) are dissolved or suspended in a liquid. Today, for example, the mixing of buffers or media, especially for fermentation and purification steps, is often carried out in batch mode. Here, a vessel is filled with the base liquid to be mixed, and then the components to be incorporated (solids or liquids) are added and mixed by dynamic stirring for an extended period until the desired mixing or dissolution ratio is achieved, after which the finished solution can be further processed.

[0005] However, the use of such intermediate containers has the significant drawback that sensitive biological products, such as antibodies produced by bioprocesses, may be destroyed due to very long storage times. In this respect, it is important to keep the storage time of biological products as short as possible.

[0006] For these reasons, it is desirable to realize the mixing process "inline," i.e., within the pipelines of a pipeline assembly, rather than in an intermediate vessel. Therefore, static mixing elements for inline mixing are currently used (see U.S. Patent Application Publication No. 2017 / 216791). This is based on the fact that interesting disposable concepts for static mixing elements already exist today that can be easily attached directly to the pipelines of bioprocessing equipment. Such mixing elements are flow-through systems in which mixing is achieved by conveying liquids through a pipeline system that is equipped with special geometric attachments, particularly screws, paddles, and / or pipe wall attachments with a wide variety of geometries. These attachments serve to disrupt the flow and create vortices, thus mixing the components to be mixed during flow. Furthermore, these attachments can accommodate two liquid streams to be mixed or mix just one liquid stream.

[0007] However, all static mixers have the problem that, based on their functioning principle, the entire system is dependent on various parameters that are often difficult to control. As a result, the system can only provide predictable mixing results if input parameters, including at least the flow rates, viscosities, and temperatures of the streams to be mixed, are known and can be kept as constant as possible. In other words, even a slight change in the flow rate immediately changes the dynamic vortex inside the static mixer, and thus the mixing output. Therefore, such static mixers are used in industrial fields where the precision of the mixing process is not very important, such as when mixing two-component adhesives.

[0008] However, when the mixing process is one where precision in the mixing step is important, such as the addition and mixing of buffers or media for use in bioprocessing, dynamic in-line mixers are used in industry today, which are suited to the increasing demands on mixing output and predictability of the mixing process in industry.

[0009] The known device and method for dynamic in-line mixing (WO 2021 / 133487), which form the starting point of the present invention, serve to dynamically in-line mix two or more substances, allowing the participating substances, in particular chromatography buffers, to be produced at a desired concentration or the like. These substances are mixed at an opening in a conduit assembly to form a composite liquid stream. A first pump is arranged in the conduit assembly, which directs the composite liquid stream into the dynamic in-line mixing and drives the liquid flow.

[0010] As a result, known devices and known methods for dynamic in-line mixing can result in critical pressure buildup within the system, which can create problems with respect to the liquid flows to be mixed and the reproducibility of the mixing results, especially in tubing systems.

[0011] By "tube system" herein is meant the configuration of at least one conduit as a tube, preferably as a disposable tube, and liquid flow can be generated using at least one tube pump assigned to the tube extending through the tube. Summary of the Invention [Problem to be solved by the invention]

[0012] The problem underlying the present invention is to configure and improve known methods for dynamic in-line mixing in such a way that the mixing output and reproducibility of the bioprocess are improved while at the same time increasing user friendliness. [Means for solving the problem]

[0013] The above problem is solved in a method for dynamic in-line mixing according to the preamble of claim 1 by the features of the characterizing part of claim 1 .

[0014] The method involves the provision of a non-positive displacement pump, in particular a centrifugal pump, in a reverse installation direction, thereby allowing the liquid flow to flow through the pump in the opposite direction for dynamic in-line mixing.

[0015] The special design of the proposed method has the advantage that by running the non-positive displacement pump in a direction opposite to the normal direction, the pump's pumping power is at least reduced, and in particular eliminated, thereby avoiding critical pressure buildup downstream. Additionally, the rotating impeller can be operated as a mixer, allowing for variable mixing power to be regulated by controlling the impeller's speed, preferably with a synchronized magnetic pump drive, while simultaneously ensuring constant flow conditions (regulating the residence time in the pump / mixing chamber). If the pump were installed in the normal, i.e., normal, orientation, it would be impossible to achieve the desired speed (and thus the mixing power), which would increase the pumping power and thus cause a pressure buildup in the system. This is far from the purpose of the non-positive displacement pump, since it is no longer used for pumping but rather as a resistance unit for generating dynamic vortices in the liquid flow or suspension.

[0016] In particular, it is proposed that the non-positive displacement pump be run in a reverse flow direction compared to normal operation for dynamic in-line mixing.

[0017] The preferred configurations described in claims 2 to 4 relate to the use of a reverse mounting orientation for non-positive displacement pumps. These configurations allow for easy adjustment of the desired rotation speed of the rotating shaft and thus the desired mixing power, without increasing the pumping power, which could cause an undesirable pressure buildup in the system. With these configurations, the pump body of the non-positive displacement pump can simply be regarded as a penetrating body to which the agitator is attached.

[0018] According to a preferred feature of claim 5, the method specifies at least two containers from which a liquid component and at least one other liquid or solid component are released into the conduit assembly. This feature allows for particular flexibility in the applicability of the method. Such a feature can be used, for example, to add all types of culture medium or buffer and is not limited to only liquid or solid components.

[0019] According to preferred features of claims 6 and 7, the pump assembly comprises one second pump and at least one third pump, which are adapted to dispense a metered amount of liquid or solid material. These features also highlight the particular flexibility of the method with regard to its versatile applicability.

[0020] According to another preferred feature of claim 8, the first pump is configured as a non-positive displacement pump, and the mixing output is controllable or closed-loop controllable by adapting at least one parameter of the non-positive displacement pump. It may further be specified that the degree of adaptation of the mixing model is derived by an electronic process controller. This feature offers the advantage that the method is controllable or closed-loop controllable by adapting the impeller speed of the non-positive displacement pump, and that this control or closed-loop control can be performed automatically.

[0021] According to another preferred feature of claim 9, an electronic process controller controls at least the valve assembly and the pump assembly. Furthermore, the pumps of the pump assembly can be selectively controlled by the electronic process controller, whereby it can be determined that predetermined target conditions are to be created in the composite liquid flow. This feature makes the proposed method particularly controllable.

[0022] According to a likewise preferred configuration as set forth in claim 10, a sensor assembly is provided with at least one sensor for generating sensor data of the combined liquid flow, the sensor data representing the actual conditions in the combined liquid flow at one measurement location and transmitted to an electronic process controller, which offers the advantage of inspection of the obtained mixed output and the advantage of automated control based on the measured sensor values.

[0023] According to another preferred embodiment of the present invention, a feedback line is provided, which allows for renewed mixing of the combined liquid streams by newly and possibly repeatedly introducing the combined liquid stream upstream of the non-positive displacement pump. The feedback line can be selectively switched off when a feedback threshold is met. This allows for particularly precise control of the desired mixed output, even if the desired mixed output has not yet been successfully achieved after the initial mixing.

[0024] According to another preferred embodiment of claim 12, the combined liquid stream is introduced downstream of the non-positive displacement pump into at least one downstream-arranged unit for intermediate storage or further processing. This allows for particular flexibility with regard to the further processing of the combined liquid stream. For example, the combined liquid stream can be introduced into a downstream-arranged chromatography unit for direct purification or into an intermediate container for intermediate storage.

[0025] According to another teaching of independent claim 13, there is claimed a bioprocess assembly for dynamic in-line mixing of a pressurized medium, in particular a buffer and / or culture medium, comprising a liquid and at least one other liquid or solid component, wherein the liquid and the at least one other liquid or solid component are mixed at an opening in a predefined volumetric ratio to form a composite liquid stream, the bioprocess assembly comprising a conduit assembly with at least one conduit for conducting the media to be mixed, the bioprocess assembly comprising a pump assembly with a first pump arranged in a conduit of the conduit assembly, the first pump being configured as a non-positive displacement pump, in particular a centrifugal pump, and configured for dynamic in-line mixing of the media, the first pump having a liquid inlet forming a suction side of the pump during normal operation and a liquid outlet forming a discharge side of the pump during normal operation, the medium being conducted through the non-positive displacement pump for dynamic in-line mixing. To that extent, reference is made to all descriptions of the proposed method for dynamic in-line mixing.

[0026] In particular, it is proposed that the non-positive displacement pump is arranged to pass through in a reverse flow direction compared to normal operation for dynamic in-line mixing during operation of the bioprocess assembly.

[0027] According to a particularly preferred configuration of claim 14, the line assembly and / or the non-positive displacement pump are configured as disposable components in the bioprocess assembly. The corresponding replacement of these components, either entirely or at least partially, after a single use has the advantage that sterility is guaranteed and possible cleaning steps after the process are eliminated. A non-positive displacement pump also has the advantage that it can be shipped fully assembled and sterile before use without risk of contamination.

[0028] According to another teaching of the independent claim 15, an electronic process controller of the proposed bioprocess assembly is claimed. To that extent, reference is made to all the descriptions of the proposed method for dynamic in-line mixing and the proposed bioprocess assembly.

[0029] According to a preferred configuration as claimed in claim 16, the electronic process controller comprises a data processing system for implementing the proposed method.

[0030] According to another teaching of the independent claim 17, the use of a non-positive displacement pump for realizing the proposed method is claimed. To this extent, reference is made to all descriptions of the proposed method for dynamic in-line mixing, the proposed bioprocess assembly and the proposed electronic process controller.

[0031] According to another teaching of the independent claim 18, a computer program for the proposed electronic process controller is claimed. To this extent, reference is made to all statements to the proposed method for dynamic in-line mixing, the proposed bioprocess assembly, the proposed electronic process controller and the proposed use.

[0032] According to another teaching of the independent claim 19, a computer-readable storage medium for storing the proposed computer program is claimed. To this extent, reference is made to all descriptions of the proposed method for dynamic in-line mixing, the proposed bioprocess assembly, the proposed electronic process controller, the proposed use and the proposed computer program.

[0033] The invention will now be explained in more detail on the basis of the drawings, which are merely exemplary embodiments. [Brief explanation of the drawings]

[0034] [Figure 1] FIG. 1 shows a schematic diagram of the proposed method. [Figure 2] FIG. 1 shows an example of a non-positive displacement pump for implementing the proposed method. [Figure 3] FIG. 3 is a diagram schematically illustrating a flow state during operation of the non-positive displacement pump shown in FIG. 2. DETAILED DESCRIPTION OF THE INVENTION

[0035] FIG. 1 shows a method for dynamic in-line mixing of a pressurized medium 1. The method is used during the production and / or quality control of biopharmaceuticals, for example during the production of proteins using bioprocesses. Such proteins may be, for example, growth factors, hormones, enzymes, in particular antibodies, antibody derivatives, or the like. The proposed method can be used to ensure dynamic in-line mixing of a pressurized medium 1 comprising a liquid and at least one other liquid or solid component. The method is particularly used for in-line mixing of biotechnological media 2, such as buffers and / or culture media, or the like, in a bioprocess assembly 3.

[0036] The liquid is mixed with at least one other liquid or solid component in a predefined volume ratio at the opening point 4 to form a combined liquid stream 5 .

[0037] By "predefined volume ratio" it is meant herein that the volume ratio of the liquid volumes and / or solid volumes forming medium 1 is already defined before the implementation of the proposed method or is adapted during the proposed use of the method. Preferably, the definition and / or adaptation of the volume ratio of the liquid volumes and / or solid volumes forming medium 1 is performed by the user. The possible adaptation is preferably performed based on measured parameters, as described further below, which allows reactive control of the volume ratios.

[0038] The bioprocess assembly 3 includes a conduit assembly 6 with at least one conduit 7 for conducting media 1 to be mixed or components to be mixed with one another. The bioprocess assembly 3 further includes a pump assembly 8 with a first pump 9, which is arranged in the conduit 7 of the conduit assembly 6. The first pump 9 is configured as a non-positive displacement pump 10, in particular a centrifugal pump, and is configured for dynamic in-line mixing of the media 1. The first pump 9 has a liquid inlet 9a, which forms the suction side of the pump 9 in a specified flow direction, and a liquid outlet 9b, which forms the discharge side of the pump in a specified operation. The media 1 is conducted through the first pump 9, which is configured as a non-positive displacement pump 10, for dynamic in-line mixing.

[0039] The term "as specified" in this specification means that the flow conforms to a specification preset by the manufacturer of the pump 9. In this case, the "prescribed flow direction" ultimately means the flow direction of the pump 9 that is preset by the manufacturer.

[0040] The term "medium" as used herein generally refers to a liquid, a liquid mixture, or a suspension consisting of a liquid and at least one other liquid or solid component. Medium 1 in the sense of the present patent application may be a biotechnological medium 2, such as a buffer and / or a culture medium, in a bioprocess assembly 3. The liquid component of medium 1 and / or at least one other liquid or solid component or medium 1 itself may be a concentrate, advantageously a product stream, more preferably a protein-product stream, and / or a solvent, in particular water, ethanol, an acid or base, or the like. Consequently, the proposed method is versatile and can be used not only for mixing or diluting buffers and / or culture media, but also for methods aimed at inactivating viruses in bioprocesses, for example.

[0041] The term "dynamic" in this context refers to a mixer with a dynamic mixing output, which can be varied in relation to at least one adjustable parameter, in particular in relation to the agitator speed.

[0042] The term "in-line" refers to the interior of the lines 7 of the line assembly 6.

[0043] Importantly, in the proposed method, the non-positive displacement pump 10 is forced through in a reverse flow direction compared to normal operation for dynamic in-line mixing.

[0044] 2, the non-positive displacement pump 10 preferably has a rotating shaft 11 for driving an impeller 12 with blades, the rotating shaft 11 being driven by a motor, in particular for dynamic in-line mixing. Preferably, the rotating shaft 11 is driven so that the volumetric flow rate downstream of the pump 9 in the flow direction is equal to or less than the volumetric flow rate upstream of the pump 9. This allows the non-positive displacement pump 10 to operate as a mixer, and ultimately a variable mixing output is possible by controlling the rotation speed of the rotating shaft 11.

[0045] The term "speed control" in this specification refers to an external speed control of the rotating shaft 11, and not, for example, a speed control by the flow itself. Consequently, speed control refers to a speed control of the rotating shaft 11 by influencing the rotating shaft 11 other than by the flow, in particular by braking or accelerating the rotating shaft 11.

[0046] In this specification, the non-positive displacement pump 10 preferably has an impeller 12 with blades, the blades having curved blade surfaces as shown in FIG. 3. When the non-positive displacement pump 10 is flowing, the pressure exerted by the media to be mixed is preferably lower on the inside of the curvature of the blade surface than on the outside of the blade surface. This means that flow conditions, such as flow velocity, volumetric flow rate, liquid pressure, or the like, can be kept constant, and no critical pressure increase has to be tolerated. When using such an impeller 12, the direction of rotation of the impeller 12 preferably also corresponds to the flow direction of the combined liquid stream 5 during the proposed reverse flow of the non-positive displacement pump 10. On the other hand, the rotation of the impeller 12 acts against the flow of the combined liquid stream 5, thereby preventing the flow of the liquid stream 5 during the flow of the non-positive displacement pump 10. However, even if the rotation direction of the impeller 12 is opposite to the flow direction of the composite liquid stream 5, the desired reduction in the pumping power, and possibly the desired stoppage, of the non-positive displacement pump 10, resulting in a critical pressure increase, still occurs. The particularly preferred opposite rotation direction of the impeller 12 of the non-positive displacement pump 10 can be preferably realized by corresponding wiring, more preferably by phase reversal.

[0047] It should be noted here that the proposed invention's advantage of being able to adjust constant flow conditions while simultaneously controlling the speed of the impeller 12 without having to accept critical pressure buildup cannot be achieved by simply reversing the direction of rotation of the impeller 12 of the non-positive displacement pump 10. In fact, a pump arranged in the normal mounting direction with the impeller 12 rotating in the opposite direction would still pump in the normal direction, even though this would significantly limit the pump's efficiency, reduce flow, and increase noise generation. Since the pumping action is at least partially maintained, undesirable pressure buildup would still occur.

[0048] As can be seen in Figure 3, the non-positive displacement pump 10 herein preferably comprises a pump housing 13. The outlet from the pump housing 13 is parallel to the impeller axis of rotation 14 (Figure 2). Preferably, the inlet into the pump housing 13 is at an angle, more preferably perpendicular to the impeller axis of rotation 14.

[0049] Preferably, as can be seen in Figure 1, a liquid is discharged into the conduit assembly 6 from a first container 15 and at least one further liquid or solid component is discharged into the conduit assembly 6 from at least one second container 16. The conduit assembly 6 may have a plurality of conduits 7, which are fluidically connected to the respective assigned containers 15, 16. Preferably, the conduit assembly 6 is herein assigned a valve assembly 17 with at least one valve 18 configured to selectively fluidically connect the conduits 7.

[0050] Herein, the pump assembly 8 preferably includes a second pump 19 configured to meter a liquid from the first container 15 into the line 7 of the line assembly 6. Additionally, the pump assembly 8 preferably includes at least one third pump 20 configured to meter a separate liquid or solid component from the second container 16 into the second line 7 of the line assembly 6 (FIG. 1).

[0051] Furthermore, at least the second and / or third pumps 19, 20, preferably all pumps configured to meter a liquid flow, may be configured as metering pumps, in particular as tube pumps, rotary piston pumps or diaphragm pumps. Additionally or alternatively, at least the third pump 20, preferably all pumps configured to meter a solids flow, may be configured as a solids pump, preferably as a wastewater or sludge pump.

[0052] Preferably, all pumps configured for dynamic in-line mixing of liquids herein are configured as non-positive displacement pumps 10, preferably centrifugal pumps, more preferably disposable centrifugal pumps. Additionally or alternatively, the first pump 9, preferably all pumps configured for dynamic in-line mixing of liquids, is configured to adjust a desired mixing output in the composite liquid stream 5. The mixing output is preferably controllable, in particular in an infinitely variable manner, by adaptation of at least one parameter of the at least one non-positive displacement pump 10, preferably the rotation speed of the impeller 12 of the non-positive displacement pump 10. Preferably, the bioprocess assembly 3 comprises an electronic process controller 21, which controls at least one parameter of the at least one non-positive displacement pump 10, in particular the rotation speed of the impeller 12 of the non-positive displacement pump 10. Also additionally or alternatively, the degree of fit of at least one parameter of the non-positive displacement pump 10, preferably the rotational speed of the impeller 12 of the non-positive displacement pump 10, is derived from a mixing model 22, preferably by an electronic process controller 21 (see FIG. 1 ). Preferably, the mixing model 22 represents a relationship between the mixing output and at least one parameter of the non-positive displacement pump 10, preferably the rotational speed of the impeller 12 of the non-positive displacement pump 10.

[0053] Each electronic process controller 21 controls at least a valve assembly 17 and a pump assembly 8. The pumps of the pump assembly 8 are preferably selectively controllable by the electronic process controller 21 to create predefined target conditions in the composite liquid stream 5. The target conditions are preferably buffer or medium conditions, such as a defined pH, concentration of at least one substance, conductivity, or the like.

[0054] 1, a sensor assembly 23 with at least one sensor 24, in particular a pH sensor, a conductivity sensor, a flow rate sensor or a concentration sensor or the like, is provided for generating sensor data of the composite liquid stream 5. The sensor 24 is preferably arranged in the pipe 7 of the pipe assembly 6 downstream of the non-positive displacement pump 10. Preferably, the sensor data, which are representative of the actual conditions in the composite liquid stream 5 at the measurement location 25, are transmitted to an electronic process controller 21. Additionally or alternatively, the sensor data may be incorporated into a mixing model 22 and / or preferably utilized by the electronic process controller 21, so that the mixing output in the composite liquid stream 5 can be evaluated.

[0055] As can be seen in Figure 1, a feedback line 26 is provided that branches off downstream of the non-positive displacement pump 10. This feedback line 26 is configured to introduce the combined liquid stream 5 upstream of the non-positive displacement pump 10 for a new mixing thereof and is selectively switchable by the preferably electronic process controller 21 when a feedback criticality is met. The feedback line 26 here preferably includes a fourth pump 27, by which the combined liquid stream 5 can be introduced upstream of the non-positive displacement pump 10 for a new mixing thereof (Figure 1). The feedback criticality is preferably met when the actual conditions in the combined liquid stream 5, as measured by the sensor 24, fluctuate and / or deviate from the target conditions by more than a preset value, preferably by more than 5%, and more preferably by more than 10%.

[0056] For example, if the concentration desired by the user is still not achieved, whereby the parameter measured by the at least one sensor deviates significantly from a preset value, the combined liquid stream 5 can be introduced upstream of the non-positive displacement pump 10 for a new mixing thereof, preferably as long as the combined liquid stream 5 has the desired target condition. Furthermore, it may be specified that the feedback line 26 is configured for feedback control.

[0057] The term "feedback control" as used herein refers to the self-regulation of the system's activity, in particular with respect to the rotation of the impeller 12 of the non-positive displacement pump 10, based on sensor data measured using at least one technically connected sensor 24.

[0058] In the specified assembled state, the composite liquid stream 5 is here preferably introduced into at least one unit 28 arranged downstream of the non-positive displacement pump 10 for intermediate storage or further processing (FIG. 1). This downstream arranged unit 28 is preferably an intermediate vessel for intermediate storage of the composite liquid stream 5. In the case of intermediate storage, it may be aimed, for example, that a specified minimum target volume is accumulated in the intermediate vessel and then further processed.

[0059] Alternatively, this downstream arranged unit 28 is a processing unit consisting of a group comprising a filter unit, a chromatography unit, a virus filtration unit or the like. Furthermore, it may be specified that the composite liquid stream 5 is first introduced into an intermediate container for intermediate storage and then introduced into at least one processing unit after a predefined, preferably user-defined, time for further processing has elapsed.

[0060] According to another teaching of an independent claim, a bioprocess assembly 3 is specified for dynamic in-line mixing of a pressurized medium 1 comprising a liquid and at least one liquid or solid component, in particular a buffer and / or a culture medium. The liquid with at least one other liquid or solid component is mixed in a predefined volumetric ratio at an opening 4 to form a composite liquid stream 5. The bioprocess assembly 3 further comprises a conduit assembly 6 with at least one conduit 7 for conducting the medium 1 to be mixed. The bioprocess assembly 3 further comprises a pump assembly 8 with a first pump 9, which is arranged in the conduit 7 of the conduit assembly 6. The first pump 9 is configured as a non-positive displacement pump 10, in particular a centrifugal pump, and is configured for dynamic in-line mixing of the medium 1. The first pump 9 has a liquid inlet 9a which in normal operation forms the suction side of the pump and a liquid outlet 9b which in normal operation forms the discharge side of the pump, and the medium 1 is guided through a non-positive displacement pump 10 for dynamic in-line mixing. Insofar as this is concerned, reference is made to all the descriptions given for the proposed method.

[0061] Importantly, in the proposed bioprocess assembly 3, the non-positive displacement pump 10 is arranged to flow in a reverse flow direction compared to normal operation for dynamic in-line mixing during operation of the bioprocess assembly 3.

[0062] Preferably, the conduit assembly 6 and / or the non-positive displacement pump 10 are configured as disposable components herein. Additionally or alternatively, the non-positive displacement pump 10 includes at least one disposable pump head and / or disposable pump housing. Accordingly, the proposed method specifies that the non-positive displacement pump 10, preferably a centrifugal pump, more preferably a disposable centrifugal pump, is used in a reverse (wrong) installation orientation for in-line mixing, and that the non-positive displacement pump 10 is preferably fully assembled prior to use and shipped sterile without risk of contamination.

[0063] According to another teaching of the independent claim 15, an electronic process controller of the proposed bioprocess assembly is claimed. To this extent, reference is made to all the descriptions of the proposed method for dynamic in-line mixing and the proposed bioprocess assembly.

[0064] According to a preferred configuration as claimed in claim 16, the electronic process controller comprises a data processing system for implementing the proposed method.

[0065] According to another teaching of the independent claim 17, the use of a non-positive displacement pump for realizing the proposed method is claimed. To this extent, reference may be made to all descriptions of the proposed method for dynamic in-line mixing, the proposed bioprocess assembly and the proposed electronic process controller.

[0066] According to another teaching of the independent claim 18, a computer program for the proposed electronic process controller is claimed. To this extent, reference is made to all statements to the proposed method for dynamic in-line mixing, the proposed bioprocess assembly, the proposed electronic process controller and the proposed use.

[0067] According to another teaching of the independent claim 19, a computer-readable storage medium for storing the proposed computer program is claimed. To this extent, reference may be made to all descriptions of the proposed method for dynamic in-line mixing, the proposed bioprocess assembly, the proposed electronic process controller, the proposed use, and the proposed computer program.

Claims

1. A method for dynamically in-line mixing a pressurized medium (1) comprising a liquid and at least one other liquid or solid component within a bioprocess assembly (3), particularly for in-line mixing buffers and / or culture media, wherein the liquid and the at least one other liquid or solid component are mixed at a predetermined volume ratio at an opening (4) to form a synthetic liquid flow (5), the bioprocess assembly (3) having a conduit assembly (6) with at least one conduit (7) for guiding the medium (1) to be mixed, and the bioprocess assembly (3) having a pump (9) A method comprising a pump assembly (8), wherein the first pump (9) is located within the conduit (7) of the conduit assembly (6), and the first pump (9) is configured as a non-positive displacement pump (10), particularly a centrifugal pump, and is configured to dynamically mix the medium (1) in-line, wherein the first pump (9) has a liquid inlet (9a) that forms the suction side of the pump during specified operation, and a liquid outlet (9b) that forms the discharge side of the pump during specified operation, and the medium (1) is guided through the non-positive displacement pump (10) for dynamic in-line mixing, The method is characterized in that the non-positive displacement pump (10) is flowed through in a reverse flow direction compared to the specified operation for dynamic in-line mixing.

2. The method according to claim 1, wherein the non-positive displacement pump (10) has a rotating shaft (11), and the rotating shaft (11) is driven by a motor, preferably for dynamic in-line mixing, such that the volumetric flow rate of the flow is less than or equal to the volumetric flow rate on the upstream side of the pump (9) downstream of the pump (9) in the flow direction.

3. The method according to claim 1 or 2, wherein the non-positive displacement pump (10) has an impeller (12) equipped with blades having a curved blade surface, and the pressure applied by the medium (1) to be mixed during flow through the pump (9) is lower on the inside of the curve than on the outside.

4. The method according to claim 1, wherein the non-positive displacement pump (10) has a pump housing (13), and the outflow from the pump housing (13) is parallel to the axis of rotation (14), and preferably the inflow into the pump housing (13) is at an angle to the axis of rotation (14), particularly perpendicular to it.

5. The method according to claim 1, wherein the liquid is discharged from a first container (15) into the conduit assembly (6), and the at least one other liquid or solid component is discharged from at least one second container (16) into the conduit assembly (6), preferably the conduit assembly (6) having a plurality of conduits (7) that are fluid-technically connected to the respective assigned containers (15, 16), and more preferably the conduit assembly (6) is assigned a valve assembly (17) having at least one valve (18) for selectively fluid-technically connecting the conduits (7).

6. The method according to claim 5, wherein the pump assembly (8) comprises a second pump (19) configured to meter and discharge the liquid, preferably from the first container (15) into one of the conduits (7) of the conduit assembly (6), and at least one third pump (20) configured to meter and discharge each of the other liquid or solid components, preferably from the second container (16) into the second conduits (7) of the conduit assembly (6).

7. The method according to claim 6, characterized in that at least the second pump (19) and / or the third pump (20), preferably all pumps configured to meter and discharge a liquid flow, are configured as metering pumps, preferably each of the pumps is configured as a tube pump, rotary piston pump or diaphragm pump, and / or at least the third pump (20), preferably all pumps configured to meter and discharge solids, are configured as solids pumps, preferably each of the pumps is configured as a wastewater pump or a sludge pump.

8. All pumps configured to dynamically mix liquids in-line are formed as non-positive displacement pumps (10), preferably centrifugal pumps, more preferably disposable centrifugal pumps, and / or the first pump, preferably all pumps configured to dynamically mix liquids in-line, are configured to adjust a desired mixing output in the synthetic liquid flow (5), the mixing output being particularly steplessly controllable by matching at least one parameter of at least one of the non-positive displacement pumps, preferably matching the rotational speed of the impeller (12) of the non-positive displacement pump (10), preferably the bioprocess assembly (3) has an electronic process controller (21), more preferably the electronic The method according to claim 1, wherein the process controller (21) controls at least one parameter of at least one non-positive displacement pump (10), in particular the rotational speed of the impeller (12) of the non-positive displacement pump (10), and / or the degree of suitability of the at least one parameter of the non-positive displacement pump (10), preferably the rotational speed of the impeller (12) of the non-positive displacement pump (10), is derived from a mixing model (22), preferably by an electronic process controller (21), wherein the mixing model (22) preferably represents a relationship between the mixing output and at least one parameter of the non-positive displacement pump (10), preferably the rotational speed of the impeller (12) of the non-positive displacement pump (10).

9. The method according to claim 5 or 8, characterized in that the electronic process controller (21) controls at least the valve assembly (17) and the pump assembly (8), and preferably the pump of the pump assembly (8) is selectively controllable by the electronic process controller (21), thereby forming predetermined target conditions, preferably buffer conditions or medium conditions, in the synthetic liquid flow (5).

10. The method according to claim 8, wherein a sensor assembly (23) is provided, comprising at least one sensor (24) for generating sensor data of the synthetic liquid flow (5), the sensor (24) being located in one conduit (7) of the conduit assembly (6) downstream of the non-positive displacement pump (10), the sensor data being transmitted to the electronic process controller (21), and the sensor data representing actual conditions in the synthetic liquid flow (5) at one measurement position (25).

11. The method according to claim 10, wherein a feedback pipeline (26) is provided that branches downstream of the non-positive displacement pump (10), the feedback pipeline (26) is configured to introduce the synthetic liquid flow upstream of the non-positive displacement pump (10) for its new mixing, the feedback pipeline (26) is preferably selectively switchable by the electronic process controller (21) when a feedback critical is met, preferably the feedback critical is met when the actual conditions in the synthetic liquid flow (5), as measured by the sensor (24), vary by a preset value, preferably by more than 5%, more preferably by more than 10%, and / or deviate from target conditions.

12. The method according to claim 1, characterized in that the synthetic liquid flow (5) is introduced into at least one unit (28) located downstream of the non-positive displacement pump (10) for intermediate storage or subsequent processing.

13. A bioprocess assembly for dynamically in-line mixing a pressurized medium (1), particularly a buffer and / or culture medium, comprising a liquid and at least one other liquid or solid component, wherein the liquid and the at least one other liquid or solid component are mixed at a predetermined volume ratio at an opening (4) to form a synthetic liquid flow (5), the bioprocess assembly (3) having a conduit assembly (6) with at least one conduit (7) for guiding the medium (1) to be mixed, and the bioprocess assembly (3) having a pump assembly (8) with a first pump (9). The first pump (9) is located within the conduit (7) of the conduit assembly (6), and the first pump (9) is configured as a non-positive displacement pump (10), particularly a centrifugal pump, and is configured to dynamically mix the medium (1) in-line, and the first pump (9) has a liquid inlet (9a) that forms the suction side of the pump during specified operation and a liquid outlet (9b) that forms the discharge side of the pump during specified operation, and the medium (1) is led through the non-positive displacement pump (10) for dynamic in-line mixing, in a bioprocess assembly, The bioprocess assembly is characterized in that the non-positive displacement pump (10) is arranged to flow in a reverse flow direction compared to the specified operation for dynamic in-line mixing when the bioprocess assembly (3) is in operation.

14. The bioprocess assembly according to claim 13, characterized in that the pipeline assembly (6) and / or the non-positive displacement pump (10) are formed as disposable components, and / or the non-positive displacement pump (10) has at least one disposable pump head and / or disposable pump housing.

15. An electronic process controller for a bioprocess assembly (3) according to claim 13 or 14, wherein the conduit assembly (6) is assigned a valve assembly (17) having at least one valve (18) for selectively connecting the conduit (7) fluidly, and the electronic process controller (21) is configured to carry out the method according to claim 1 by controlling at least the non-positive displacement pump (10), the pump assembly (8) and / or the valve assembly (17).

16. The electronic process controller (21) according to claim 15, characterized in that it has a data processing system for realizing the method described in claim 1.

17. A use of a non-positive displacement pump (10), particularly a centrifugal pump, to realize the method of claim 1, wherein the non-positive displacement pump (10), particularly comprising at least a pump head and a pump housing (13), has at least the components necessary for the specified function, forming a group of components, more preferably the group of components is formed as a pre-assembled or integrated unit, the unit is preferably formed as a disposable component and / or has a sterile package for sterile use.

18. A computer program for an electronic process controller (21) according to claim 15.

19. A computer-readable storage medium in which the computer program according to claim 18 is preferably stored in a non-volatile form.

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