Method for inactivating virus in fluid

Abstract

The invention relates to a method for inactivating viruses in a fluid, in which a starting fluid (AF) laden with an active virus is mixed in a first mixing device (2) with a virus inactivation reagent (R1) to form a reactive fluid (F) and the active virus is inactivated by incubating the reactive fluid (F), and stopping the inactivation of the virus in the reactive fluid (F) by mixing the reactive fluid (F) with another reagent (R2) or by removing the virus inactivation reagent (R1) from the reactive fluid (F), thereby producing the resulting fluid (RF). It is proposed that the active virus is inactivated by incubating a reactive fluid (F) in a container device (3) different from the first mixing device (2) and comprising a plurality of separate containers (4), the reactive fluid (F) being guided from the first mixing device (2) to the container device (3) before incubation.

Description

[0001] The present invention relates to a method for inactivating viruses in a fluid according to the preamble of claim 1 , a method for incubating a fluid according to the preamble of claim 8 and an incubation device for incubating a fluid according to the preamble of claim 9.

[0002] In the field of biotechnology, different methods for inactivating viruses in fluids are known. For example, in processes containing active viruses in certain biopharmaceutical products (e.g., protein solutions), it is necessary to inactivate viruses. Viruses can, for example, be added by external sources (e.g., starting materials for fermentation) during production or introduced into the process by internal sources (e.g., cell lines used in the process). By inactivating viruses, potential viral contamination in the product can be reliably prevented from causing subsequent infection in patients.

[0003] In order to deactivate, at first the starting fluid that will be loaded with active virus and virus inactivation reagent are mixed in mixing apparatus to form reactive fluid.Mixing comprises that this reagent is added in the starting fluid, and homogenizes at least in part.Available reagent comprises the reagent that for example reduces or raises fluid pH value, so that virus is inactivated in acidic or alkaline environment (for example, by oxidizing reaction).Yet alternative virus inactivation reagent and the chemical substance that causes corresponding deactivation also can be used as reagent.

[0004] Active viruses are inactivated by incubating the reactive fluid. The incubation of the reactive fluid is carried out for a desired period of time to inactivate a certain proportion of the initial active viruses. Generally, it is not necessary to inactivate all active viruses, but only a certain proportion of the active viruses.

[0005] After incubating the fluid, the virus inactivation in the reactive fluid is stopped. This is done by mixing the reactive fluid with other reagents or by removing the virus inactivation reagent from the reactive fluid.

[0006] For example, if the starting fluid was previously mixed with a reagent that lowers or raises the pH, the pH can be raised or lowered again by mixing the reactive fluid with other reagents. However, if an alternative viral inactivation reagent or an alternative viral activation chemical was previously mixed as a reagent, it can be removed from the reactive fluid again. A resulting fluid is generated from the reactive fluid by mixing with other reagents or by removing the contained reagents.

[0007] The prior art (US2013 / 0260419 A1) on which the present invention is based relates to this method. A fluid loaded with active virus is mixed with a pH-lowering agent in a mixing device comprising multiple mixers and incubated in the mixing device, thereby inactivating the active virus over time. The inactivation is then stopped by mixing the fluid with another agent that raises the pH, thereby obtaining the resulting fluid.

[0008] While such methods can reliably inactivate viruses in liquids, they are relatively inflexible and can hardly be individually adapted to varying process conditions. This is because, for example, the capacity of such methods, in terms of fluid volume and incubation time, is limited by the available mixers in the mixing device, making it difficult to adapt the methods to varying process conditions, such as larger fluid volumes or longer incubation times.

[0009] The present invention is therefore based on the problem of designing and developing the methods known from the prior art in order to obtain a flexible method for inactivating viruses in fluids which can be individually adapted to different process conditions.

[0010] In the method according to the preamble of claim 1 , this problem is solved by the characterizing features of claim 1 .

[0011] The basic principle is that the incubation of reactive fluid and therefore the inactivation of active viruses are carried out in a plurality of independent containers, rather than being carried out in a mixing apparatus as usual in the prior art. Reactive fluid can be contained in each container respectively, and under specific, particularly adjustable incubation conditions, incubate the specific incubation time, and in the mixing apparatus, further starting fluid can be mixed with a virus inactivation reagent. This makes it possible, for example, to incubate reactive fluid in the first container, and in the first mixing apparatus, further starting fluid can be mixed with a virus inactivation reagent to form a further reactive fluid simultaneously. Then, reactive fluid from the first mixing apparatus can enter the second container and incubate, and can not damage the incubation in the first container thus. After incubating in the first container, it can be emptied, and the reactive fluid incubated is further processed, and simultaneously in the second container, continues the incubation reactive fluid. Simultaneously, further mixing can be carried out in the first mixing apparatus.

[0012] Specifically, it is generally proposed that active viruses are inactivated by incubating a reactive fluid in a container device that is different from the first mixing device and includes multiple independent containers, wherein the reactive fluid is directed to the container device from the first mixing device before incubation. Spatially separated by mixing and incubation, different from methods known in the prior art, the parallelization type of method steps is achieved, so the method can be particularly flexible and personalized to adapt to different process conditions. For example, if the incubation time of the inactivated active virus is to be extended, the reactive fluid contained in the independent container can be incubated for a longer time with ease, while the mixing device has mixed further starting fluid and virus inactivation reagent to form a reactive fluid, and then the reactive fluid is directed to another container without damaging the incubation of the remaining containers. For example, if a larger amount of fluid is to be incubated, the reactive fluid can be directed to multiple containers with ease, especially without the need for complex redesign.

[0013] Claims 2 and 3 define preferred embodiments regarding mixing in the first mixing device. By means of the embodiment according to claim 2, fluids can be mixed alternately in the first mixing device. In particular, by distributing the temporally successive input flows of the starting fluid to different mixers and / or tangential flow filters, discontinuously flowing starting fluid can also be mixed with the virus inactivation reagent to form a reactive fluid. For example, the starting fluid and the reagent can be mixed in the first mixer, while the starting fluid is filled in the second mixer; or, for example, the reactive fluid in the first mixer is emptied, while the starting fluid and the reagent are mixed in the second mixer. Reliable virus inactivation in the reactive fluid can be achieved by increasing or decreasing the pH value of the fluid (claim 3). By increasing or decreasing the pH value in steps according to the preferred embodiment of claim 3, the pH value can be gradually adjusted.

[0014] Claims 4 and 5 define preferred embodiments regarding mixing in a second mixing device and removal via a separation device. The embodiment according to claim 4 with a second mixing device enables mixing of the reactive fluid with other reagents after incubation of the fluid, thereby stopping inactivation after inactivating viruses in the fluid. For example, it is conceivable that the pH value, which has been lowered or raised for inactivation, can be raised or lowered again to neutralize the virus-inactivating reagent. An alternative embodiment according to claim 4 with a separation device enables removal of the virus-inactivating reagent from the reactive fluid after incubation of the fluid, thereby stopping inactivation after inactivating viruses in the fluid. The embodiment according to claim 5 with a second mixing device particularly enables mixing of discontinuously flowing reactive fluid with other reagents to form a resulting fluid by distributing the input streams sequentially over time to different mixers and / or tangential flow filters. Additionally or alternatively, the embodiment according to claim 5 enables continuous discharge of the resulting fluid. For example, the first mixer can be emptied to allow the resulting fluid to flow out, while the reactive fluid is simultaneously mixed with other reagents in the second mixer to form the resulting fluid. Once mixing in the second mixer is complete, the second mixer can be emptied and the resulting fluid can be discharged. The advantages described above also apply to the embodiment according to claim 5 with a separating device.

[0015] The embodiment according to claim 6 involves filling the container with the reactive fluid from a first mixing device and emptying the reactive fluid from the container, in particular an individually controllable container, into a second mixing device or a separation device. By filling and emptying sequentially or simultaneously or at least partially simultaneously, the method allows particularly simple adjustment of the fluid quantities and incubation times.

[0016] The embodiment according to claim 7 makes it possible to convert a discontinuous inflow of the starting fluid into a continuous outflow of the fluid obtained after viral inactivation. This allows the method to be used also for an input stream of the starting fluid, which, for example, is discontinuously inflowing due to a previous discontinuous process (e.g., a previous chromatography, such as rapid cycle chromatography or a previous batch process), while simultaneously achieving a continuous outflow.

[0017] According to the further teaching of claim 8, which has independent significance, a method for incubating a fluid, preferably for inactivating viruses, is proposed, having the features according to claim 8. Reference may be made to all the statements above regarding the proposed method for inactivating viruses, in particular the statements regarding mixing the starting fluid with a reagent, in particular a first reagent, in a first mixing device to form a reactive fluid, the statements regarding incubating the reactive fluid, the statements regarding mixing the reactive fluid with a further reagent, in particular a second reagent, to form the resulting fluid, the statements regarding removing the reagent, in particular the first reagent, and the statements regarding the features of the characterizing section.

[0018] According to the further teaching of claim 9, which has independent significance, an incubation device for incubating fluids, in particular for inactivating viruses, is provided. This incubation device can be used, for example, in the method provided above. In this regard, reference is made to all the statements made above regarding the method provided above.

[0019] According to the embodiment of claim 10, the incubation device includes a second mixing device or a separation device. The second mixing device allows the reactive fluid to be mixed with other reagents that can stop the virus inactivation after incubation. The separation device allows the virus inactivation reagent to be separated from the reactive fluid after incubation. This allows, in particular, the inactivation process to be stopped.

[0020] Claims 11 to 13 define advantageous embodiments of the first mixing device and the second mixing device and the separation device. By using a plurality of mixers or a plurality of tangential flow filters, or a combination of a mixer and a tangential flow filter, for example, discontinuously flowing fluids can be mixed by alternating the mixing of the one or more mixers and / or the one or more tangential flow filters, or the mixed fluid can be discharged continuously by alternately emptying the one or more mixers and / or alternating the flow through the one or more tangential flow filters (claim 11). For example, it can be provided that the starting fluid can be mixed with the reagent in the first mixer while the second mixer is simultaneously filled with the starting fluid; or that the reactive fluid can be drained from the first mixer while the starting fluid is mixed with the reagent in the second mixer. The embodiment of the separation device according to claim 11 also offers the same advantages, for example, by allowing the separation device to process discontinuously flowing fluids and to discharge the fluid continuously after the reagents have been removed. The modular expandability of the incubation device (claim 12) allows for particularly flexible and individual adaptation to processes and process conditions, particularly without requiring a major redesign of the incubation device. Via the recycling section (claim 13), the mixed fluid can be recycled to the mixer of the first mixing device and / or the tangential flow filter and / or the filter and / or the centrifuge of the second mixing device and at least a part of the mixing process (in particular selectively) or the separation process (i.e., removal of the reagent, in particular selectively) can be repeated.

[0021] According to the embodiment of claim 14, the incubation device has a first distributor and / or a second distributor. The reactive fluid can be guided from the first mixing device to the container of the container device by the first distributor, and the reactive fluid can be guided from the container of the container device to the second mixing device or the separation device by the second distributor. According to another embodiment of claim 14, the container can be selectively connected to and / or separated from the first distributor and / or the second distributor. This enables the incubation device to be flexibly and individually further adapted to the process and process conditions without the need for extensive redesign, for example, if a larger amount of fluid should be incubated and / or the incubation time should be increased, the container is connected to the distributor; or, if a smaller amount of fluid should be incubated and / or the incubation time should be reduced, the container is separated from the distributor. It is also conceivable to connect containers of different sizes.

[0022] According to another embodiment of claim 15, the container is designed to be suspended, thereby making it possible to save space for incubating the fluid. According to another embodiment of claim 15, the container has at least one pressure equalization opening. This pressure equalization opening allows pressure within the container to be equalized, so that no overpressure or underpressure occurs within the container during filling or emptying of the container with fluid.

[0023] According to a further embodiment according to claim 16, a weighing device and / or a flow sensor and / or a level probe are provided, by means of which the mass, the fill amount and / or the level in the container can be determined, so that it is possible to specify, in particular at any time, which containers are filled and / or emptied.

[0024] According to another embodiment of claim 17, a pump arranged downstream of the first mixing device in the flow direction pumps the reactive fluid from the first mixing device to the container, and / or a pump arranged downstream of the container in the flow direction pumps the reactive fluid from the container to the second mixing device or the separation device. This allows for the transport of the respective fluids.

[0025] The present invention will be described in more detail below with reference to the accompanying drawings showing a number of embodiments.

[0026] Figure 1 Schematic diagram of an apparatus for carrying out the proposed method, wherein the apparatus comprises a first mixing apparatus having a mixer and a second mixing apparatus having a mixer,

[0027] Figure 2 Schematic diagram of another device for carrying out the proposed method, wherein the device comprises a first mixing device having a tangential flow filter and a second mixing device having a tangential flow filter,

[0028] Figure 3 Schematic diagram of another device for carrying out the proposed method, wherein the device comprises a first mixing device having a mixer and a separating device having a filter,

[0029] Figure 4 Schematic diagram of another device for carrying out the proposed method, wherein the device comprises a first mixing device having two mixers and a second mixing device having one mixer,

[0030] Figure 5 Schematic diagram of another device for carrying out the proposed method, wherein the device comprises a first mixing device having two mixers and a second mixing device having two mixers,

[0031] Figure 6 Schematic diagram of another apparatus for carrying out the proposed method, wherein the apparatus comprises a first mixing apparatus having a recirculation section,

[0032] Figure 7 Embodiment of the proposed incubation device for implementing the proposed method, a) first view and b) second view,

[0033] Figure 8Another embodiment of the proposed incubation device for implementing the proposed method, a) first view, b) second view,

[0034] Figure 9 a) The container arrangement of the first embodiment and b) the second embodiment.

[0035] First refer to Figure 1 Describe the proposed method for inactivating viruses in fluids, Figure 1 An exemplary embodiment of an incubation device 1 is shown. However, the method is by no means limited to the incubation device 1 but can also be applied to other devices and systems. In principle, it is conceivable that each of the method steps specified and explained in more detail below can be initiated or carried out automatically, in particular by a correspondingly configured control device.

[0036] Depending on the type of biopharmaceutical product and the production method, the fluid may contain different viruses. These viruses include, for example, herpes viruses, human adenovirus type 1, parainfluenza virus type 3, Cache Valley virus, or reovirus type 3. In principle, it is also conceivable that the fluid contains different types of viruses.

[0037] In the proposed method for inactivating viruses in a fluid, a starting fluid AF loaded with active viruses is mixed with a virus inactivating reagent R1 in a first mixing device 2 to form a reactive fluid F. The mixing in the first mixing device 2 comprises adding the reagent R1 to the starting fluid AF and mixing to at least partially homogenize the reagent R1 and the starting fluid AF.

[0038] Active viruses are inactivated by incubation with the reactive fluid F. Incubation is preferably performed after mixing. Incubation can be performed under prescribable incubation conditions, such as a specific temperature, a specific pressure, a specific time, specific irradiation of the reactive fluid F, etc. During the incubation period, the reactive fluid can be at least temporarily retained in one or more of the containers 4.

[0039] As used herein, "inactivation" includes inactivation of at least a certain proportion of the initially active viruses. In particular, during incubation, only a portion of the total active viruses may be inactivated. As used herein, "incubation" specifically includes inducing changes in a fluid by subjecting the fluid to specific conditions (e.g., temperature, pH, etc.) for a certain period of time. These conditions may vary over time.

[0040] The inactivation of viruses in the reactive fluid F is stopped by mixing the reactive fluid F with the other reagent R2, see Figure 1 In this respect, the virus inactivation reagent R1 can start the virus inactivation, while the other reagent R2 can stop the virus inactivation. This is preferably done after incubation. Alternatively, the inactivation of viruses in the reactive fluid F is stopped by removing the virus inactivation reagent R1 from the reactive fluid F, see e.g. Figure 3 This is preferably done after incubation.

[0041] In both cases, stopping the deactivation will produce a resultant fluid RF. The resultant fluid RF can be further processed, for example, in subsequent steps and methods.

[0042] Now the key is, for example, Figure 1 It can be seen that active viruses are inactivated by incubating the reactive fluid F in a container device 3 that is different from the first mixing device 2 and includes a plurality of independent containers 4, wherein the reactive fluid F is guided from the first mixing device 2 to the container device 3 before incubation. The guidance of the fluid F can be defined by, for example, conventional fluid guidance means, such as by a pipeline, such as a hose or a pipe. In particular, the guidance of the fluid F can be achieved by flowing, preferably conveying, in particular pumping the fluid F through one or more pipelines.

[0043] Therefore, the reactive fluid F is not incubated in the first mixing device 2 itself, but in a separate container 4 of the container device 3. In the mixing device 2, only the virus inactivation reagent R1 is added to the starting fluid AF and mixed therewith; however, the incubation of the reactive fluid F and the associated virus inactivation are carried out in a container 4 which is independent of the mixing device 2, i.e. designed separately and in particular connected by a pipeline.

[0044] The first mixing device preferably comprises at least one mixer 5 and / or at least one tangential flow filter 6, which is used to mix the starting fluid AF and the virus inactivating agent R1. The mixing is performed by fluid movement in the mixer 5 and the tangential flow filter 6. The starting fluid AF and the virus inactivating agent R1 can be independently introduced into the mixer 5 and / or the tangential flow filter 6, such as Figure 1 or Figure 2 or as a common fluid stream in which the virus inactivation reagent R1 has been added to the starting fluids AF but not yet mixed.

[0045] In general, in this context, the mixers 5, 9 are preferably dynamic mixers, wherein a driven agitator sets the fluid present in the mixer in motion, so that mixing occurs, e.g. Figure 1 , or a static mixer, in which rigid or movable flow elements within the mixer 5 cause the fluid to move as it flows through the mixer, thereby causing mixing, or a combination of static and dynamic mixers.

[0046] In this context, mixing of the fluids preferably occurs within the tangential flow filters 6, 10. This mixing is ensured, for example, by internal flows that occur as the fluids flow through the tangential flow filters and that do not flow in the main flow direction. Tangential flow filters are typically preferably passed through by a continuous fluid flow. In particular, the tangential flow filters can have a dual function, mixing the fluids flowing through them while also preferably filtering at least a portion of the fluids flowing through them. A portion of the fluid is separated by the tangential flow filter as a permeate, while another portion of the fluid is separated by the tangential flow filter as a retentate.

[0047] exist Figure 1 In the embodiment of the present invention, the first mixing device 2 includes, for example, a mixer 5. The starting fluid AF and the virus inactivation reagent R1 are mixed in the mixer 5 to form the reactive fluid F. This is achieved by introducing the starting fluid AF and the virus inactivation reagent R1 into the mixer 5 and mixing them. The mixer 5 is preferably different from the container 4 and is preferably arranged upstream of the container 4 in the flow direction.

[0048] exist Figure 2 In the embodiment of the mixing device 2, the mixing device 2 comprises, for example, a tangential flow filter 6. The tangential flow filter 6 is preferably distinct from the container 4, more preferably arranged upstream of the container 4 in the flow direction.

[0049] Preferably, if Figure 4 As shown, the starting fluid AF is mixed with the virus inactivating reagent R1 in at least two mixers 5 of the first mixing device 2 to form the reactive fluid F. Preferably, the mixers 5 can be controlled individually in terms of fluid dynamics. This makes it possible to selectively and in particular to fill and empty the mixers 5 one after another in any order. Preferably, the mixers 5 can be filled sequentially, i.e., one after another in time, or simultaneously or partially simultaneously. For example, in Figure 4 In the embodiment of the incubation device 1 shown, it can be provided that one of the mixers 5 is filled with the starting fluid AF and the virus inactivation reagent R1 and mixed, while the other mixer 5 is filled with the starting fluid AF and the virus inactivation reagent R1 only later in time. The reactive fluid RF can also be emptied from the mixers 5 sequentially, partially simultaneously, or simultaneously.

[0050] Alternatively and preferably, the starting fluid AF is mixed with the virus inactivating reagent R1 in at least two tangential flow filters 6 or at least one mixer 5 and at least one tangential flow filter 6 of the first mixing device 2 to form the reactive fluid F. These are preferably filled and / or emptied and / or flowed through sequentially, simultaneously or partially simultaneously. The tangential flow filters 6 or the mixer 5 and the tangential flow filter 6 are preferably independently controllable in terms of fluid dynamics.

[0051] In the proposed method, the active viruses in the reactive fluid F are preferably concentrated by the one or more tangential flow filters 6, see Figure 2 . The starting fluid AF is guided through the tangential flow filter 6 and mixed with the virus inactivation reagent R1. The virus inactivation reagent R1 can be added to the starting fluid AF upstream of the tangential flow filter 6. Alternatively, it is also conceivable that the reagent R1 is added to the starting fluid AF in the tangential flow filter 6. The viruses are preferably retained in the reactive fluid F in the form of a retentate, wherein in particular the retentate is subsequently incubated. The advantage of concentration by means of the one or more tangential flow filters 6 is advantageously that, after mixing, only a smaller amount of reactive fluid F needs to be incubated to inactivate the viruses. Alternatively, it is also conceivable that the viruses are retained in the reactive fluid F in the form of a permeate, wherein in particular the permeate is subsequently incubated.

[0052] In the proposed method, the pH value of the fluid is preferably reduced or increased by mixing the starting fluid AF with a virus inactivation reagent R1 (preferably an acid or a base) in a first mixing device 2 to form a reactive fluid F. For example, the pH value can be reduced by adding an acid as reagent R1 to create an acidic virus inactivation environment. Viruses can be inactivated in an acidic or alkaline environment during incubation. However, the pH value can also be increased by adding an alkali as reagent R2 to create an alkaline virus inactivation environment. In principle, the virus inactivation reagent R1 can be an acid, an alkali, a detergent (especially polysorbate), a solvent and / or a salt, or a mixture of multiple acids, alkalis, detergents, solvents and / or salts.

[0053] Preferably, add virus inactivation reagent R1 in the mixing process and carry out in at least two steps.In the first step, only a part of required virus inactivation reagent R1 total amount, preferably 5% to 98%, more preferably 50% to 95% is mixed with starting fluid AF, and the pH value of fluid is measured.In the second step, the remainder of required virus inactivation reagent R1 total amount is mixed with fluid in the first mixing device 2.Between these two steps, the pH value of fluid can be preferably measured after at least partial homogenization, for example, by measuring tool, for example probe or disposable measuring tool, for example disposable probe.Particularly, the part that adds in the first step of required reagent R1 total amount can be estimated.Based on the pH value measured subsequently, the total amount of reagent R1 and therefore the remainder of reagent R1 can be derived now, particularly by simulation.Preferably, multi-step mixing can be carried out by artificial intelligence, and this artificial intelligence learns from the repeated mixing process, to particularly estimate required reagent R1 total amount subsequently.

[0054] For example, in Figure 1In the embodiment shown, the further reagent R2 is preferably mixed with the reactive fluid F in the second mixing device 7 to form the resulting fluid RF. The mixing in the second mixing device 7 comprises adding the further reagent R2 to the reactive fluid F and mixing. The second mixing device 7 is preferably designed to be different from the container device 3, in particular separate therefrom. The second mixing device 7 is preferably located downstream of the first mixing device 2 and the container device 3 in the flow direction of the fluid. Figure 1 The flow direction in FIG. 1 is from the mixing device 2 via the container device 3 to the second mixing device 7 .

[0055] It is preferably conceivable that separation is performed downstream in the direction of flow after the second mixing device 7. This separation can be performed, for example, using a filter and / or a centrifuge or other separation means. The resulting fluid RF is passed from the second mixing device 7 to a filter and / or a centrifuge and / or other separation means. Other components of the resulting fluid RF can be separated using a filter, a centrifuge and / or other separation means.

[0056] Alternatively and preferably, the virus inactivating reagent R1 is removed from the reactive fluid F in a separation device 8, such as e.g. Figure 3 The separation device 8 is preferably distinct from the container device 3 and is preferably located downstream of the first mixing device 2 and the container device 3 in the flow direction of the fluid. Figure 3 The flow direction in the flow is from the mixing device 2 through the container device 3 to the separation device 8. Here, the separation device preferably includes a filter 11, which is designed as a tangential flow filter. As mentioned above, tangential flow filters are generally used for both mixing and separation due to their dual function. Alternatively or additionally, the separation device 8 may also include a centrifuge or other separation means to separate the virus inactivation reagent R1.

[0057] It should be noted at this point that the difference between the second mixing device 7 and the separation device 8 is that, as described above, in the second mixing device 7, the further reagent R2 is added to the resulting fluid RF and mixing is carried out, while the purpose of the separation device 8 is also as described above to remove the virus inactivating reagent R1 from the reactive fluid F. It is conceivable that in addition to mixing in the second mixing device 7, separation is also carried out, and / or in addition to separation in the separation device 8, mixing is also carried out.

[0058] In the proposed method, it is further preferably provided that the mixing of the reactive fluid F with the second reagent R2 takes place in a second mixing device 7 having a mixer 9, see for example Figure 1 , or in a tangential flow filter 10, see for example Figure 2 .

[0059] The second mixing device 7 preferably has at least two mixers 9, for example Figure 5 As shown, or at least two tangential flow filters 10, or at least one mixer 9 and at least one tangential flow filter 10. They are preferably different from the container 4 and are preferably filled and / or emptied and / or flowed through successively, simultaneously or at least partially simultaneously. For example, the one or more mixers 9 can be filled and / or emptied and flowed through the one or more tangential flow filters 10. The one or more mixers 9 and / or the one or more tangential flow filters 10 can be controlled separately in terms of fluid mechanics. This can be conceived as selective and in particular in any order. Each mixer 9, each tangential flow filter 10, or a mixer 9 and a tangential flow filter 10 can be filled with a reactive fluid F from each container 4, respectively. Preferably, due to the emptying or flowing through of the mixer 9 or the tangential flow filter 10 successively or simultaneously or at least partially simultaneously, a continuous fluid flow flows out of the second mixing device 7.

[0060] In the proposed method, the active viruses in the resulting fluid RF are preferably concentrated by means of said one or more tangential flow filters 10, see Figure 2 The reactive fluid F is guided through the tangential flow filter 10 and mixed with the further reagent R2. The further reagent R2 can be added to the reactive fluid F upstream of the tangential flow filter 6. Alternatively, it is also conceivable that the reagent R2 is added to the reactive fluid F via the tangential flow filter 6. The viruses are preferably retained in the resulting fluid RF in the form of a retentate, wherein in particular the retentate is subsequently further processed. Alternatively, it is also conceivable that the viruses are retained in the resulting fluid F in the form of a permeate, in particular the permeate is subsequently further processed.

[0061] Alternatively and preferably, the separation device 8 has at least two filters 11 or two centrifuges or at least one filter 11 and at least one centrifuge. These are preferably different from the container 4. Furthermore, these are preferably filled or flowed through sequentially or simultaneously or at least partially simultaneously, wherein preferably, due to the sequential or simultaneous or at least partially simultaneous flow through the one or more filters 11 and / or the one or more centrifuges, a continuous fluid flow flows out of the separation device 8. In particular, the filter 11 can be flowed through, and the centrifuge can be filled and emptied in particular. The filter 11 can preferably be designed as a tangential flow filter.

[0062] More preferably, the reactive fluid F from the first mixing device 2 is filled into the container 4 sequentially, i.e., sequentially in time, or simultaneously or at least partially simultaneously. The containers 4 can be controlled individually. Preferably, the containers 4 can be filled selectively and / or preferably in any order. The reactive fluid F from the first mixing device 2 can be directed to one of the containers 4 or to a plurality of containers 4 in proportion.

[0063] Preferably, the reactive fluid F is conducted from the first mixing device 2 to the container device 3, in particular to the container 4, via a distributor 14 before incubation. The distributor 14 can preferably be designed as a line 16 with at least one valve 17. The line 16 can be designed, for example, as one or more hoses and / or one or more pipes. The distributor 14 preferably enables individual, in particular selective, control of the containers 4.

[0064] It is further preferred that the reactive fluid F from the container 4 is discharged sequentially, i.e., sequentially, or simultaneously or at least partially simultaneously, into the second mixing device 7 or the separation device 8. The containers 4 can be controlled individually. The containers 4 can preferably be emptied selectively and / or preferably in any order. The reactive fluid F from the container 4 can be directed to one or more mixers 9 or one or more tangential flow filters 10 of the second mixing device 7.

[0065] Preferably, the reactive fluid F is incubated in the container device 3, in particular from the container 4, via a distributor 15 to the second mixing device 7 or the separation device 8. The distributor 15 preferably comprises a line 18 and at least one valve 19. The line 18 can be designed, for example, as one or more hoses and / or one or more pipes. The containers 4 can preferably be controlled individually, in particular selectively, via the distributor 15.

[0066] It is conceivable that the reactive fluid F is at least temporarily mixed in the container 4, for example by mixing means of the container 4 and / or by movement of the container 4. This can, for example, achieve homogenization of the reactive fluid F or prevent demixing of the reactive fluid F. In particular, however, no reagents, in particular no further reagents, are added to the container 4.

[0067] In the proposed method, it is preferably provided that the starting fluid AF flows discontinuously, i.e., not constantly over time, into the first mixing device 2, while the resulting fluid RF flows continuously, i.e., constantly over time, out of the second mixing device 7 or the separation device 8. "Discontinuous" can include both the inflow or outflow of the fluid at a volume flow rate that is not constant over time and the inflow or outflow of the fluid only at specific times. "Continuous" can include both the inflow or outflow of the fluid at a volume flow rate that is constant over time and the permanent inflow or outflow of the fluid, at least during the process, in particular at a volume flow rate that varies over time or that is constant over time.

[0068] The method therefore preferably results in a conversion of a discontinuous, ie temporally discontinuous, in particular non-constant volumetric flow, fluid input stream into a continuous, ie temporally continuous, in particular constant volumetric flow, fluid output stream.

[0069] Preferably, in the proposed method it is conceivable that the starting fluid AF is subjected to chromatography, in particular rapid cycle chromatography, before flowing into the first mixing device 2 .

[0070] The above-described method and its features, in particular the incubation principle, are also applicable to other methods for incubating fluids, in particular synthetic methods. Therefore, as a further teaching having independent significance, a method for incubating fluids, preferably for inactivating viruses, is proposed.

[0071] In the proposed method for incubating fluids, preferably for inactivating viruses, a starting fluid AF is mixed with a reagent R1 in a first mixing device 2 to form a reactive fluid F, and the reactive fluid F is incubated. The incubation of the reactive fluid F is stopped by mixing the reactive fluid F with a further reagent R2 or by removing the reagent R1 from the reactive fluid F, thereby obtaining a resulting fluid RF. It is essential that the reactive fluid F is incubated in a container means 3, which is different from the first mixing device 2 and comprises a plurality of separate containers 4, wherein the reactive fluid F is guided from the first mixing device 2 to the container means 3 before incubation.

[0072] All the above-mentioned features can be applied to the proposed method individually or in combination accordingly. Reference is made to all statements concerning the proposed method for inactivating viruses in fluids.

[0073] The method proposed above can be realized, for example, by the proposed incubation device 1 for incubating fluids, in particular for inactivating viruses. Figures 1 to 6 Except for the embodiment, Figure 7 a), b) and Figure 8 a) and b) also show the proposed incubation device 1 .

[0074] The incubation device 1 for incubating fluids, in particular for inactivating viruses, comprises a first mixing device 2 for mixing a starting fluid AF loaded with active viruses with a virus inactivating reagent R1 to form a reactive fluid F. Thus, the starting fluid AF can be mixed with the reagent R1 to form a reactive fluid F through the first mixing device 2 .

[0075] The incubation device 1 further comprises a container 4 for incubating a reactive fluid F, see for example Figure 7 a), 7b and 8a), 8b). The reactive fluid F can be incubated in the container 4 so that at least a certain proportion of the viruses contained therein are inactivated over time.

[0076] For example, from Figure 1 and Figure 7a) and b) It can be seen that it is important that the container 4 is designed as an independent container 4 of the container device 3 which is different from the first mixing device 2. Therefore, the container device 3 is designed separately from the mixing device 2 so that mixing can be carried out spatially separately from incubation.

[0077] The incubation device 1 is preferably designed as one unit. However, it is also conceivable to design the incubation device 1 as a plurality of units.

[0078] The container device 3 is preferably fluidically connected to the first mixing device 2 , so that the reactive fluid F can flow from the first mixing device 2 to the container device 3 and fill the container 4 .

[0079] The containers 4 are preferably designed individually. They are preferably individually controllable and can therefore be filled and / or emptied selectively and / or in any order. In particular, the containers 4 can be filled and / or emptied sequentially, i.e., in succession, partially simultaneously, or simultaneously.

[0080] Preferably, during the incubation process, the reactive fluid F does not flow through the containers 4. This is because during the incubation process, the reactive fluid F at least temporarily remains in one of the containers 4.

[0081] Furthermore, it is preferably conceivable that the container 4 is designed without internal components. Thus, the container 4 does not contain internal components, in particular, does not contain mixing tools that come into contact with the reactive fluid F contained in the container 4. Internal components herein refer to tools that at least partially come into contact with and influence the reactive fluid F contained in the container 4, such as mixing tools, such as a stirrer, baffles, or fillers, or certain temperature control tools. Sensors for measuring the properties of the reactive fluid contained in the container 4 are not to be understood as internal components herein. Alternatively, it is also conceivable that the container 4 has internal components, such as mixing tools for homogenizing the fluid contained in the container 4.

[0082] The incubation device 1 preferably has a second mixing device 7 for mixing the reactive fluid F with other reagents R2 that stop virus inactivation, such as e.g. Figure 7 Here, the second mixing device 7 is preferably different from the container device 3, and more preferably is located downstream of the first mixing device 2 and the container device 3 in the flow direction of the fluid.

[0083] Alternatively, the incubation device 1 preferably has a separation device 8 for removing the virus inactivation reagent R1 from the reactive fluid F, see for example Figure 3 The separation device 8 is preferably distinct from the container device 3 and is more preferably located downstream of the first mixing device 2 and the container device 3 in the flow direction of the fluid. The incubation device 1 with the separation device 8 has proven to be particularly useful in cases where viral inactivation is stopped, for example by removing the viral inactivation reagent R1.

[0084] The separation device 8 preferably comprises at least one separation means, for example a filter 11, such as a tangential flow filter or a membrane filter, and / or a centrifuge, such as a fluidized bed centrifuge. The virus inactivation reagent R1 can be separated from the reactive fluid F by the separation means.

[0085] Preferably, if Figure 7 As shown in 7a) and 7b), the second mixing device 7 is designed structurally identically to the first mixing device 2. Alternatively, however, it is also conceivable that they are designed structurally differently.

[0086] The first mixing device 2 and the second mixing device 7 preferably each comprise a dynamic mixer 5, 9. The dynamic mixer 5, 9 can be equipped, for example, with a driven stirrer, in particular a magnetic stirrer, a rod stirrer or the like.

[0087] Alternative embodiments are also conceivable, in which preferably the first mixing device 2 and / or the second mixing device 7 has at least one static mixer 5, 9, such as Figure 5 、 6 and 8a) for the first mixing device 2, and / or at least one dynamic mixer 5, 9 and / or at least one tangential flow filter 6, 10, in particular a single-pass tangential flow filter, which is preferably different from the container 4. For example, in Figure 2 In the embodiment, the first mixing device 2 has a dynamic mixer 5 and the second mixing device 7 has a tangential flow filter 10.

[0088] In static mixers 5, 9, the flow motion of the fluid flowing through the mixer 5, 9 can cause mixing. Static mixers 5, 9 are typically passed through by a continuous fluid stream. In dynamic mixers 5, 9, the movement of the mixing elements can cause both movement and mixing of the fluid. Dynamic mixers are typically operated discontinuously, so the fluid stream exits the dynamic mixer 5, 9 discontinuously.

[0089] In the tangential flow filters 6, 10, the flow motion of the fluid flowing through the tangential flow filters 6, 10 can cause mixing. Tangential flow filters 6, 10 are usually flowed through by a continuous fluid stream. The tangential flow filters 6, 10 can perform a dual function, because the tangential flow filters 6, 10 can cause the fluid flowing through the tangential flow filters 6, 10 to mix, while preferably filtering out at least a portion of the fluid flowing through. Here, a portion of the fluid is separated into permeate by the tangential flow filters 6, 10, and another portion of the fluid is separated into retentate by the tangential flow filters 6, 10. Through the separation in the tangential flow filters 6, 10, concentration can occur in the retentate, in particular concentration of active viruses or inactivated viruses. This concentration results in a smaller volume flow of the retentate being further processed.

[0090] The tangential flow filter 6 and / or the tangential flow filter 10 can preferably be designed as a single-pass tangential flow filter. In a single-pass tangential flow filter, the fluid only flows through the filter once and is filtered there.

[0091] The filter 11 of the separation device 8 is preferably designed as a tangential flow filter, wherein the virus inactivation reagent R1 can be separated out by the filter 11, see Figure 3 It is conceivable that the virus inactivation reagent R1 is separated as a permeate. Alternatively, it is also conceivable that the virus inactivation reagent R1 is separated as a retentate.

[0092] Preferably, for example Figure 4 、 7 a) and 8a), the first mixing device 2 has at least two mixers 5. The mixers 5 are preferably different from the containers 4, and more preferably are arranged in parallel with each other in terms of fluid mechanics. Due to the parallel arrangement in terms of fluid mechanics, the starting fluids AF can be selectively guided to the mixers 5 successively or partially simultaneously or simultaneously. In particular, in the case of discontinuous inflow of the starting fluids AF, the respective starting fluids AF can be mixed in different mixers 5, in particular alternately. For example, one of the two mixers 5 can be filled with the starting fluid AF first, the virus inactivation reagent R1 can be added, and the starting fluid AF can be mixed with the virus inactivation reagent R1. Then mixing can be carried out in the other of the two mixers 5. In Figure 7 In a), the mixer 5 is designed as a dynamic mixer 5. Figure 8 In a), the mixers 5 are designed as static mixers 5. The fluid-dynamically parallel arrangement preferably enables the fluid to be transferred from one mixer 5 to another mixer 5. The fluid-dynamically parallel arrangement of the mixers 5 also provides a certain degree of redundancy of the mixers 5, so that mixing can still be performed even if one mixer 5 fails.

[0093] Alternatively and preferably, it is conceivable to arrange the mixers 5 in series with one another in terms of fluid dynamics. For example, a portion of the mixing can take place in one of the two mixers 5 and another portion of the mixing can take place in the other of the two mixers 5.

[0094] The first mixing device 2 can alternatively also have two tangential flow filters 6 or at least one mixer 5 and at least one tangential flow filter 6. These are preferably distinct from the container 4 and are preferably arranged fluidically in parallel or in series with one another.

[0095] Preferably, for example Figure 5 、 Figure 7 b) and Figure 8b) As shown, the second mixing device 7 has at least two mixers 9. The mixer 9 is preferably different from the container 4 and is preferably arranged in parallel with each other in terms of fluid mechanics. By arranging in parallel in terms of fluid mechanics, the reactive fluid F can be selectively directed to the mixer 9 one after another or partly at the same time or simultaneously. The reactive fluid F from the container 4 can be mixed in different mixers 9, in particular alternately mixed. For example, one of the two mixers 9 can be filled with the reactive fluid F first, then other reagents R2 are added, and the reactive fluid F is mixed with the reagent R2 to form the resulting fluid RF. Then mixing can be carried out in the other of the two mixers 9. The parallel arrangement in terms of fluid mechanics also preferably enables the fluid to be selectively directed from one mixer 9 to another mixer 9. The parallel arrangement in terms of fluid mechanics of the mixer 9 also provides a certain degree of redundancy of the mixer 9, so that mixing can still be carried out even if a mixer 9 fails.

[0096] As an alternative to a fluid-dynamically parallel arrangement, it is preferably conceivable to arrange the mixers 9 in fluid-dynamic series. For example, this allows a portion of the mixing to take place in one of the two mixers 9 and another portion of the mixing to take place in the other of the two mixers 9.

[0097] The second mixing device 7 can alternatively also comprise two tangential flow filters 10 or at least one mixer 9 and at least one tangential flow filter 10. These are preferably distinct from the container 4 and are further preferably arranged fluidically in parallel or in series.

[0098] Preferably, the separation device 8 comprises at least two filters 11 or at least two centrifuges or at least one filter 11 and at least one centrifuge, which are preferably arranged fluidically in parallel or in series with one another.

[0099] Preferably, in the incubation device 1, the first mixing device 2 and / or the second mixing device 7 are designed so that the first mixing device 2 and / or the second mixing device 7 can be selectively modularly expanded by one or more mixers 5, 9, preferably one or more dynamic mixers or static mixers, and / or tangential flow filters 6, 10. For example, Figure 7 In the incubation devices 1 of a) and b), further mixers 5, 9 can be connected in addition to the already connected mixers 5, 9, allowing the incubation device 1 to be expanded, for example, if the amount of reactive fluid F to be incubated and / or the incubation time vary. In principle, it is also conceivable to selectively remove one or more connected mixers 5, 9 and / or one or more connected tangential flow filters 6, 10. The first mixing device 2 and / or the first mixing device 7 can be modularly expanded, in particular without the need for tools. This allows for easy adjustment of the incubation device 1.

[0100] Preferably, if the incubation device 1 comprises a separation device 8 , the separation device 8 is designed such that it can be modularly expanded selectively by one or more filters 11 and / or by one or more centrifuges and / or by one or more separation tools.

[0101] Preferably, the first mixing device 2 and / or the second mixing device 7 has a recirculation section 12, through which the fluid flowing out of the at least one mixer 5, 9 and / or the at least one tangential flow filter 6, 10, in particular the starting fluid AF and / or the reactive fluid F, can be recirculated so that at least a part of the fluid flows through the at least one mixer 5, 9 and / or the at least one tangential flow filter 6, 10 multiple times. Figure 6 In the embodiment of the present invention, the first mixing device 2 has a recirculation section 12. The recirculation section 12 allows at least part of the fluid flowing out of the mixer 5 to be recirculated so that the fluid can be returned to the mixer 5. Thus, for example, a stepwise mixing process can be achieved using only one mixer 5. The recirculation of the fluid can be performed in particular by means of a pump 24.

[0102] Preferably, the separation device 8 has a recirculation section 12, through which the fluid flowing out of the at least one filter 11 and / or from the at least one centrifuge and / or from the at least one separation tool, in particular the reactive fluid F, can be recirculated so that at least a portion of the fluid flows through the at least one filter 11 and / or the at least one centrifuge and / or the at least one separation tool multiple times.

[0103] It is conceivable that the first mixing device 2 and / or the second mixing device 7 has a storage tank 13. The storage tank 13 is preferably arranged upstream of the at least one mixer 5, 9 or the at least one tangential flow filter 6, 10 in the flow direction of the fluid. Alternatively, Figure 6 As shown, the storage tank 13 can also be arranged downstream of the at least one mixer 5, 9 in the flow direction of the fluid. Figure 6 As shown, the tank 13 is designed as part of the recirculation section 12 so that, in particular, the recirculated fluid can be returned to the tank 13. The fluid can preferably be temporarily stored in the tank 13 so that, for example, discontinuously flowing starting fluid AF and / or recirculated fluid can be temporarily stored in the tank 13. The tank 13 is in particular different from the mixers 5 and 9. The tank 13 can preferably include at least one mixing tool for homogenizing the fluid contained in the tank 13.

[0104] Furthermore, it is conceivable that the separation device 8 comprises a tank 13, which is preferably designed as part of the recirculation section 12 so that in particular the recirculated fluid can be returned to the tank 13. The design of the tank 13 of the separation device 8 can be identical to or different from the tank 13 described above with respect to the first mixing device 2 or the second mixing device 7.

[0105] For example Figure 1 、 7 As shown in Figures 8a) and 8b), the incubation device 1 preferably has a first distributor 14 for distributing the reactive fluid F mixed in the first mixing device 2 from the first mixing device 2 to the container 4. The fluid from the mixing device 2 can be conducted to the container device 3, in particular the container 4, via the first distributor 14. Each container 4 can preferably be filled with the reactive fluid F from each mixer 5 and / or each tangential flow filter 6 via the first distributor 14. If, for example, the first mixing device 2 has a plurality of mixers 5, such as Figure 7 If the incubation device 1 in a) and 8a) is provided, the fluid from each mixer 5 can be selectively conducted to each of the containers 4. Thus, the containers 4 can be controlled individually in terms of fluid dynamics.

[0106] Alternatively or additionally, it is conceivable that the incubation device 1 has a second distributor 15 for distributing the incubated reactive fluid F from the container 4. The fluid from the container arrangement 3, in particular the container 4, can be conducted to the second mixing device 7 via the second distributor 15. Preferably, each mixer 9 and / or tangential flow filter 10 can be filled with or flowed through by the reactive fluid F from the respective container 4. Thus, if, for example, the second mixing device 7 has a plurality of mixers 9, for example Figure 7 b) and 8b), the fluids from the individual containers 4 can be selectively conducted to individual mixers 9. The mixers 9 and / or the tangential flow filters 10 can preferably be controlled individually in terms of fluid dynamics.

[0107] Alternatively or additionally, it is conceivable that the fluid from the container device 3, in particular the container 4, can be guided to the separation device 8 via a second distributor 15. Preferably, each filter 11 and / or each centrifuge and / or each separation tool can be filled with or flowed through by the reactive fluid F from the respective container 4. Thus, if, for example, the separation device 8 has a plurality of mixers 9, the fluid from the respective container 4 can be selectively guided to each of the filters 11. Preferably, the filters 11 and / or the centrifuges can be controlled individually, preferably in terms of fluid dynamics.

[0108] The distributor 14 and the distributor 15 are preferably fluidically connected to one another via the container 4. The spatial separation prevents the incubated reactive fluid F in the distributor 15 from being contaminated by the previously unincubated reactive fluid F in the distributor 14.

[0109] Preferably, if Figure 1 、 7 As shown in Figures a) and b) and 8a) and b), the first distributor 14 and / or the second distributor 15 are designed as pipelines 16, 18 with multiple valves 17, 19, or as pipelines 16, 18 with multi-way valves, which in particular have more than three possible switching positions. Valves 17, 19 are preferably designed as 3 / 2-way valves. A 3 / 2-way valve has three connections and two switching positions. Pipelines 16, 18 are preferably designed as pipelines 16, 18 with multiple sections. Pipelines 16, 18 can preferably be designed as pipes or hose lines.

[0110] Preferably, the first dispenser 14 and / or the second dispenser 15 are designed such that the container 4 can be selectively connected to and / or disconnected from the first and / or second dispenser 14, 15, in particular without the need for tools. Figure 7 In the incubation devices 1 of a), b) and 8a), b), the first distributor 14 and the second distributor 15 each have a free connection point, so that another container 4 can be connected to the distributors 14 and 15. This allows, for example, the amount of incubatable fluid and / or the incubation time to be adjusted without further structural changes. Preferably, the containers 4 are designed to be modular so that they can be selectively connected to the distributors 14, 15 and / or disconnected therefrom, especially without the need for tools.

[0111] like Figure 9 As shown in Figures 9a) and 9b), it has proven advantageous if the containers 4 each have a container inlet 20 and a container outlet 21. The container 4 can be filled with the reactive fluid F from the first mixing device 2 via the container inlet 20, in particular via the first distributor 14, and can be emptied into the second mixing device 7 or the separation device 8 via the container outlet 21, in particular via the second distributor 15).

[0112] It is preferably conceivable that the container 3 and / or the one or more mixers 5 and / or the one or more mixers 9 and / or the one or more tangential flow filters 6 and / or the one or more tangential flow filters 10 are designed as disposable products. By regularly replacing the components, contamination can be avoided.

[0113] Preferably, the container 4 is designed to be hangable, see Figure 7a), b), 8a), b) and 9a), b). This allows for space-saving incubation in the containers 4, since they can be stored in a correspondingly space-saving manner. It has proven particularly advantageous to design the containers 4 in the form of individually hangable bags, or as Figure 9 a) and b) are each in the form of a hanging bag, in particular an infusion bag. Figure 9 As shown in a) and b), the containers 4 more preferably each have an eyelet 22, through which the respective container 4 can be hung. The incubation device 1 can have, for example, a hanging rod 26, on which the containers 4 can be arranged directly in a row through the eyelets 22, in particular hung, for example Figure 9 It is also conceivable to arrange, in particular hang, a plurality of hooks 27 on the hanging rod 26 and to arrange, in particular hang, the container 4 on the hooks 27, for example Figure 9 b). The container 4 may preferably be made of flexible plastic.

[0114] Preferably, if Figure 9 As shown in a) and b), each container 4 has at least one pressure-balancing opening 23 for balancing the pressure in the respective container 4. When the reactive fluid F flows into and out of the container 4, the pressure changes generated in the respective container 4 can be compensated through the respective pressure-balancing opening 23, which is achieved, for example, by ambient air or protective gas flowing into the container 4 through the pressure-balancing opening 23, or by gas flowing out of the container 4 through the pressure-balancing opening 23. In order to prevent the fluid contained in the container 4 from being contaminated, for example, by impurities in the ambient air, the pressure-balancing opening 23 preferably has an opening filter 28. As an alternative to the pressure-balancing opening 23 designed for inflow and outflow, it is also conceivable to provide each container 4 with multiple independent pressure-balancing openings 23, so that, for example, ambient air or protective gas can flow in through the first pressure-balancing opening 23, and the gas can flow out of the container 24 through the second pressure-balancing opening 23. The pressure-balancing opening 23 can especially have a valve.

[0115] It has proven advantageous if the incubation device 1 includes a weighing device, preferably a load cell and / or a force sensor, in particular for weighing the reactive fluid F in the container 4; a flow sensor for regulating the fill level of the reactive fluid F in the container 4; and / or a level probe for detecting the liquid level of the reactive fluid F in the container 4. The mass of the reactive fluid in the container 4 can be determined using the weighing device, for example by weighing it. The flow sensor can be used to measure the flow rate of the respective fluid in one of the containers 4. The level probe can be used to measure the liquid level of the respective reactive fluid F in one of the containers 4. The proposed embodiment with a weighing device and / or a flow sensor and / or a level probe allows the amount of reactive fluid F in each container 4 to be determined. The flow sensor can also preferably be configured to determine the fluid pressure of the fluid flowing through the flow sensor. Preferably, the incubation device 1 includes a first flow meter and a second flow meter, wherein the first flow meter can detect the fluid flow rate into the container 4, and the second flow meter can detect the fluid flow rate out of the container 4.

[0116] like Figures 1 to 6 As shown, the incubation device 1 preferably includes a pump 24, particularly a peristaltic pump, arranged downstream of the first mixing device 2 in the flow direction, for pumping the reactive fluid F mixed in the first mixing device 2 to the container 4; and / or a pump 25, particularly a peristaltic pump, arranged downstream of the container 4 in the flow direction, for pumping the incubated reactive fluid F to the second mixing device 7 or the separation device 8. Thus, the reactive fluid F can be conveyed to the container 5 via the pump 24 and / or from the container 5 via the pump 25. Thus, the reactive fluid F can be conveyed to or from any number of containers 4 via each of the pumps 24 and 25. The fluid can preferably be conveyed via each of the pumps 24 and 25 through the first distributor 14 and / or the second distributor 15. Alternatively, multiple pumps 24 and 25 may be provided. The pump 24, 25 or the pumps 24, 25 can preferably be designed as a peristaltic pump or multiple peristaltic pumps.

[0117] The proposed incubation device 1 is capable of incubating fluids, in particular for virus inactivation. However, the incubation device 1 is in principle also suitable for other methods involving incubation of fluids, such as in particular different synthesis methods.

Claims

1. A method for inactivating viruses in a fluid, wherein: A starting fluid (AF) loaded with active viruses is mixed with a virus inactivating agent (R1) in a first mixing device (2) to form a reactive fluid (F), and the active viruses are inactivated by incubating the reactive fluid (F), and the inactivation of the viruses in the reactive fluid (F) is stopped by mixing the reactive fluid (F) with another agent (R2) or by removing the virus inactivating agent (R1) from the reactive fluid (F), thereby producing a resulting fluid (RF), It is characterized by Active viruses are inactivated by incubating a reactive fluid (F) in a container means (3) which is different from the first mixing means (2) and comprises a plurality of separate containers (4), wherein the reactive fluid (F) is led from the first mixing means (2) to the container means (3) before incubation.

2. The method according to claim 1, characterized in that The starting fluid (AF) is mixed with the virus inactivating reagent (R1) in at least two mixers (5) or at least two tangential flow filters (6) or at least one mixer (5) and at least one tangential flow filter (6) of the first mixing device (2) to form a reactive fluid (F), wherein the mixers (5) and the tangential flow filters (6) are preferably filled and / or emptied and / or flowed through sequentially or simultaneously or partially simultaneously.

3. The method according to claim 1 or 2, characterized in that The pH value of the fluid is lowered or increased by mixing a starting fluid (AF) with a virus inactivating agent (R1), preferably an acid or a base, in a first mixing device (2). Preferably, the virus inactivating agent (R1) is added in at least two steps during the mixing process, wherein in the first step, only a part of the total amount of the required virus inactivating agent (R1), preferably 5% to 98%, more preferably 50% to 95%, is mixed with the starting fluid (AF) and the pH value of the fluid is determined, and in the second step, the remaining part of the total amount of the required virus inactivating agent (R1) is mixed with the fluid in the first mixing device (2).

4. The method according to any one of the preceding claims, characterized in that The other reagent (R2) is mixed with the reactive fluid (F) in a second mixing device (7) to form a resulting fluid (RF), and the second mixing device (7) is preferably different from the container device (3) and is preferably located downstream of the first mixing device (2) and the container device (3) in the flow direction of the fluid, or the virus inactivation reagent (R1) is removed from the reactive fluid (F) in a separation device (8), and the separation device (8) is preferably different from the container device (3) and is preferably located downstream of the first mixing device (2) and the container device (3) in the flow direction of the fluid.

5. The method according to claim 4, characterized in that The second mixing device (7) has at least two mixers (9) or at least two tangential flow filters (10) or at least one mixer (9) and at least one tangential flow filter (10), the mixers (9) and tangential flow filters (10) preferably being different from the container (4) and preferably being filled and / or emptied and / or flowing through successively or simultaneously or at least partially simultaneously, preferably a continuous fluid flow emerges from the second mixing device (7) by successively or simultaneously or at least partially simultaneously emptying or flowing through the mixers (9) or tangential flow filters (10), or, The separation device (8) has at least two filters (11) or at least two centrifuges or at least one filter (11) and at least one centrifuge, which are preferably different from the container (4) and through which fluid is preferably flowed sequentially or simultaneously or at least partially simultaneously, preferably by flowing sequentially or simultaneously or at least partially simultaneously through the filters (11) or the centrifuges or the filters and the centrifuge, a continuous fluid flow emerges from the separation device (8).

6. The method according to any one of the preceding claims, characterized in that The container (4) is filled with the reactive fluid (F) from the first mixing device (2) successively or simultaneously or at least partially simultaneously and / or the reactive fluid (F) is emptied from the container (4) into the second mixing device (7) or the separation device (8) successively or simultaneously or at least partially simultaneously.

7. The method according to any one of the preceding claims, characterized in that The starting fluid (AF) flows discontinuously or semi-continuously into the first mixing device (2), and the resulting fluid (RF) flows continuously out of the second mixing device (7).

8. A method for incubating a fluid, preferably for inactivating viruses, wherein: mixing a starting fluid (AF) with a reagent (R1) in a first mixing device (2) to form a reactive fluid (F), incubating the reactive fluid (F), and stopping the incubation of the reactive fluid (F) by mixing the reactive fluid (F) with a further reagent (R2) or by removing the reagent (R1) from the reactive fluid (F), thereby producing a resulting fluid (RF), It is characterized in that The reactive fluid (F) is incubated in a container means (3) which is different from the first mixing means (2) and comprises a plurality of separate containers (4), wherein the reactive fluid (F) is led from the first mixing means (2) to the container means (3) before incubation.

9. An incubation device for incubating a fluid, in particular for inactivating viruses in a fluid, comprising a first mixing device (2) for mixing a starting fluid (AF) loaded with active viruses with a virus inactivating reagent (R1) to form a reactive fluid (F); and a container (4) for incubating the reactive fluid (F); It is characterized in that The container (4) is designed as an independent container (4) different from the container device (3) of the first mixing device (2).

10. The incubation device according to claim 9, characterized in that The incubation device (1) has a second mixing device (7) for mixing the reactive fluid (F) with another reagent (R2) for stopping virus inactivation, and the second mixing device (7) is preferably different from the container device (3), or the incubation device (1) has a separation device (8) for removing the virus inactivation reagent (R1) from the reactive fluid (F), and the separation device (8) is preferably different from the container device (3). Preferably, the second mixing device (7) and / or the separation device (8) are located downstream of the first mixing device (2) and the container device (3) in the flow direction of the fluid.

11. The incubation device according to claim 9 or 10, characterized in that The first mixing device (2) and / or the second mixing device (7) comprises at least two mixers (5, 9) or at least two tangential flow filters (6, 10) or at least one mixer (5, 9) and at least one tangential flow filter (6, 10), the mixers (5, 9) and tangential flow filters (6, 10) preferably being distinct from the container (4) and preferably being arranged fluidically in parallel or in series with one another, and / or The separation device (8) comprises at least two filters (11) or at least two centrifuges or at least one filter (11) and at least one centrifuge, which are preferably arranged fluidically in parallel or in series with one another.

12. The incubation device according to any one of claims 9 to 11, characterized in that The first mixing device (2) and / or the second mixing device (7) are designed to be modularly expandable, optionally by one or more static mixers (5, 9) and / or dynamic mixers (5, 9) and / or tangential flow filters (6, 10), and / or, The separation device (8) is designed to be modularly expandable, optionally by one or more filters (11) and / or one or more centrifuges.

13. The incubation device according to any one of claims 9 to 12, characterized in that The first mixing device (2) and / or the second mixing device (7) has a recirculation section (12) through which the fluid flowing out of the at least one mixer (5, 9) and / or from the at least one tangential flow filter (6, 10) can be recirculated so that at least a portion of the fluid flows through the at least one mixer (5, 9) and / or the at least one tangential flow filter (6, 10) multiple times, and / or The separation device (8) has a recirculation section (12) through which the fluid flowing out of the at least one filter (11) and / or from the at least one centrifuge can be recirculated so that at least a part of the fluid flows through the at least one filter (11) and / or the at least one centrifuge multiple times.

14. The incubation device according to any one of claims 9 to 13, characterized in that The incubation device (1) has a first distributor (14) for distributing the reactive fluid (F) mixed in the first mixing device (2) from the first mixing device (2) to the container (4), preferably, each container (4) can be filled with the reactive fluid (F) from each mixer (5) and / or the tangential flow filter (6) of the first mixing device (2) through the first distributor (14), and / or the incubation device (1) has a second distributor (15) for distributing the reactive fluid (F) from the container (4) The incubated reactive fluid (F), preferably, the individual mixers (9) and / or the tangential flow filter (10) of the second mixing device (7) can be filled or flowed through by the reactive fluid (F) from the individual containers (4) via the distributor (15), and / or the first distributor (14) and / or the second distributor (15) are designed so that the container (4) can be selectively connected to the first and / or second distributor (14, 15) and / or separated from the first and / or second distributor (14, 15), in particular without the need for tools.

15. The incubation device according to any one of claims 9 to 14, characterized in that The container (4) is designed to be hangable, in particular in the form of a hangable sac or a hangable bag. Preferably, the containers (4) designed to be hangable each have an eyelet (22) for hanging the container (4), and / or the containers (4) each have at least one pressure-balancing opening (23) for balancing the pressure in the respective container (4), the pressure-balancing opening (23) in particular having an opening filter (28).

16. The incubation device according to any one of claims 9 to 15, characterized in that The incubation device (1) has a weighing tool, preferably a weighing sensor and / or a force sensor, and / or the incubation device (1) has at least one flow sensor for adjusting the filling amount of the reactive fluid (F) in the container (4), and / or the incubation device (1) has at least one liquid level probe for detecting the liquid level of the reactive fluid (F) in the container (4), wherein the respective mass of the reactive fluid (F) in the container (4) can be determined by the weighing tool, and the respective fluid flow rate flowing into the container (4) and / or flowing out of the container (4) can be determined by the flow sensor, and the respective liquid level of the reactive fluid (F) in the container (4) can be determined by the liquid level probe.

17. The incubation device according to any one of claims 9 to 16, characterized in that The incubation device (1) has a pump (24), in particular a peristaltic pump, arranged downstream of the first mixing device (2) in the flow direction, which is used to pump the reactive fluid (F) mixed in the first mixing device (2) to the container (4), and / or the incubation device (1) has a pump (25), in particular a peristaltic pump, arranged downstream of the container (4) in the flow direction, which is used to pump the incubated reactive fluid (F) to the second mixing device (7) or the separation device (8).

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