Method and assembly for operating continuous downstream process

Abstract

The invention relates to a method for operating a continuous downstream process, in particular a continuous bacterial inactivation process or an in-line dilution process, using a bioprocess assembly (1), the bioprocess assembly (1) having a homogenization tank (2), which has a first fluid inlet (3) and a second fluid inlet (4), the first fluid inlet is configured to introduce a concentrate stream, in particular a product concentrate stream or a buffer concentrate stream, into the homogenizing tank (2); at least one second fluid inlet (4) which is designed to introduce a diluent stream, in particular a product diluent stream or a buffer diluent stream, into the homogenization tank (2); a fluid outlet (5), which is designed to discharge a liquid flow from the homogenizing tank (2), the bioprocess assembly (1) having a conveying assembly (6) for conveying a fluid, which conveying assembly is associated with the first fluid inlet (3) and the second fluid inlet (4) in order to convey at least one liquid flow into the homogenizing tank (2), the homogenizing tank (2) is provided with a delivery assembly (7), and the delivery assembly is associated with the fluid outlet (5) to deliver the liquid flow out of the homogenizing tank (2), and wherein the bioprocess assembly (1) has an electronic process control device (7). According to the invention, the electronic process control device (7) adjusts the liquid level in the homogenizing tank (2) by controlling and / or adjusting the conveying assembly (6) in such a way that the liquid level does not fall below a predefined minimum liquid level in the homogenizing tank (2).

Description

Field of the Invention

[0001] The present invention relates to a method for operating a continuous downstream process as described in the preamble of claim 1, a bioprocess assembly for operating a continuous downstream process as described in claim 25, an electronic process control device for the proposed bioprocess assembly as described in claim 26, a use of an electronic process control device for implementing the proposed method as described in claim 28, a computer program for the proposed electronic process control device as described in claim 29, and a computer-readable storage medium for storing the computer program as described in claim 30. Background Art

[0002] The methods discussed for operating continuous downstream processes, in particular continuous virus inactivation processes or online dilution processes, are applied within the scope of bioprocesses for the manufacture and / or quality control of biopharmaceutical biological products (in particular proteins, vectors, cells, etc.). Thereby, a continuous flow from a preceding unit, in particular a preceding chromatographic unit, can be provided to a subsequent unit, in particular a subsequent chromatographic unit or a filtration unit.

[0003] In process technology, "downstream process" refers to all processes for separating and purifying a fermentation product from the fermentation broth of a biotechnological process. This term encompasses mechanical, thermal, electrical, and physicochemical processes.

[0004] The term "bioprocess" herein refers to the biotechnological and biopharmaceutical processes involved in the manufacture of therapeutic biological products (such as vaccines, biologics, components for cell or gene therapy) or non-therapeutic biological products (such as pigments, biofuels, or nutrients). Such biological products can either be produced by living cells, or the cells themselves can be the biological product, or the biological product can be a cell-free produced product based on cell components from non-natural or natural sources.

[0005] In the biopharmaceutical industry, there is a trend towards process centralization, whereby an increasing number of continuous process steps are realized. In batch production, for example, carried out in a routine and standardized manner, the product passes through one process step after another batch by batch and is collected in storage containers after each of these process steps. This approach may limit the utilization rate of bioprocess components and the productivity of the process. In contrast, a continuous process means that the product passes through multiple production steps without interruption. Thus, a continuous process enables individual work steps to be carried out on a significantly smaller scale, thereby saving consumable materials (such as buffers, solvents, etc.), and even enables a process on a larger scale in a one-time form. In addition, fewer and smaller storage containers also result in a shorter residence time of the product in the bioprocess.

[0006] The advantages of continuous production lie especially in the fact that the control of product quality reaches an unprecedented level and that there is better agility and flexibility in meeting product requirements. Due to the smaller facility layout, another advantage is a significant reduction in the scale-up risk. Thus, continuous manufacturing as a whole offers great potential for improving the economic efficiency of bioprocesses.

[0007] In the context of process centralization, new methods have been increasingly developed, such as single-use centrifugation, tangential flow filtration (TFF), or rapid cycle chromatography (RCC), all of which aim to achieve a continuous product flow and thus design the process steps applied in the downstream process as space-saving and cost-saving as possible.

[0008] Immediately following the first chromatography step (especially the protein A affinity chromatography step), a first virus inactivation step is usually carried out. The implementation of a continuous virus inactivation step is a challenge for process development in the context of process integration.

[0009] The known method (EP 2 867359B1) on which the present invention is based for operating a continuous downstream process is used for semi-continuously inactivating viruses during a protein production process, wherein large storage tanks are not required for virus inactivation. This is because smaller stirred mixing tanks are used for virus inactivation, whereby better conditions can be created for production and structural space can be saved. In addition, the incubation time required for complete virus inactivation can be shortened from a minimum of one hour to a maximum of one hour.

[0010] However, this is likewise not a continuous method, because at this time, the protein A eluate is incubated with the virus inactivator in a mixing tank, wherein complete virus inactivation may still take up to one hour. During this time, the protein A eluate containing the target protein must be incubated with the virus inactivator for a longer time and stirred (similar to a traditional batch process) before being transferred to the next process step. This can cause problems because biological products from bioprocesses (which are inherently very sensitive), such as antibodies, may be damaged due to too long storage or process times. The longer the stirred incubation time of the biological product, especially the target protein, with the virus inactivator, the higher the probability of damage to the biological product due to the mechanical forces generated by the stirrer and the decomposition of the virus inactivator.

[0011] Similar challenges also exist when implementing continuous on-line dilution processes in which two or more liquids are mixed with each other. Currently, for example, the mixing of buffers or media is usually carried out batchwise, especially for downstream processes. At this time, the base liquid to be mixed is loaded into a container, and then the components to be mixed are added, and the mixture is continuously stirred with a mixer until the desired degree of mixing or dissolution is achieved, so that the finished solution can be further processed subsequently.

[0012] However, similar to the problems in virus inactivation described above, the use of such an intermediate container also has a decisive disadvantage here, namely, the process flow is interrupted by the mixing process with the mixing tank, in which the mixing is carried out batchwise.

[0013] This is accompanied by more time, space and equipment investment, which in turn results in higher costs and a lower economic efficiency of the bioprocess.

[0014] For this reason, the mixing process should preferably not be carried out in an intermediate container, but should be implemented "on-line", that is, within the pipeline of the pipeline assembly. Thus, static mixing elements are currently preferably used for on-line mixing. Known methods for operating continuous downstream processes, especially continuous on-line dilution processes (WO 2015 117 884A1) include a first chromatographic column and at least one second chromatographic column, a plurality of buffer containers and an additional on-line dilution system, the on-line dilution system having an inlet and a bioprocess outlet. However, the additional on-line dilution system requires additional production space and results in increased material costs, increased structural complexity and increased maintenance costs.

[0015] Therefore, the known methods are very limited in terms of the longer process time that endangers biological products on the one hand and the production cost and utilization of production space on the other hand. Overall, the implementation of known methods for operating continuous downstream processes, especially continuous virus inactivation processes or on-line dilution processes, is relatively complex. Summary of the Invention

[0016] The problem underlying the present invention is to design and improve the known methods for operating continuous downstream processes in such a way that their implementation is simplified.

[0017] In the method for operating a continuous downstream process according to the preamble of claim 1, the above problem is solved by the features of the characterizing part of the claim.

[0018] The main basic idea is that the electronic process control device adjusts the liquid level in the homogenization tank by controlling and / or regulating the conveying assembly to avoid falling below the minimum liquid level, thereby ensuring a continuous liquid flow from the bioprocess assembly.

[0019] The term "equalization tank" shall be understood in a broad sense herein and refers herein to any reservoir or container established for holding liquids. The equalization tank can be designed from flexible or rigid materials, especially from metals, glass, plastics, etc. Additionally or alternatively, the equalization tank can be designed for multiple uses or designed as a single-use container.

[0020] A particular configuration of the proposed method for operating a continuous downstream process has the advantage that a particularly discontinuous liquid stream from a preceding process step, especially a preceding Protein A chromatography step (in which there may be fluctuations in volume and product concentration, i.e., in which, for example, sometimes no liquid flow at all occurs and in which the product concentration may generally fluctuate during the chromatography phase), is converted into a continuous liquid stream and, following the proposed continuous downstream process, especially a continuous virus inactivation process or an online dilution process, this liquid stream is continuously output into a subsequent process step.

[0021] The term "continuous liquid stream" refers herein to a liquid stream that is not interrupted (e.g., interrupted due to incubation in a container, etc.), but the flow rate of the liquid stream can vary.

[0022] Specifically, it is proposed that the electronic process control device adjusts the liquid level in the equalization tank by controlling and / or regulating a conveying assembly such that a predefined minimum liquid level in the equalization tank is not undershot.

[0023] According to a preferred configuration as claimed in claim 2, the electronic process control device adjusts the liquid level in the equalization tank such that a predefined target liquid level is reached or the liquid level is maintained within a target liquid level range. This enables the user to not only avoid emptying of the equalization tank but also, additionally, set a predefined target liquid level. Preferably, the predefined target liquid level is higher than the minimum liquid level and is especially reset after the liquid level has dropped below the target liquid level or exceeded the liquid level.

[0024] The preferred configuration according to claim 3 or 4 relates to details of at least one conveying device associated with the conveying assembly and enables flexible fluid controllability in a simple manner.

[0025] The term "conveying assembly" shall be understood in a broad sense herein and refers herein to any type of assembly established for conveying and / or regulating, especially interrupting liquid conveyance, especially a pump assembly having at least one pump and / or a valve assembly with at least one valve. Thus, such a pump and such a valve each form a "conveying device" of the conveying assembly. Preferably, such a conveying device refers to a conveying device designed as a metering pump, especially a peristaltic pump, a rotary piston pump, or a diaphragm pump. Such a valve especially refers to a valve established for establishing a selective and quantitative fluid connection, preferably a continuous valve, a regulating valve, etc.

[0026] According to the preferred design according to claim 5, the electronic process control device derives the actual value of the liquid level parameter in the homogenization tank from the process data in the monitoring routine. Based on the deviation between the derived actual value of the liquid level parameter and the predefined minimum value of the liquid level parameter corresponding to the predefined minimum liquid level in the homogenization tank, the electronic process control device adjusts the conveying power of the first conveying device, the second conveying device, and / or the third conveying device to prevent the liquid level from dropping below the minimum level. This design enables the electronic process control device to respond to any deviation from the minimum liquid level and prevent the liquid level from dropping below the minimum level by adjusting the corresponding pumps. Alternatively, the conveying power of the first conveying device, the second conveying device, and / or the third conveying device is adjusted based on the deviation between the derived actual value of the liquid level parameter and the predefined target value of the liquid level parameter corresponding to the predefined target liquid level in the homogenization tank to reach the target liquid level, or the conveying power of the first conveying device, the second conveying device, and / or the third conveying device is adjusted based on the deviation between the derived actual value of the liquid level parameter and the predefined limit value of the predefined target liquid level range in the homogenization tank to keep the liquid level within the target liquid level range.

[0027] According to the particularly preferred design according to claim 6, the electronic process control device generates a first model from the process data. The degree of adjustment of the conveying power is derived from this first model. The advantage of this design is that the method can be adjusted not only by adjusting the conveying power of the first conveying device, the second conveying device, and / or the third conveying device, but also automatically by the underlying first model.

[0028] The first model reflects the relationship between the liquid level parameter in the homogenization tank on the one hand and the conveying power of the first conveying device, the second conveying device, and / or the third conveying device on the other hand based on the included process data.

[0029] According to the preferred design according to claim 7, the bioprocess assembly has a first bioprocess inlet and a fourth conveying device associated with the first bioprocess inlet, and the fourth conveying device is configured to output a liquid stream into the pipeline assembly in a metered manner. Through this additional bioprocess inlet, an additional liquid stream can be supplied. This design opens up the possibility of generating a reactive liquid stream to adjust additional parameters in a particularly simple manner without compromising performance.

[0030] According to the further preferred design according to claim 8, in the homogenization tank, a concentrated liquid stream and a dilution liquid stream are combined into a first liquid stream containing a target factor, and then the first liquid stream is combined with a second liquid stream in a precisely predefined volume ratio to form a reactive third liquid stream. Through this simple process, predefined, especially virus inactivation or buffer dilution conditions can be created in a particularly simple manner.

[0031] According to a further preferred design according to claim 9, the bioprocess assembly has at least one mixer for mixing the reactive third liquid stream. The mixer enables the homogenization of target parameters, in particular the pH value or the conductivity, in a particularly simple manner.

[0032] According to a particularly preferred design according to claim 10, the bioprocess assembly has a residence time assembly downstream of the mixer for setting a shortest residence time of the liquid stream. The residence time assembly ensures in a particularly simple manner the liquid stream, in particular the incubation time required together with the virus inactivator.

[0033] According to a further preferred design according to claims 11 and 12, the sensor assembly generates process data which includes the liquid parameters of the first liquid stream containing the target factor and the liquid parameters of the reactive third liquid stream. Based on the actual values of the liquid parameters determined by measurement, the electronic process control device implements a virus inactivation routine in order to adjust the target values of the liquid parameters in the liquid stream, in particular the target pH value or the target conductivity. This allows the continuous adjustment of originally deviated values, in particular by adjusting the acid concentration or the buffer concentration, in order to keep them as constant as possible and thus to achieve continuous virus inactivation or continuous online dilution in a particularly effective manner.

[0034] According to a further preferred design according to claim 13, the disposal line is provided for discharging the liquid stream from the bioprocess assembly. The advantage of this variant is that the liquid stream or part of the liquid stream which should no longer be guided through the bioprocess assembly can be diverted and in particular discharged or disposed of from the bioprocess assembly for further use. Thereby, so-called system priming is achieved, that is to say, flooding the line assembly with buffer, disposing of the (part of the) liquid stream which is no longer required and / or the like, and overall increasing the flexibility of the proposed method. For these purposes, according to claim 14, a valve assembly with at least one valve is furthermore provided for selectively fluidly connecting the respective line to the line assembly.

[0035] According to a further preferred design according to claim 15, the design of a bioprocess assembly is concerned, which has a second bioprocess inlet to which a fifth conveying device is associated, whereby a neutralizing fourth liquid stream is introduced and combined with the reactive third liquid stream to produce a synthetic fifth liquid stream. The advantage of this is that the virus inactivation conditions are particularly simply neutralized.

[0036] In claim 16, a particularly preferred design of the conveying device for metering the output of the liquid stream is described.

[0037] According to a further preferred design according to claim 17, the bioprocess assembly has at least one second mixer which is configured to mix the synthesized fifth liquid stream. This mixer enables the neutralization conditions, in particular the pH value, to be homogenized in a particularly simple manner and allows the process to run continuously.

[0038] The preferred designs according to claims 18 and 19 relate to the preferred measurement locations and measurement parameters of the sensors of the sensor assembly, such that process data can be generated in a particularly simple and effective manner. In addition, the electronic process control device implements a neutralization routine to adjust the target values of the liquid parameters, in particular the pH value or conductivity, in the liquid stream. This allows for the continuous adjustment of originally deviating values, in particular by adjusting the acid concentration or the buffer concentration, in order to keep them as constant as possible and thereby to achieve continuous virus inactivation or continuous online dilution in a particularly effective manner.

[0039] According to a further preferred design according to claim 20, the electronic process control device generates a second model from the process data and determines the degree of adjustment of the delivery power of the fourth delivery device and / or the fifth delivery device from the second model. The advantage of this design is that the method is not only adjustable, but can be automatically adjusted by the underlying second model to particularly simply implement a continuous virus inactivation process or an online dilution process.

[0040] According to the preferred design according to claim 21, the first model and / or the second model is a statistical model or an analytical model. This ensures particular flexibility of the proposed method in terms of applicability and efficiency.

[0041] The preferred design according to claim 22 relates to the continuous discharge of the liquid stream from the bioprocess assembly and consolidates in a particularly simple manner the connectability of the proposed process to subsequent, preferably continuous processes.

[0042] The preferred design according to claim 23 relates to the design of the first mixer and / or the second mixer. Preferably, a rotary pump for dynamic online mixing is used, which is flowed through in the opposite flow direction compared to its specified operation. This design opens up the possibility of using the impeller of the rotary pump rotating in the opposite direction to the expected direction as a mixer, which enables the setting of a variable mixing power by adjusting the rotational speed without causing an increase in pressure in the system.

[0043] According to the equally preferred design according to claim 24, the proposed method is carried out in combination with a chromatographic method and / or a filtration method. This provides the possibility of simply integrating the proposed method into existing processes.

[0044] According to another teaching of independent significance according to claim 25, there is claimed a bioprocess component for operating a continuous downstream process, in particular a continuous bacterial inactivation process or an online dilution process, during a bioprocess, wherein the bioprocess component has a homogenization tank which has: a first fluid inlet configured to introduce a concentrated fluid stream, in particular a product concentrated fluid stream or a buffer concentrated fluid stream, into the homogenization tank; at least one second fluid inlet configured to introduce a dilution fluid stream, in particular a product dilution fluid stream or a buffer dilution fluid stream, into the homogenization tank; a fluid outlet configured to discharge a liquid stream from the homogenization tank, wherein the bioprocess component has a conveying component for fluid conveyance, the conveying component being associated with the first fluid inlet and the second fluid inlet to convey the respective at least one liquid stream into the homogenization tank, and the conveying component being associated with the fluid outlet to convey the liquid stream out of the homogenization tank, and wherein the bioprocess component has an electronic process control device. In this regard, all embodiments regarding the proposed method for operating a continuous downstream process can be referred to.

[0045] Specifically, it is proposed herein that when the bioprocess component is operating as prescribed, the electronic process control device adjusts the liquid level in the homogenization tank by controlling and / or regulating the conveying component such that a predefined minimum liquid level in the homogenization tank is not exceeded.

[0046] According to another teaching of independent significance according to claim 26, there is claimed an electronic process control device of the proposed bioprocess component. In this regard, all embodiments regarding the proposed method for operating a continuous downstream process and the proposed bioprocess component can be referred to.

[0047] According to the preferred design according to claim 27, the electronic process control device has a data processing system for implementing the proposed method.

[0048] According to another teaching of independent significance according to claim 28, there is claimed a use of an electronic process control device for implementing the proposed method. In this regard, all embodiments regarding the proposed method for operating a continuous downstream process, the proposed bioprocess component, and the proposed electronic process control device can be referred to.

[0049] According to another teaching of independent significance according to claim 29, there is claimed a computer program for the proposed electronic process control device. In this regard, all embodiments regarding the proposed method for operating a continuous downstream process, the proposed bioprocess component, the proposed electronic process control device, and the proposed use can be referred to.

[0050] According to another teaching of independent significance according to claim 30, a computer-readable storage medium for storing the proposed computer program is claimed. In this regard, all embodiments regarding the proposed method for running a continuous downstream process, the proposed bioprocess component, the proposed electronic process control device, the proposed use, and the proposed computer program can be referred to. Description of the Drawings

[0051] The present invention will be explained in more detail below with reference to the drawings which only show embodiments. Among them:

[0052] Figure 1 An embodiment of the proposed method for running a continuous downstream process is shown,

[0053] Figure 2 Another embodiment of the proposed method for running a continuous downstream process, in particular a continuous virus inactivation process, is shown,

[0054] Figure 3 Shows a flowchart presenting the preferred working principle of the proposed method according to Figure 1 of. Detailed Description of the Invention

[0055] In Figure 1 the proposed method for running a continuous downstream process, in particular a continuous virus inactivation process or an online dilution process, is shown. This method is applied in the downstream process of a bioprocess using the bioprocess component 1, in particular in the production, purification, and / or quality control of biopharmaceutical products, for example during the production of proteins. Such proteins can be growth factors, hormones, enzymes, and in particular can be antibodies, antibody derivatives, etc. The proposed method can be used to ensure that a biopharmaceutical product does not contain any type of active virus particles exceeding a specific threshold set by, for example, manufacturers and / or regulatory authorities, etc., in particular does not contain any active virus particles at all. Alternatively, the proposed method can be used for continuous online dilution, in particular the dilution of buffers.

[0056] Here, the target protein can either directly or indirectly originate from a bioreactor, in particular after process steps, in particular downstream process steps (such as separation steps of filtration, precipitation, and / or chromatography, etc.) have been performed. Such a chromatography step can be, for example, an affinity chromatography step, in particular an affinity chromatography step using Protein A.

[0057] Here, the bioprocess component 1 has a homogenization tank 2 which has a first fluid inlet 3 and at least one second fluid inlet 4. The first fluid inlet is provided for introducing a concentrate stream, in particular a product concentrate stream or a buffer concentrate stream, into the homogenization tank 2, and the second fluid inlet is provided for introducing a dilution stream, in particular a product dilution stream or a buffer dilution stream, into the homogenization tank 2. Here and preferably, the homogenization tank 2 is a stirred homogenization tank 2, as shown in Figure 1 and Figure 2 and is thus provided for homogenization.

[0058] The term "product concentrate stream" here refers to a liquid stream which mainly contains a product from a preceding process step, in particular an eluate from a preceding chromatographic step.

[0059] The term "buffer concentrate stream" here refers to a liquid stream which mainly contains a buffer, in particular a concentrated buffer, which is diluted online for further use in the bioprocess.

[0060] The term "product dilution stream" here refers to a liquid stream which mainly contains a solvent provided for diluting a product from a preceding process step, in particular a buffer suitable for the respective product.

[0061] The term "buffer dilution stream" here refers to a liquid stream which mainly contains a solvent provided for diluting a buffer, in particular water.

[0062] The bioprocess component 1 has a fluid outlet 5 which is provided for discharging a liquid stream from the homogenization tank 2. In addition, the bioprocess component 1 has a conveying component 6 for fluid conveyance, which is associated with the first fluid inlet 3 and the second fluid inlet 4 to convey the respective at least one liquid stream into the homogenization tank 2, and which is associated with the fluid outlet 5 to convey the liquid stream out of the homogenization tank 2. In addition, the bioprocess component 1 has an electronic process control device 7.

[0063] The term "fluid conveyance" should be understood in a broad sense herein and refers to any form of conveyance and / or adjustment of a fluid, in particular a liquid, in particular interruption of conveyance.

[0064] Now, what is important in the proposed method is that the electronic process control device 7 adjusts the liquid level in the homogenization tank 2 by controlling and / or regulating the conveying component 6 such that a predefined minimum liquid level in the homogenization tank 2 is not undershot. This ensures a continuous liquid stream that can be discharged from the bioprocess component 1 ( Figure 1 ).

[0065] The term "minimum liquid level" shall be understood in a broad sense herein and preferably refers to any form of liquid level in the homogenization tank preferably defined by the user as the minimum liquid level. According to a particularly preferred design, the minimum liquid level is preferably less than 50%, further preferably less than 25%, further preferably less than 10%, and further preferably less than 5% of the total volume of the homogenization tank 2.

[0066] Preferably, the electronic process control device 7 adjusts the liquid level in the homogenization tank 2 by controlling and / or regulating the conveying assembly 6 in such a way that a predefined target liquid level is reached or the liquid level is maintained within a target liquid level range.

[0067] The term "target liquid level" herein refers to any liquid level preferably defined by the user as the liquid level to be reached. The "target liquid level range" is the range between the upper limit and the lower limit of the liquid level within which the liquid level is maintained.

[0068] Preferably, the conveying assembly 6 has a first conveying device 8 for fluid conveyance, which is associated with the first fluid inlet 3. Additionally or alternatively, the conveying assembly 6 preferably has a second conveying device 9 for fluid conveyance, which is associated with the second fluid inlet 4. Furthermore, additionally or alternatively, the conveying assembly 6 preferably has a third conveying device 10 for fluid conveyance, which is associated with the fluid outlet 5.

[0069] Preferably, the bioprocess assembly 1 has a bioprocess outlet 11, which is provided for discharging liquid from the bioprocess assembly 1. Furthermore, the bioprocess assembly 1 has a pipeline assembly 12, which has at least one pipeline 13 for fluidly connecting the fluid outlet 5 of the homogenization tank 2 to the bioprocess outlet 11. Preferably, it is discharged from the bioprocess outlet 11 when the liquid flow has undergone the proposed method and is guided to subsequent process steps, preferably subsequent chromatographic steps, etc. for further processing.

[0070] As visible in Figure 1 and Figure 2 it can be seen that the third conveying device 10 is herein and preferably provided for fluid conveyance through at least one pipeline 13 of the pipeline assembly 12.

[0071] Furthermore, the bioprocess assembly 1 has a sensor assembly 14 for generating process data 15, and the sensor assembly has at least one sensor 16 associated with the homogenization tank 2.

[0072] At least one sensor 16 in the homogenization tank 2 is preferably designed as a level sensor. Further preferably, the sensor is provided for measuring the liquid level and / or for measuring the change in the liquid level per unit time. Further preferably, the level sensor is provided for measuring a level parameter.

[0073] The term "level parameter" should be understood in a broad sense herein. Preferably, the level parameter is a measure of the liquid filling state of the homogenization tank 2 in a very general sense and can be expressed by the filling percentage of the homogenization tank 2, a specific mass, a specific volume, a specific concentration, etc. In addition, the level parameter can be expressed by a specific liquid level at a specific time or as the change in the liquid level over time, and thus can also be expressed by a flow rate.

[0074] The term "liquid" should also be understood in a broad sense. The liquid includes not only the pure liquid itself but also emulsions or suspensions, such as a heterogeneous mixture composed of at least two different liquids or a heterogeneous mixture composed of a solid part and a liquid.

[0075] Additionally or alternatively, at least one sensor 16 in the homogenization tank 2 can be designed as a force sensor, preferably a load cell. Further preferably, the sensor is provided for measuring force, especially mass, and / or for measuring the change in mass per unit time. Preferably, the force, especially the mass and / or the change in mass per unit time, can be converted into a liquid level and / or a change in the liquid level per unit time.

[0076] Preferably, the electronic process control device 7 derives at least one actual value of the level parameter in the homogenization tank 2 from the process data 15 in the monitoring routine 17, preferably in the information retrieval 18. Depending on the preferably determined deviation at the decision point 19 between the derived actual value of the level parameter and the predefined minimum level parameter corresponding to the predefined minimum liquid level in the homogenization tank 2, the electronic process control device 7 preferably adjusts the conveying power of the first conveying device 8, the second conveying device 9, and / or the third conveying device 10 in the adjustment step 20 to prevent the liquid level from dropping below the minimum level, as shown in Figure 3 shown.

[0077] Alternatively, the electronic process control device 7 adjusts the conveying power of the first conveying device 8, the second conveying device 9, and / or the third conveying device 10 according to the deviation between the derived actual value of the level parameter and the predefined target value of the level parameter corresponding to the predefined target liquid level in the homogenization tank 2 to reach the target liquid level.

[0078] Alternatively, the electronic process control device 7 adjusts the conveying power of the first conveying device 8, the second conveying device 9, and / or the third conveying device 10 based on the deviation between the actual value of the obtained liquid level parameter and the predefined limit value of the predefined target liquid level range in the homogenization tank 2 to keep the liquid level within the target liquid level range.

[0079] The term "deviation" should be understood in a broad sense herein and includes not only any subtraction between the measured value and the target value, but also any other type of mathematical deviation, including variance, difference, and / or integral of the difference, etc.

[0080] Preferably, in the adjustment step 20, the conveying power of at least the first conveying device 8 and / or the second conveying device 9 is adjusted, preferably increased. Additionally or alternatively, the conveying power of preferably at least the third conveying device 10 is adjusted, further preferably decreased.

[0081] Now, as Figure 1 shown, the electronic process control device 7 obtains the liquid level parameter in the homogenization tank 2 from the process data 15 in the monitoring routine and determines the deviation from the predefined target liquid level in the homogenization tank 2. Preferably, the electronic process control device 7 adjusts the conveying power of at least the first conveying device 8 and / or the second conveying device 9, further preferably increases the conveying power. As a result, more liquid is output into the homogenization tank 2, so that the continuous liquid flow flowing out of the homogenization tank 2 can be maintained. Preferably, in order to reach the predefined target liquid level, the liquid flow conveyed into the homogenization tank 2 is a concentrated liquid flow and / or a diluted liquid flow. For this reason, it is preferred that, unless the continuous liquid flow flowing out of the homogenization tank 2 may thus stop, the conveying of the liquid flow to maintain the continuity of the liquid flow flowing out of the homogenization tank 2 does not exceed the extent that may result in a concentration lower than the target factor concentration in the homogenization tank 2.

[0082] The term "target factor" herein refers to the product, preferably the eluate or buffer solution. Similarly, the term "target factor concentration" herein refers to the product concentration, preferably the eluate concentration or buffer solution concentration. It should be noted that, as already described above, the conveying of the liquid flow into the homogenization tank 2 does not exceed the extent that results in a concentration lower than the preferably predefined product concentration, preferably the eluate concentration, or preferably the predefined buffer solution concentration. Preferably, this can be set by the user of the proposed method before and / or during the method for operating the continuous downstream process.

[0083] Additionally or alternatively, adjust, and further preferably reduce, preferably the conveying power of at least the third conveying device 10. Although this again results in a reduced flow velocity of the liquid flow flowing out of the homogenization tank 2, the continuity of the liquid flow flowing out of the homogenization tank 2 can thereby be maintained. Particularly preferably, in order to maintain continuous flow, first adjust, preferably increase, the conveying power of at least the first conveying device 8 and / or the second conveying device 9

[0084] Preferably, when adjusting the conveying power of at least the first conveying device 8 and / or the second conveying device 9 is not sufficient to maintain a continuous liquid flow, adjust the conveying power of at least the third conveying device 10. Preferably, the conveying power of the third conveying device 10 remains substantially constant. Otherwise, changes in the flow velocity may cause the residence time of the liquid flow in the bioprocess assembly 1 (which will be described in more detail later) to be lower than a predefined minimum residence time.

[0085] As Figure 1 、 Figure 2 and Figure 3 shown, and preferably herein, the electronic process control device 7 generates a first model 21 from the process data 15. Herein, the first model always refers to a mathematical model. Preferably, the degree of adjustment of the conveying power of the conveying assembly 6 is derived from the first model 21. Further preferably, the first model 21 reflects the relationship between on the one hand the liquid level parameter in the homogenization tank 2, preferably the target liquid level change per unit time, and on the other hand the conveying power of the first conveying device 8, the second conveying device 9, and / or the third conveying device 10. Preferably, the first model 21 is set up to predict the future target liquid level in the homogenization tank 2, preferably at a predefined moment, based on the change per unit time.

[0086] As Figure 2 shown, and preferably herein, the bioprocess assembly 1 has a first bioprocess inlet 22 downstream of the homogenization tank 2, which is configured to introduce the liquid flow into the pipeline assembly 12 of the bioprocess assembly 1. The first bioprocess inlet is preferably located downstream of the third conveying device 10. Preferably, the conveying assembly 6 has a fourth conveying device 23, which is associated with the first bioprocess inlet 22 and is configured to meter out the liquid flow into the pipeline assembly 12.

[0087] Here and preferably, in the homogenization tank 2, a concentrated liquid stream and a dilution liquid stream are combined into a first liquid stream 24 containing the target factor. The first liquid stream 24 containing the target factor preferably either contains the target product of biopharmaceuticals (such as an antibody or a vector) as the target factor and contains viruses in a process-related manner. Alternatively, the first liquid stream 24 preferably contains a target buffer (such as a balance buffer, a washing buffer, or an elution buffer, etc.) as the target factor. In this regard, the term "target factor" thus refers to a specific property of the liquid in the liquid stream 24, as described above.

[0088] Preferably, the first liquid stream 24 containing the target factor is introduced from the homogenization tank 2 into at least one fluid-connected pipeline 13 of the pipeline assembly 12 through the fluid outlet 5. Immediately afterwards, the first liquid stream is preferably combined with a second liquid stream 25 introduced through the first bioprocess inlet 22 and conveyed by the fourth conveying device 23 in a predefined volume ratio to form a reactive third liquid stream 26, so as to set predefined target values of the liquid parameters, especially the pH value and / or the conductivity, in the reactive third liquid stream 26.

[0089] As a characteristic required to meet the expected function, the second liquid stream 25 either has a virus inactivation condition with a pH value less than 3, especially. The virus inactivation condition of the second liquid stream 25, especially the pH value, is selected such that after combination with the first liquid stream 24 containing the target factor, the resulting reactive third liquid stream 26 also has a virus inactivation condition, especially a pH value of 3 to 3.8 and / or a detergent concentration between 0.05% and 10% (v / v). Such conditions result in effective virus inactivation without damaging the corresponding product of the bioprocess, especially proteins. The pH value is achieved by adding acids such as lactic acid, ascorbic acid, acetic acid, hydrochloric acid, phosphoric acid, citric acid, glycine, succinic acid, and / or sulfuric acid, etc. Preferably, the virus inactivation reagent can contain an acid with a titratable group having a pKs between 2.0 and 4.3. Here, the virus inactivation condition can be selected such that the concentration of the acid can be up to 100 mM and still has sufficient buffering properties to, on the one hand, achieve effective virus inactivation and, on the other hand, not destroy the protein product, for example, due to acid denaturation. Additionally or alternatively, the virus inactivation condition can be produced by a non-ionic detergent having a chromophore group. Such a detergent can be, for example, Triton-X 100 or other polyethylene oxides.

[0090] By the proposed method, the virus inactivation condition can be selected such that at least 1×10 1 、preferably at least 1×10 3 、more preferably at least 1×10 6the virus inactivation coefficient, and in particular regardless of whether it is exactly one specific virus type, multiple virus types, and / or multiple different virus types. The virus inactivation conditions can be selected such that the residence time of less than 1 ppm, preferably less than 1 ppb, of the volume of the reactive third liquid stream 26 is at least 1×10 1 and in particular at least 1×10 6 times.

[0091] As shown in Figure 2 the second liquid stream 25 is preferably mixed with the first liquid stream 24 containing the target factor in a precisely predefined volume ratio of the two liquid streams 24, 25 to each other for virus inactivation, so that the conditions for fulfilling the intended function can be ensured to actually exist and be evenly distributed in the reactive third liquid stream 26. For example, such a volume ratio can be 19:1, where 19 parts are the first liquid stream 24 containing the target factor and 1 part is the second virus inactivation liquid stream 25.

[0092] Alternatively, as a characteristic required to meet the intended function, the second liquid stream 25 preferably has buffer dilution conditions. Preferably, the second liquid stream 25 consists of a dilution buffer and / or water, etc. In this alternative, the buffer dilution conditions of the second liquid stream 25 are selected such that after combination with the first liquid stream 24 containing the target factor, the resulting reactive third liquid stream 26 also has buffer dilution conditions, in particular the target buffer concentration. The dilution for generating the target buffer concentration is achieved by adding a dilution buffer and / or water, etc.

[0093] Here and preferably, the bioprocess assembly 1 preferably has a first mixer 27 downstream of the first bioprocess inlet 22, which is set up for fluid mixing. Preferably, the reactive third liquid stream 26 is guided through the first mixer 27 for fluid mixing. Preferably, the mixer 27 is designed as an in-line static mixer, in particular a radial or laminar static mixer, etc., as shown in Figure 2 Preferably, multiple static mixers can be connected in series according to process requirements or accuracy requirements. Additionally or alternatively, a dynamic mixer can also be provided as the first mixer 27.

[0094] The term "fluid mixing" should be understood in a broad sense herein and refers to any form of mixing of fluids, in particular liquids. Fluid mixing goes beyond simply guiding fluids through pipelines, in particular hoses or conduits.

[0095] Preferably, the bioprocess assembly 1 here and preferably has a residence time assembly 28 (see Figure 2)。Preferably, the reactive third liquid stream 26 is directed through the residence time component 28 to set a minimum residence time.

[0096] The delivery of liquid streams to the homogenization tank 2 as described above to maintain a continuous liquid stream results in a change in concentration in the homogenization tank 2, preferably a change in product concentration or buffer concentration. Both of these parameters can affect the logarithmic reduction of the virus load, so that the residence time of the liquid stream in the residence time component 28 is at least 15 minutes, preferably up to 1 hour, so that such changes also remain non-critical.

[0097] The term "fluid connection" herein refers to a sealed connection that enables fluid to reach from one area to another at least unidirectionally, preferably bidirectionally, within it. Here, the fluid connection is also disconnected by mechanical disconnection.

[0098] A "residence time component" herein refers to a device that, in its properly assembled state, is used to allow a specific volumetric flow consisting of one or more combined fluid streams, especially liquid streams, to "reside" within the device, in such a way that the residence time component 28 is designed such that the path that the volumetric flow has to pass through is artificially extended, so that it has to pass through a distance that is many times the extension of the component. As explained above, it is crucial that the residence time distribution of the individual volumetric fractions to be inactivated be as uniform as possible in order to obtain reproducible inactivation results.

[0099] Here and preferably, the sensor assembly 14 for generating process data 15 has at least one sensor 29 for measuring liquid parameters, especially pH value and / or conductivity, of the first liquid stream 24 containing the target factor. The sensor is preferably designed as a pH sensor and is set up to measure the pH value in the first liquid stream 24 containing the target factor. Alternatively, the sensor 29 is preferably designed as a conductivity sensor. Further preferably, the sensor is set up to measure the conductivity in the first liquid stream 24 containing the target factor. The sensor 29 is here and preferably arranged downstream of the homogenization tank 2 and upstream of the first bioprocess inlet 22 ( Figure 2 ).

[0100] Additionally, the sensor assembly 14 here and preferably has at least one sensor 30, 31, preferably at least two sensors 30, 31, which are used to measure liquid parameters, especially pH value and / or conductivity, of the reactive third liquid stream 26. The sensor 30 is here and preferably arranged downstream of the first mixer 27. Additionally or alternatively, the sensor assembly 14 here and preferably has at least one sensor 31 for measuring liquid parameters in the reactive third liquid stream 26 downstream of the residence time component 28. The sensor 31 is especially used to measure the flow rate and / or protein concentration, preferably by means of UV (ultraviolet) measurement.

[0101] Preferably, the measurement of the flow rate is used to particularly precisely determine the residence time required for the reactive third liquid stream 26 in the residence time component 28. This is because, as already described above, the varying flow velocity causes the residence time of the liquid stream required for the specified method in the residence time component 28 to also vary. Therefore, the residence time of the liquid stream in the residence time component 28 can be set by adjusting the flow velocity.

[0102] Preferably, the measurement of UV absorption is used to particularly precisely determine the target factor concentration, especially the protein concentration. Depending on being below a preferably predefined minimum protein concentration, the electronic process control device 7 can control the delivery assembly 6 such that the flow direction of the reactive third liquid stream 26 is redirected via a line 13 of the line assembly 12, which will be described in more detail later, and the reactive third liquid stream 26 can be continuously guided further to a subsequent process step or can be disposed of in a subsequent treatment step. Preferably, this is the case when the predefined minimum protein concentration has already been undershot, because otherwise continuing to inactivate the product may not be economically viable. Especially at the start (during the so-called start-up period or shortly after start-up) or at the end of a continuous downstream process, especially a continuous virus inactivation process, the predefined minimum protein concentration may be undershot.

[0103] Preferably, the electronic process control device 7 adjusts the delivery power of the fourth delivery device 23 in the virus inactivation routine 32 to set a target value for the liquid parameters in the reactive third liquid stream 26. Preferably, this is done based on the deviation between the actual value of the liquid parameters of the first liquid stream 24 containing the target factor determined by measurement and the predefined target value of the liquid parameters in the reactive third liquid stream 26.

[0104] Preferably, the conductivity enables the electronic process control device 7 to derive the buffer concentration. According to this embodiment, if there is a deviation between the actual pH value in the first liquid stream 24 containing the target factor and the target value of the liquid parameters in the reactive third liquid stream 26, the electronic process control device 7 can preferably adjust the actual value of the liquid parameters, preferably the actual pH value or the actual conductivity, in the reactive third liquid stream 26 by controlling and / or regulating the fourth delivery device 23, which is preferably configured to output acid, buffer, and / or water in a metered manner.

[0105] Therefore, by measuring the pH value, preferably, on the one hand, the actual pH value in the first liquid stream 24 containing the target factor can be determined, and on the other hand, the electronic process control device 7 can calculate the volume and / or volume flow to be delivered in the reactive third liquid stream 26 to reach the target value of the liquid parameters, especially the target pH value, based on the process data 15.

[0106] Alternatively, by measuring the conductivity, preferably, on the one hand, the actual conductivity in the first liquid stream 24 containing the target factor can be determined, and on the other hand, the electronic process control device 7 can calculate, based on the process data 15, the volume and / or volume flow to be delivered in the reactive third liquid stream 26 to achieve the target value of the liquid parameter, in particular the target conductivity.

[0107] Furthermore, the pipeline assembly 12 preferably has a disposal pipeline 33 downstream of the residence time assembly 28, which is provided for discharging the liquid stream from the bioprocess assembly 1.

[0108] "Disposal pipeline" here refers to the pipeline 13 of the pipeline assembly 12 for establishing a fluid connection, where this pipeline provides the user of the proposed method with the possibility of not compulsorily guiding the liquid stream introduced into the bioprocess assembly 1 to the bioprocess outlet 11 and discharging it from the bioprocess outlet. This is particularly advantageous if, for example, the bioprocess assembly 1 is flushed with a buffer solution before the proposed continuous downstream process, especially if the bioprocess assembly 1 is flushed with a newly used buffer solution and / or a newly used concentrated liquid stream (especially a new product concentrated liquid stream or buffer concentrated liquid stream) in the proposed first continuous downstream process.

[0109] Additionally or alternatively, the situation is that the proposed method is used for a continuous online dilution process and the reactive third liquid stream 26 preferably already has the desired predefined target value of the liquid parameter in the reactive third liquid stream 26 and thus represents the finally diluted buffer solution. In this case, the finally diluted buffer solution can be continuously discharged from the bioprocess assembly 1 through the disposal pipeline 33 and directly used in a subsequent process step, especially a subsequent chromatographic step.

[0110] Here and preferably, the pipeline assembly 12 is associated with a valve assembly 34, and the valve assembly has at least one valve for selectively fluidly connecting at least one pipeline 13 of the pipeline assembly 12, especially the disposal pipeline 33.

[0111] Preferably, the bioprocess assembly 1 here and preferably has a second bioprocess inlet 35 downstream of the disposal pipeline 33, which is provided for introducing a liquid stream into the pipeline assembly 12 of the bioprocess assembly 1. Preferably, the conveying assembly 6 has a fifth conveying device 36. The fifth conveying device is preferably associated with the second bioprocess inlet 35 and is provided for meteringly outputting a liquid stream into the pipeline assembly 12.

[0112] According to Figure 2, the reactive third liquid stream 26 is combined here and preferably downstream of the residence time component 28 with a neutralizing fourth liquid stream 37 introduced through the second bioprocess inlet 35 to form a synthetic fifth liquid stream 38 in order to neutralize a predefined target value of the liquid parameters in the synthetic fifth liquid stream 38.

[0113] "Neutralization" here refers to a partial or complete reversal of a previous change in the liquid parameters and thereby the elimination and / or removal of virus inactivation conditions, in particular by the reaction of an equal amount of an acid (e.g., 1.5 to 3 M acetic acid) or acid derivative (e.g., 2 M glycine) and a base (e.g., 1 M to 2 M HEPES with a pH of 8 or Tris with a pH of 11). The neutralizing fourth liquid stream 37 is used to neutralize, consume, and / or remove virus inactivation conditions. By combining the third liquid stream 26 with the fourth liquid stream 37, a synthetic fifth liquid stream 38 is produced, which can be discharged from the bioprocess assembly 1 through the bioprocess outlet 11 and has a pH value, preferably a pH value between 5 and 8.5, which enables further processing. Here and preferably, the mixing of these two liquid streams 26, 37 is also carried out in a precisely predefined volume ratio so that it can be ensured that the neutralization conditions for fulfilling the intended function are indeed present and evenly distributed in the synthetic fifth liquid stream 38.

[0114] Preferably, in a continuous online dilution process, the introduction of the neutralizing fourth liquid stream 37 is optional. In cases where the buffer has to be further diluted to reach predefined conditions, a diluted buffer, water, etc. can be additionally added to the reactive third liquid stream 26 through the second bioprocess inlet 35. If the predefined conditions have been reached, alternatively no addition may be made, such that the reactive third liquid stream 26 leaves the bioprocess assembly 1 through the bioprocess outlet 11.

[0115] Here and preferably, the corresponding conveying devices (8, 9, 23, 36), especially all conveying devices designed to output liquid streams in a metered manner, are designed as metering pumps, further preferably as peristaltic pumps, rotary piston pumps, or diaphragm pumps, or as valves, especially continuous valves, regulating valves, etc.

[0116] Here and preferably, the bioprocess assembly 1 has at least one second mixer 39 downstream of the second bioprocess inlet 35, which is provided for fluid mixing. Preferably, the synthetic fifth liquid stream 38 is guided through the at least one second mixer 39 for fluid mixing and is discharged from the bioprocess assembly 1 through the bioprocess outlet 11 after the fluid mixing is completed. The second mixer 39 can also be designed as an online static mixer, especially a radial or laminar static mixer, etc., as in Figure 2As shown. Preferably, a plurality of static mixers can be connected in series according to process requirements or precision requirements. Additionally or alternatively, a dynamic mixer can also be provided as the second mixer 39.

[0117] Here and preferably, the sensor assembly 14 for generating the process data 15 has at least one sensor 40 for measuring the liquid parameters, in particular the pH value and / or the conductivity, of the synthesized fifth liquid stream 38. The sensor 40 is here and preferably arranged downstream of the second mixer 39.

[0118] Preferably, the electronic process control device 7 adjusts the delivery power of the fifth delivery device 36 in the neutralization routine 41 to set a target value for the liquid parameters in the synthesized fifth liquid stream 38. Preferably, this is done based on the deviation between the actual value of the liquid parameters of the reactive third liquid stream 26 determined by measurement and the predefined target value of the liquid parameters in the synthesized fifth liquid stream 38.

[0119] Preferably, the conductivity enables the electronic process control device 7 to derive the buffer concentration. According to this embodiment, if there is a deviation between the actual pH value in the reactive third liquid stream 26 and the target value of the liquid parameters in the synthesized fifth liquid stream 38, the electronic process control device 7 can preferably adjust the actual value of the liquid parameters, preferably the actual pH value or the actual conductivity, in the synthesized fifth liquid stream 38 by controlling and / or regulating the fifth delivery device 36 (which is preferably set up to output acid, buffer and / or water in a metered manner).

[0120] Therefore, by measuring the pH value, preferably, on the one hand, the actual pH value in the reactive third liquid stream 26 can be determined, and on the other hand, the electronic process control device 7 can calculate, based on the process data 15, the volume and / or volume flow to be delivered to achieve the target parameter value, in particular the target pH value, in the synthesized fifth liquid stream 38.

[0121] Alternatively, by measuring the conductivity, preferably, on the one hand, the actual conductivity in the reactive third liquid stream 26 can be determined, and on the other hand, the electronic process control device 7 can calculate, based on the process data 15, the volume and / or volume flow to be delivered to achieve the target value of the liquid parameters, in particular the target conductivity, in the synthesized fifth liquid stream 38.

[0122] According to a particularly preferred design, the respective sensors 16, 29, 30, 31, 40 for generating process data 15 measure at least one parameter from the following group, which includes pH value, conductivity, liquid level, change in liquid level per unit time, conveying power of at least one conveying device, flow rate of at least one liquid stream, protein concentration, and / or other spectrophotometric characteristics of at least one liquid stream. In a design with multiple sensors 16, 29, 30, 31, 40, at least two of them can measure the same or different parameters.

[0123] Here, the electronic process control device 7 can generate a second model 42 from the process data 15. Preferably, the degree of adjustment of the conveying power of the fourth conveying device 23 and / or the fifth conveying device 36 is derived from the second model 42. Preferably, the second model 42 reflects the relationship between the liquid parameters of the reactive third liquid stream 26 on the one hand and the conveying power of the fourth conveying device 23 on the other hand. Additionally or alternatively, the second model 42 preferably reflects the relationship between the liquid parameters of the synthesized fifth liquid stream 38 on the one hand and the conveying power of the fifth conveying device 36 on the other hand. The electronic process control device 7 adjusts preferably at least the conveying assembly 6 based on the second model 42. Here and preferably, as shown in Figure 2 the electronic process control device 7 calculates, based on the process data 15, how much volume, volume flow, etc. of the second liquid stream 25 must be added to the first liquid stream 24 containing the target factor in order to generate a target value of the liquid parameter, in particular a target pH value or a target conductivity, in the reactive third liquid stream 26. Additionally or alternatively, here and preferably, as shown in Figure 2 the electronic process control device 7 calculates, based on the process data 15, how much volume, volume flow, etc. of the fourth liquid stream 37 must be added to the reactive third liquid stream 26 in order to generate a target value of the liquid parameter, in particular a target pH value or a target conductivity, in the synthesized fifth liquid stream 38.

[0124] Especially in a continuous online dilution process, the second model 42 preferably calculates the degree of adjustment of the conveying power of the fourth conveying device 23 based on at least one characteristic curve between the conductivity measured in the first liquid stream 24 containing the target factor and the corresponding buffer concentration. Additionally or alternatively, the second model 42 preferably calculates the degree of adjustment of the conveying power of the fifth conveying device 36 based on at least one characteristic curve between the conductivity measured in the reactive third liquid stream 26 and the corresponding buffer concentration.

[0125] Here and preferably, the first model 21 and / or the second model 42 is a statistical model or an analytical model.

[0126] The term "statistical model" refers to a mathematical model in which several or all of the input data have a certain degree of randomness, which is represented, for example, by a probability distribution, such that for a specific set of input data, the output is not repeatable but is described by a probability distribution. Output data are obtained by running the model multiple times using new input values each time extracted from the probability distribution.

[0127] The term "analytical model" refers to a quantitative model used to answer specific questions. Its main objective is to provide a closed formula for a specific characteristic. Thus, an analytical model is a mathematical model that has a closed-form solution, that is, the solution of the equations used to describe the changes in a system can be expressed as a mathematical analytical function.

[0128] Herein and preferably, the liquid stream discharged from the bioprocessing component 1, preferably the reactive third liquid stream 26 or the synthesized fifth liquid stream 38, continuously leaves the bioprocessing component 1. Further preferably, the discharged reactive third liquid stream 26 continuously leaves the bioprocessing component 1 through the disposal pipeline 33. Alternatively, the discharged synthesized fifth liquid stream 38 continuously leaves the bioprocessing component 1 through the bioprocess outlet 11.

[0129] "Continuously" herein means that the liquid streams 25, 35 leaving the bioprocessing component 1 are not interrupted (such as being interrupted by incubation in a container, etc.), and their flow rates may vary.

[0130] Herein and preferably, at least the first mixer 27 and / or the second mixer 39, preferably all mixers, are provided for online mixing of liquid streams and are designed as static mixers or rotary pumps, especially centrifugal rotary pumps. Further preferably, the rotary pumps for dynamic online mixing are flowed through in the opposite flow direction compared to the specified operation.

[0131] Preferably, the proposed method can be carried out in combination with a preposed, preferably discontinuous or continuous chromatography method, especially an affinity chromatography method and an ion exchange chromatography method. Additionally or alternatively, the proposed method is carried out in combination with a preposed, preferably discontinuous or continuous filtration method, especially a tangential flow filtration method, etc. Additionally or alternatively, a continuous chromatography method or filtration method is postposed to the proposed method.

[0132] In principle, the proposed method can be used in combination with all purification methods, filtration methods, chromatography methods, separation methods, centrifugation methods, concentration methods, and / or precipitation methods or other methods related to downstream processes during the bioprocess.

[0133] According to another teaching of independent significance, a bioprocess component 1 for operating a continuous downstream process, in particular a continuous bacterial inactivation process or an online dilution process, during a bioprocess is provided. The bioprocess component 1 has a homogenization tank 2 which has a first fluid inlet 3 and at least one second fluid inlet 4. The first fluid inlet is provided for introducing a concentrate stream, in particular a product concentrate stream or a buffer concentrate stream, into the homogenization tank 2. The second fluid inlet is provided for introducing a dilution stream, in particular a product dilution stream or a buffer dilution stream, into the homogenization tank 2. The bioprocess component 1 has a fluid outlet 5 which is provided for discharging a liquid stream from the homogenization tank 2. In addition, the bioprocess component 1 has a conveying assembly 6 for fluid conveyance, which is associated with the first fluid inlet 3 and the second fluid inlet 4 to convey the corresponding at least one liquid stream into the homogenization tank 2. Additionally, the conveying device 6 is associated with the fluid outlet 5 to convey the liquid stream out of the homogenization tank. The bioprocess component 1 has an electronic process control device 7.

[0134] Now, what is important in the proposed bioprocess component 1 is that, when the bioprocess component 1 is operating as specified, the electronic process control device 7 adjusts the liquid level in the homogenization tank 2 by controlling and / or regulating the conveying assembly 6. This adjustment is made such that a predefined minimum liquid level in the homogenization tank 2 is not undershot, in order to thereby ensure a continuous liquid stream from the bioprocess component 1.

[0135] Here and preferably, at least one component of the bioprocess component 1, preferably all components, are designed as single-use components.

[0136] According to another teaching of independent significance as claimed in claim 26, an electronic process control device 7 of the proposed bioprocess component 1 is claimed. In this regard, reference may be made to all embodiments of the proposed method for operating a continuous downstream process and the proposed bioprocess component 1.

[0137] Here and preferably, a valve assembly 34 is associated with the pipeline assembly 12, which valve assembly has at least one valve for selectively fluidly connecting at least one pipeline 13, in particular all pipelines, of the pipeline assembly 12. The electronic control unit 7 is provided to perform the proposed method by controlling and / or regulating at least the conveying device 6.

[0138] According to the preferred design as claimed in claim 27, the electronic process control device 7 preferably has a data processing system for implementing the proposed method.

[0139] According to another teaching having independent significance as claimed in claim 28, there is claimed the use of an electronic process control device 7 for implementing the proposed method. In this regard, reference may be made to all embodiments of the proposed method for operating a continuous downstream process, the proposed bioprocess component 1, and the proposed electronic process control device 7.

[0140] According to another teaching having independent significance as claimed in claim 29, there is claimed a computer program for the proposed electronic process control device 7. In this regard, reference may be made to all embodiments of the proposed method for operating a continuous downstream process, the proposed bioprocess component 1, the proposed electronic process control device 7, and the proposed use.

[0141] According to another teaching having independent significance as claimed in claim 30, there is claimed a computer-readable storage medium for storing the proposed computer program. In this regard, reference may be made to all embodiments of the proposed method for operating a continuous downstream process, the proposed bioprocess component 1, the proposed electronic process control device 7, the proposed use, and the proposed computer program.

Claims

1. A method for operating a continuous downstream process, in particular a continuous bacteria inactivation process or an inline dilution process, during a bioprocess using a bioprocess component (1), in, The bioprocess component (1) comprises a homogenization tank (2), wherein the homogenization tank comprises: a first fluid inlet (3), which is configured to introduce a concentrate flow, in particular a product concentrate flow or a buffer concentrate flow, into the homogenization tank (2); at least one second fluid inlet (4), which is configured to introduce a diluent flow, in particular a product dilution flow or a buffer dilution flow, into the homogenization tank (2); a fluid outlet (5), which is configured to discharge a liquid flow from the homogenization tank (2), wherein the bioprocess component (1) comprises a conveying component (6) for fluid conveying, wherein the conveying component is associated with the first fluid inlet (3) and the second fluid inlet (4) to convey at least one corresponding liquid flow into the homogenization tank (2), and the conveying component is associated with the fluid outlet (5) to convey the liquid flow out of the homogenization tank (2), and wherein the bioprocess component (1) comprises an electronic process control device (7), It is characterized in that The electronic process control (7) regulates the liquid level in the homogenization tank (2) by controlling and / or regulating the conveying assembly (6) in such a way that the liquid level does not fall below a predefined minimum level in the homogenization tank (2).

2. The method according to claim 1, It is characterized in that The electronic process control device (7) regulates the liquid level in the homogenization tank (2) by controlling and / or regulating the conveying component (6) in such a way that a predefined target liquid level is reached or the liquid level is kept within a target liquid level range.

3. The method according to claim 1 or 2, It is characterized in that The conveying component (6) has a first conveying device (8) for fluid conveying, the first conveying device is associated with the first fluid inlet (3), and / or the conveying component (6) has a second conveying device (9) for fluid conveying, the second conveying device is associated with the second fluid inlet (4), and / or the conveying component (6) has a third conveying device (10) for fluid conveying, the third conveying device is associated with the fluid outlet (5).

4. The method according to any one of the preceding claims, It is characterized in that The bioprocess component (1) has a bioprocess outlet (11), which is configured to discharge fluid from the bioprocess component (1). The bioprocess component (1) has a pipeline assembly (12), which has at least one pipeline (13) for fluidly connecting the fluid outlet (5) of the homogenization tank (2) to the bioprocess outlet (11). The third conveying device (10) is configured to convey the fluid through at least one pipeline (13) of the pipeline assembly (12).

5. The method according to any one of the preceding claims, It is characterized in that The bioprocess component (1) has a sensor component (14) for generating process data (15), the sensor component having at least one sensor (16) associated with the homogenization tank (2), and the electronic process control device (7) derives from the process data (15) an actual value of a level parameter in the homogenization tank (2) in a monitoring routine (17) and adjusts the delivery capacity of the first conveying device (8), the second conveying device (9) and / or the third conveying device (10) as a function of a deviation between the determined actual value of the level parameter and a predefined minimum value of the level parameter corresponding to a predefined minimum level in the homogenization tank (2) to prevent the level from falling below the minimum level, or According to the deviation between the obtained actual value of the liquid level parameter and the predefined target value of the liquid level parameter corresponding to the predefined target liquid level in the homogenization tank (2), the conveying power of the first conveying device (8), the second conveying device (9) and / or the third conveying device (10) is adjusted to achieve the target liquid level, or According to the deviation between the actual value of the obtained liquid level parameter and the predefined limit value of the predefined target liquid level range in the homogenization tank (2), the delivery power of the first delivery device (8), the second delivery device (9) and / or the third delivery device (10) is adjusted to keep the liquid level within the target liquid level range.

6. The method according to any one of the preceding claims, It is characterized in that The electronic process control device (7) generates a first model (21) from the process data (15) and derives from the first model (21) the degree of adjustment of the delivery capacity of the delivery component (6), preferably, the first model (21) reflects the relationship between the liquid level parameter in the homogenization tank (2) on the one hand and the delivery capacity of the first delivery device (8), the second delivery device (9) and / or the third delivery device (10) on the other hand.

7. The method according to any one of the preceding claims, It is characterized in that The bioprocess component (1) has a first bioprocess inlet (22) downstream of the homogenization tank (2), and the first bioprocess inlet is configured to introduce a liquid flow into the pipeline component (12) of the bioprocess component (1). The conveying component (6) has a fourth conveying device (23), which is associated with the first bioprocess inlet (22) and is configured to output the liquid flow to the pipeline component (12) in a metered manner.

8. The method according to any one of the preceding claims, It is characterized in that The concentrate stream and the dilute stream are combined in the homogenization tank (2) to form a first liquid stream (24) containing a target factor, and the first liquid stream (24) containing the target factor is introduced from the homogenization tank (2) into at least one fluid-connected pipeline (13) of the pipeline assembly (12) through the fluid outlet (5), and the first liquid stream is combined in a predefined volume ratio with a second liquid stream (25) preferably introduced through the first bioprocess inlet (22) and transported through the fourth transport device (23) to form a reactive third liquid stream (26), so as to set a predefined target value of a liquid parameter in the reactive third liquid stream (26), in particular a pH value and / or conductivity.

9. The method according to claim 8, It is characterized in that The bioprocess component (1) preferably has a first mixer (27) downstream of the first bioprocess inlet (22), the first mixer being configured for fluid mixing, and the reactive third liquid flow (26) is guided through the first mixer (27) for fluid mixing.

10. The method according to claim 8 or 9, It is characterized in that The bioprocess component (1) preferably has a residence time component (28) downstream of the at least one mixer (27) and is fluidically connected to the first mixer (27) for setting a minimum residence time of the liquid flow, and the reactive third liquid flow (26) is directed through the residence time component (28) immediately following the at least one mixer (27) to set the minimum residence time.

11. The method according to any one of claims 7 to 10, It is characterized in that The sensor component (14) for generating process data (15) comprises: at least one sensor (29) for measuring liquid parameters, in particular pH value and / or conductivity, of the first liquid flow (24) containing the target factor; and at least one sensor (30, 31), preferably at least two sensors (30, 31), for measuring liquid parameters, in particular pH value and / or conductivity, of the reactive third liquid flow (26), the sensors being preferably arranged downstream of the first mixer (27) and / or the residence time component (28).

12. The method according to claim 11, It is characterized in that The electronic process control device (7) adjusts the delivery power of the fourth delivery device (23) in the virus inactivation routine (32) to set the target value of the liquid parameter in the reactive third liquid flow (26) based on the deviation between the actual value of the liquid parameter of the first liquid flow (24) containing the target factor determined by the measurement and the predefined target value of the liquid parameter in the reactive third liquid flow (26).

13. The method according to any one of the preceding claims, It is characterized in that The line module (12) preferably has a disposal line (33) downstream of the residence time module (28), which is designed to discharge a liquid stream from the bioprocess module (1).

14. The method according to any one of the preceding claims, It is characterized in that The pipeline assembly (12) is associated with a valve assembly (34) having at least one valve for selectively fluidically connecting at least one pipeline (13), in particular the disposal line (33), of the pipeline assembly (12).

15. The method according to any one of the preceding claims, It is characterized in that The bioprocess component (1) preferably has a second bioprocess inlet (35) downstream of the disposal line (33), and the second bioprocess inlet is configured to introduce a liquid flow into the pipeline component (12) of the bioprocess component (1). The conveying component (6) has a fifth conveying device (36), which is associated with the second bioprocess inlet (35) and is configured to output the liquid flow to the pipeline component (12) in a metered manner. Preferably, the reactive third liquid flow (26) is combined with the neutralizing fourth liquid flow (37) introduced through the second bioprocess inlet (35) downstream of the residence time component (28) to form a synthetic fifth liquid flow (38) so as to neutralize the predefined liquid parameters in the synthetic fifth liquid flow (38).

16. A method according to any one of the preceding claims, It is characterized in that The corresponding conveying devices (8, 9, 23, 36), preferably all conveying devices set up for metering liquid flows, are designed as metering pumps, in particular as peristaltic pumps, rotary piston pumps or diaphragm pumps, or as valves, in particular continuous valves, regulating valves, etc.

17. A method according to any one of the preceding claims, It is characterized in that The bioprocess component (1) preferably has at least one second mixer (39) downstream of the second bioprocess inlet (35), which is configured for fluid mixing, and the synthesized fifth liquid flow (38) is guided through the second mixer (39) for fluid mixing.

18. A method according to any one of the preceding claims, It is characterized in that The sensor assembly (14) for generating process data (15) preferably has at least one sensor (40) for measuring a liquid parameter, in particular a pH value and / or conductivity, of the synthesized fifth liquid flow (38) downstream of the second mixer (39), and the electronic process control device (7) adjusts the delivery power of the fifth delivery device (36) in a neutralization routine (41) to set a target value for the liquid parameter in the synthesized fifth liquid flow (38) based on a deviation between an actual value of the liquid parameter of the reactive third liquid flow (26) determined by the measurement and a predefined target value for the liquid parameter in the synthesized fifth liquid flow (38).

19. A method according to any one of the preceding claims, It is characterized in that The corresponding sensors (16, 29, 30, 31, 40) for generating process data (15) measure at least one parameter from the following group, the group including pH value, conductivity, liquid level, liquid level change per unit time, delivery power of at least one delivery device, flow rate of at least one liquid flow, protein concentration and / or other spectrophotometric properties of at least one liquid flow.

20. The method according to any one of the preceding claims, It is characterized in that The electronic process control device (7) generates a second model (42) from the process data (15), and derives the degree of adjustment of the delivery capacity of the fourth delivery device (23) and / or the fifth delivery device (36) from the second model (42). Preferably, the second model (42) reflects the relationship between the liquid parameters of the reactive third liquid flow (26) on the one hand and the delivery capacity of the fourth delivery device (23) on the other hand, and / or the second model (42) reflects the relationship between the liquid parameters of the synthetic fifth liquid flow (38) on the one hand and the delivery capacity of the fifth delivery device (36) on the other hand.

21. The method according to any one of claims 6 to 20, It is characterized in that The first model (21) and / or the second model (42) is a statistical model or an analytical model.

22. A method according to any one of the preceding claims, It is characterized in that A liquid stream discharged from the bioprocess component (1), preferably the reactive third liquid stream (26) or the synthetic fifth liquid stream (38), continuously leaves the bioprocess component (1).

23. A method according to any one of the preceding claims, It is characterized in that At least the first mixer (27) and / or the second mixer (39), preferably all mixers, are set up for in-line mixing of liquid flows and are designed as static mixers or rotary pumps, in particular centrifugal rotary pumps. It is further preferred that the rotary pump for dynamic in-line mixing is circulated in the opposite flow direction compared to the prescribed operation.

24. A method according to any one of the preceding claims, It is characterized in that The proposed method is carried out in combination with a preceding, preferably discontinuous or continuous, chromatography method and / or filtering method and / or a continuous chromatography method or filtering method is arranged downstream of the proposed method.

25. A bioprocess component (1) for running a continuous downstream process during a bioprocess, in particular a continuous bacteria inactivation process or an in-line dilution process, in, The bioprocess component (1) comprises a homogenization tank (2), wherein the homogenization tank comprises: a first fluid inlet (3), which is configured to introduce a concentrate flow, in particular a product concentrate flow or a buffer concentrate flow, into the homogenization tank (2); at least one second fluid inlet (4), which is configured to introduce a diluent flow, in particular a product dilution flow or a buffer dilution flow, into the homogenization tank (2); a fluid outlet (5), which is configured to discharge a liquid flow from the homogenization tank (2), wherein the bioprocess component (1) comprises a conveying component (6) for fluid conveying, wherein the conveying component is associated with the first fluid inlet (3) and the second fluid inlet (4) to convey at least one corresponding liquid flow into the homogenization tank (2), and the conveying component is associated with the fluid outlet (5) to convey the liquid flow out of the homogenization tank (2), and wherein the bioprocess component (1) comprises an electronic process control device (7), It is characterized in that When the bioprocess component (1) is operated in accordance with regulations, the electronic process control (7) adjusts the liquid level in the homogenization tank (2) by controlling and / or regulating the conveying component (6) in such a way that the liquid level does not fall below a predefined minimum level in the homogenization tank (2).

26. An electronic process control device (7) of a bioprocess component (1) according to claim 25, It is characterized in that The pipeline assembly (12) is associated with a valve assembly (34), which has at least one valve for selectively fluidically connecting at least one pipeline (13), preferably all pipelines, of the pipeline assembly (12), the electronic process control device (7) controlling at least the conveying assembly (6) or additionally the valve assembly (34), and the electronic process control device (7) is set up to perform the method according to any one of claims 1 to 24 by controlling and / or regulating at least the conveying assembly (6).

27. The electronic process control device (7) according to claim 26, It is characterized in that The electronic process control (7) has a data processing system for implementing the method according to any one of claims 1 to 24.

28. Use of an electronic process control device (7) according to claim 26 or 27 for carrying out a method according to any one of claims 1 to 24.

29. A computer program for an electronic process control (7) according to claim 26 or 27.

30. A computer-readable storage medium on which a computer program according to claim 29 is stored, preferably in a non-volatile manner.

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