Bioreactor system and method for operating a bioprocess

Abstract

The bioreactor system (1) for accommodating a disposable bioreactor bag (100) comprises a container (10) having a container wall (11) defining a storage space (12) in which the disposable bioreactor bag (100) is accommodated during the operation of the bioreactor system (1). The agitation system (14) protrudes at least partially into the storage space (12) and is designed and configured to agitate the biological medium (101) present in the disposable bioreactor bag (100) during the operation of the bioreactor system (1). At least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) that makes the storage space (12) smaller and distinct from the container wall (11) serves to reduce the laminar flow of the biological medium (101). A temperature control medium flows through at least a portion of at least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81), said temperature control medium controlling the temperature of the baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81).

Description

Technical Field

[0001] The present invention relates to a bioreactor system for accommodating a disposable bioreactor bag, and a method for operating a bioprocess.

Background Art

[0002] A bioreactor system is used to accommodate, store, and culture a biological medium such as a fluid. The biological medium can be provided in a disposable bioreactor bag that can have a volume from several liters to several hundred liters. A disposable bioreactor bag containing the biological medium is inserted into the bioreactor system, where the biological medium is heated to a predetermined temperature for a predetermined time, usually several hours. Also, various investigations can be carried out on the biological medium in such a bioreactor system.

[0003] Since a bioreactor may be handled under cleanroom conditions, particularly high requirements are imposed on the quality assurance of the bioreactor. In particular, high quality requirements are imposed on the temperature control and mixing of the biological medium.

[0004] A bioreactor system for culturing animal cells is known from the pamphlet of International Publication No. WO 2016 / 192824. Bioreactor systems for some enhanced cell culture processes, such as microbial processes, phototrophic processes, and processes using fungal cells, still pose technical problems. Culturing such cells may require increased oxygenation, more intensive mixing (i.e., increased stirring speed and / or stirring force) and / or improved cooling. Each bioprocess may impose individual requirements and / or functions on the bioreactor system (e.g., depending on the cells being cultured). Compared to the process of cell culture, the microbial process requires several times higher oxygen transfer and several times higher cooling rates. The culture broth in the fungal process is often extremely viscous, so the appropriate bioreactor system should meet special requirements from the viewpoints of power input and stirring efficiency. SUMMARY OF THE INVENTION

[0005] The problem addressed by the present invention is to enable the execution of microbial bioprocesses and / or phototrophic bioprocesses and / or bioprocesses by fungal cells.

[0006] This problem is solved by the subject matter of the independent claims. Preferred embodiments are the subject matter of the dependent claims.

[0007] The first aspect relates to a bioreactor system for accommodating a disposable bioreactor bag in a containment vessel having a wall of the vessel that defines a containment space in which the disposable bioreactor bag is accommodated when the bioreactor system is in an operating state. The agitation system is designed and configured to project at least partially into the containment space and to agitate a biological medium present in the disposable bioreactor bag in the operating state of the bioreactor system. The bioreactor system reduces the size of the containment space and comprises at least one baffle different from the wall of the vessel and serves to reduce the laminar flow of the biological medium. The at least one baffle is at least partially flowed through by a temperature control medium that controls the temperature of the baffle.

[0008] The bioreactor system can be configured to accommodate a disposable bioreactor bag with an operating volume of from about 5 liters to about 10,000 liters. The containment vessel is designed to be sufficiently robust for repeated use to carry out a bioprocess. The containment vessel is designed as a reusable element of the bioreactor system, similar to at least part of the agitation system of the bioreactor system, such as an agitation drive unit. The disposable bioreactor bag can be designed to have walls of a flexible plastic bag so as to be discarded after each bioprocess.

[0009] The containment vessel can be made of stainless steel, for example, to enable high stability, sterility, and / or durability. The containment vessel comprises a wall of the vessel that defines the containment space. The containment space can have, for example, a substantially cylindrical shape, such as the bottom of a convex cylinder and / or the top of the cylinder. The individual elements of the bioreactor system can be configured in a manner similar to those disclosed in the above-mentioned publication WO 2016 / 192824 pamphlet. This applies in particular to the containment vessel, the agitation system, the door, and / or the cooling system of the wall of the vessel.

[0010] The bioreactor system can in particular be configured for processes of enhanced cell culture of different phylogenetic hierarchies, microbial processes, phototropic processes, and / or processes using fungal cells.

[0011] The walls of the containment vessel form a stable support for the flexible walls of the disposable bioreactor bag during the bioprocess. The disposable bioreactor bag and / or the biological medium can remain disposed within the containment space during most and / or the entire bioprocess. During the bioprocess, a portion of the biological medium can be taken, for example, as a sample, and / or components can be added to the biological medium. Ports and / or lines can be formed for this purpose to supply and / or discharge fluids. For example, a pressure relief valve for venting gas, as well as an outlet line and / or an inlet line and / or a circulation line for the biological medium can be provided.

[0012] The agitation system is used to mix the biological medium during the bioprocess. For this purpose, the agitation system can have at least one agitation shaft that projects at least partially into the containment space and / or passes completely through the containment space. Agitation elements and / or at least one agitation and / or mixing element can be arranged on the agitation shaft to completely mix the biological medium during the bioprocess.

[0013] To at least reduce the generation of laminar flow of the agitated biological medium, at least one baffle is formed within the containment space. When the biological medium is mixed, the baffle can generate turbulent flow, which disrupts the laminar flow and thus improves the mixing of the biological medium. A plurality of baffles that can be designed differently can preferably be arranged in the containment space.

[0014] The baffle can be arranged adjacent to and / or on, for example, the substantially smooth interior of the wall of the containment vessel, particularly the concave interior (seen from the inside) of the curved vessel wall. There, the baffle can break through the smooth inner surface of the vessel wall so that turbulent flow occurs during agitation. The larger and / or longer the baffle, the more and / or stronger turbulent flow can be generated. However, the baffle can also be arranged spaced apart from the wall of the containment space as long as it physically contacts the biological medium during mixing to form a physical and / or irregular barrier in the mixing space. This may already be sufficient to reduce laminar flow.

[0015] Since the baffle is different from the vessel wall, conventional baffles are not temperature-controlled like the vessel wall. When the baffle is not temperature-controlled, the effective temperature control surface of the biological medium decreases. At least in the case of conventional baffles, those contact surfaces with the biological medium are not used for temperature control and thus do not contribute to the cooling capacity.

[0016] The temperature-controlled baffle eliminates this drawback of non-temperature-controlled baffles in that a temperature-control medium can flow at least partially therethrough. For this purpose, the baffle can have, for example, temperature-control channels through which the temperature-control medium can flow. The temperature-control medium can preferably flow through the baffle along its entire propagation direction, so that substantially the entire baffle can be temperature-controlled. The baffle can be made of a material with high thermal conductivity, such as metal, particularly stainless steel, to enable effective temperature control of the biological medium by good heat conduction.

[0017] In particular, a cooling fluid can be used as the temperature-control medium, for example, the same or similar cooling fluid that is also used to cool the vessel wall. Alternatively, at least one baffle can also use an additional temperature-control medium, such as air cooling.

[0018] In other words, the bioreactor system can have a cooling system used to cool the walls of the container and / or to cool or temperature-control at least one baffle.

[0019] The potential cooling capacity of the bioreactor system is improved by the temperature control of the baffle. It can even enable processes with strict and / or enhanced requirements such as microbial processes and / or processes using fungal cells, i.e., processes of cell culture.

[0020] The baffle is designed as a mechanical obstacle in the accommodation space. The mechanical obstacle is designed and configured to affect and / or change the flow behavior of the biological medium when the biological medium is mixed by the agitation system. In particular, this can result in a reduction in laminar flow, i.e., a turbulent flow that improves and / or enhances the mixing of the biological medium, for example.

[0021] The biological medium can be designed especially as a liquid biological medium.

[0022] According to one embodiment, at least one baffle comprises at least a first baffle type that abuts against the wall of the containment vessel so as to project from the wall of the container into the accommodation space. This means that the bioreactor system comprises at least one baffle of the first baffle type. The bioreactor system preferably comprises a plurality of baffles of the first baffle type. The baffles of the first baffle type can be leaned towards the wall of the containment vessel, and thus the side surface of the baffle can face the wall of the container. The baffle can be elongated, for example, and can extend along the wall of the container, in particular from the lower end to the upper end. The baffle can extend, in particular, in a direction substantially parallel to the agitation axis of the agitation system. By protruding from the wall of the container, the baffle of the first baffle type has an expansion component arranged substantially radially with respect to the agitation axis of the agitation system. As a result, turbulent flow can be generated for better mixing of the biological medium.

[0023] According to one embodiment, at least one baffle comprises at least a second baffle type extending through the accommodation space at least along a portion spaced apart from the wall of the container of the accommodation container. The bioreactor system can comprise at least one baffle of the second baffle type, preferably a plurality of baffles of the second baffle type. The baffles of the second baffle type can, for example, hang down from above into the accommodation space and / or the disposable bioreactor bag, and / or can penetrate the accommodation space from a first, for example upper, end spaced apart from the wall of the container to a second, for example lower, end. The baffles of the second baffle type project at least partially into the disposable bioreactor bag. This enables temperature control, in particular cooling, of the biological medium in the space region spaced apart from the wall of the container. Thereby, the overall cooling capacity that can be transferred to the biological medium is increased, and a more powerful cell culture process can be enabled.

[0024] According to one embodiment, the baffle has a differential temperature control channel through which a temperature control medium flows through the baffle in two opposite directions. For example, the differential temperature control channel can flow substantially completely through the baffle in two opposite directions, such as the vertical up and down directions. The temperature control medium can pass through the baffle twice and can discharge its low-temperature content particularly well. Further, in this case, only one interruption of the wall of the container, for example, only at the upper end of the baffle, is required for the introduction and discharge of the temperature control medium to the baffle. From there, it can first flow downward through the baffle and then extend from below back to the upper end of the baffle. This double conduction of the temperature control medium through the baffle can result in particularly uniform cooling at the upper and lower ends of the baffle. At the inlet end and the outlet end of the baffle, the temperature control medium is both the coldest, i.e., when the temperature control medium is introduced, and the warmest, i.e., when the temperature control medium is discharged after the biological medium has been temperature-controlled. At the return end on the opposite side of the baffle, the temperature control medium has a moderately close temperature because it has already passed through the baffle once. Overall, the cooling performance is averaged so that the cooling performance at the inlet end and the outlet end of the baffle is almost as strong as the cooling performance at the return end of the baffle. This enables relatively uniform and thus controlled cooling of the biological medium.

[0025] The differential temperature control channel can be formed in both the baffle of the first baffle type and the baffle of the second baffle type.

[0026] According to one embodiment, at least one cooling bridge is disposed inside the baffle of the wall of at least one baffle that abuts against the wall of the disposable bioreactor bag in the operating state of the bioreactor system. The cooling bridge can be surrounded, for example, by the flow of the temperature control medium and can protrude inside the inner region of the baffle. The cooling bridge can improve cooling and can particularly reduce strong temperature fluctuations during cooling.

[0027] According to one embodiment, the baffle extends substantially vertically and substantially completely through the accommodation space. This can apply to baffles of both the first baffle type and the second baffle type. In this case, the baffle has an upper end and a lower end, and the upper end does not necessarily have to be directly above the lower end of the baffle. Rather, it can be offset laterally. The baffle can be designed to be substantially linear and / or to have a linear portion at least inside the accommodation space, along which the baffle extends substantially completely through the accommodation space.

[0028] According to one embodiment, the baffle is designed to protrude into the accommodation space from one end of the accommodation space. For example, it can protrude into the accommodation space from the upper end without being fastened to the wall of the lower container. Thus, the baffle has a free end at the end opposite to the fixed end of the baffle.

[0029] The bioreactor system can have different baffles, for example, at least one baffle of the first baffle type and at least one baffle of the second baffle type. The bioreactor system itself can have different baffles of the first baffle type and / or different baffles of the second baffle type.

[0030] A second aspect relates to a bioreactor system for containing a disposable bioreactor bag, and in particular can be designed as a bioreactor system according to the first aspect. The bioreactor system comprises a containment vessel having a vessel wall that defines a containment space in which the disposable bioreactor bag is contained in the operating state of the bioreactor system. The agitation system is configured to at least partially project into the containment space and is designed and configured to agitate the biological medium present in the disposable bioreactor bag in the operating state of the bioreactor system. At least one baffle makes the containment space smaller and is different from the vessel wall and serves to reduce the laminar flow of the biological medium, and it abuts against the vessel wall of the containment vessel so as to project from the vessel wall into the containment space. The baffle is configured to be rounded, such that the transition from the wall of the baffle and / or at least the vessel wall of the containment vessel to the wall of the baffle that abuts against the former is configured to be substantially edge-free as the wall and / or transition is abutted by the disposable bioreactor bag in the operating state.

[0031] The bioreactor system according to the second aspect can in particular be an embodiment of the bioreactor system according to the first aspect. Thus, the description of the bioreactor system according to the first aspect is at least partially relevant to the bioreactor system according to the second aspect, and vice versa. In particular, the bioreactor system according to the second aspect can be the bioreactor system according to the first aspect, and at least one baffle is designed as a baffle according to the first baffle type. This baffle abuts at least partially against the vessel wall of the containment vessel. In particular, the baffle can be formed completely along the vessel wall of the containment vessel.

[0032] The baffle has a rounded shape. The baffle is preferably designed without edges, at least on the side surfaces and / or on the side surfaces that are abutted by the disposable bioreactor bag in the operating state. The rounded design can reduce the air pockets between the disposable bioreactor bag and the baffle and / or the wall of the container. The edge-free shape of the baffle preferably allows the disposable bioreactor bag to abut against the wall of the container and / or the baffle in an operating state substantially free of air pockets. This reduces the air pockets, which can have an insulating effect and thus can interfere with and / or weaken the temperature control of the biological medium. Thereby, the temperature control is improved and more effective cooling of the biological medium becomes possible.

[0033] In particular, the baffle can be designed to have no sharp edges per se, but rather only rounded edges. For example, the baffle can have only the walls that physically contact the bioreactor bag and have no change in the direction of the cross-section that twists like the circular path of a circle with a diameter of at least about 1 centimeter. Thus, the baffle that protrudes substantially perpendicularly from the wall of the container and protrudes into the accommodation space has a minimum thickness of about 1 centimeter at least at its rounded edge.

[0034] Thus, the baffle can be designed without edges so as not to have any sharp edges directed towards the accommodation space. Additionally or alternatively, the baffle can also be designed without any corner spaces facing away from the accommodation space. This can be, for example, the corner space between the wall of the baffle and the wall of the container, which otherwise could form an air pocket. These corner spaces can also be rounded so as not to have a change in the direction of the cross-section that twists like the circular path of a circle with a diameter of at least about 1 centimeter.

[0035] The rounded design of the baffle can reduce air pockets and improve temperature control. As a result, it can enable a more complex and / or more intensive cell culture process.

[0036] In particular, the entire accommodation space can be designed to be substantially edge-free, that is, each transition between each baffle and the wall of the baffle and the wall of the container has no change in the cross-sectional direction that is as large as the circular path of a circle having a diameter of at least about 1 centimeter, as described above.

[0037] A third aspect relates to a bioreactor system for accommodating a disposable bioreactor bag, which can be, for example, an embodiment of a bioreactor system according to the first and / or second aspects. The bioreactor system includes a containment vessel having a vessel wall that defines an accommodation space in which the disposable bioreactor bag is accommodated in the operating state of the bioreactor system. The agitation system includes an agitation shaft that at least partially protrudes into the accommodation space and is designed and configured to agitate the biological medium present in the disposable bioreactor bag in the operating state of the bioreactor system. At least one baffle that makes the accommodation space smaller and is different from the vessel wall and reduces the laminar flow of the biological medium abuts against the vessel wall of the containment vessel and protrudes from the vessel wall into the accommodation space. The baffle extends in a baffle extension direction along the wall of the housing of the containment vessel. The baffle extension direction is arranged obliquely with respect to the extension direction of the agitation shaft.

[0038] The extension direction of the agitation shaft extends along the agitation shaft, that is, the agitation movement of the agitation system is performed by rotation around the extension direction of the agitation shaft.

[0039] As used herein, the term "angle" means that the baffle extending direction is not arranged parallel to the stirring shaft extending direction. Therefore, the baffle extending direction can be arranged at an angle of at least about 1°, preferably at least about 2° with respect to the stirring shaft extending direction. The arranged angle is related to the respective associated direction vectors, and thus the actual baffle extending direction does not necessarily need to intersect the stirring shaft extending direction. For example, a two-dimensional projection onto a vertical plane can include such an intersection point and an intersection angle that can be at least about 1°. The direction vectors of the two extending directions preferably form an angle of about 30° or less, preferably up to about 20°, particularly preferably up to about 10°.

[0040] The baffle can extend substantially linearly in the baffle extending direction, for example, along the wall of the container from the lower end of the baffle to the upper end of the baffle. As an alternative to this, if an arranged angle is given, the baffle can also be arranged on the floor of the containing container. However, the baffle is preferably arranged on a side wall that is substantially perpendicular to the wall of the container. The upper end of the baffle can be offset horizontally from the lower end of the baffle, for example, it can be offset horizontally by at least about 5 cm. The exact offset depends on the height of the containing container and can thus be influenced by the angle between the extending direction and the working volume part.

[0041] The baffle can form at least one part of a thread along the wall of the container in the extending direction of the stirring shaft.

[0042] In this baffle type, it is essential that the baffle extending direction is not parallel to the rotation vector of the stirring shaft, but rather different therefrom. The baffle acts in the same way as the screw thread of a screw, whereby the biological medium can not only move around the stirring shaft by the stirring motion, but also rise and / or fall in the extending direction of the stirring shaft by the baffle. The inclination of the baffle can, so to speak, screw the biological medium upward and / or downward in the accommodation space depending on the direction of stirring. This improves the execution efficiency of stirring and / or thorough mixing. Here, the mixing can be intensified and a more intensive bioprocess can be carried out in the bioreactor system.

[0043] The bioreactor system according to the third aspect can be designed as an embodiment of the bioreactor system according to the first and / or second aspects. Therefore, the description of the corresponding features (for example, the accommodation container, the accommodation space, the disposable bioreactor bag, etc.) can be applied to all bioreactor systems.

[0044] In one embodiment of the bioreactor system according to the third aspect, the baffle is designed as an internal thread of the accommodation space along the baffle extending direction. This effect can be enhanced, in particular, by the fact that two or more baffles are formed at an angle with respect to the extending direction of the stirring shaft along the inner side of the container wall, for example, parallel to each other. As a kind of internal thread, the effect of vertical mixing is enhanced and / or improved by the angled baffle. As a result, the mixing is intensified and / or becomes more effective.

[0045] According to one embodiment of the bioreactor system according to the first, second and / or third aspects, at least one baffle has a thermal conductivity greater than 10 W / (mK). The baffle may be, for example, solid. Therefore, the baffle is, for example, made of metal and has good thermal conductivity. This also improves the temperature control of the biological medium since the baffle can easily transfer the temperature control to the biological medium.

[0046] A fourth aspect relates to a bioreactor system for containing a disposable bioreactor bag, which can be an embodiment of the bioreactor system according to the first, second, and / or third aspects. The bioreactor system comprises a containment vessel having a vessel wall that defines a containment space in which the disposable bioreactor bag is contained in the operating state of the bioreactor system. Further, at least one probe window is provided, whereby the interior of the disposable bioreactor bag can be viewed in the operating state of the bioreactor system. The probe window comprises at least one thermally conductive probe window cover that is thermally conductively coupled to the cooling system of the bioreactor system.

[0047] The probe window is typically used for connecting probes and / or irradiating biological media. The probe window can also have a port through which a probe can be introduced into the interior of the containment space. Here, the probe window is thermally conductive and comprises a probe window cover coupled to the cooling system of the bioreactor system. The probe window cover may be particularly movable, for example, it may be openable and closable. The probe window cover can have, for example, one or more leaf doors. The probe window cover may be made of metal, for example, and / or can abut firmly against the vessel wall in the closed state covering the probe window. As a result, heat conduction can be established between the probe window cover and the temperature-controlled vessel wall through a sufficient bonding surface. By controlling the temperature of the vessel wall, the temperature of the probe window cover is also controlled, i.e., cooled, for example. Alternatively, the probe window cover itself can be cooled, i.e., for example, a temperature control medium can flow at least partially through it.

[0048] The cooling system of the bioreactor system can in particular be the cooling of the vessel wall and / or at least one baffle of the bioreactor system.

[0049] This type of probe window cover improves the overall cooling of the biological medium because temperature control is also possible in the probe window, thus enabling a more intensive cell culture process.

[0050] A fifth aspect relates to a bioreactor system for accommodating a disposable bioreactor bag, which can in particular be an embodiment of a bioreactor system according to the first, second, third, and / or fourth aspects. The bioreactor system comprises a containment vessel having a vessel wall that defines a containment space in which the disposable bioreactor bag is accommodated in the operating state of the bioreactor system. The agitation system is designed and configured to project at least partially into the containment space and to agitate the biological medium present in the disposable bioreactor bag in the operating state of the bioreactor system. The agitation system comprises an agitation shaft that, in the operating state of the bioreactor system, completely penetrates the containment space from a first agitation shaft end to a second agitation shaft end. At least one agitation drive of the agitation system is configured at both the first agitation shaft end and the second agitation shaft end to drive the agitation shaft.

[0051] In the conventional type, the agitation shaft is driven unidirectionally while the other agitation shaft end is freely suspended in the bioreactor. Alternatively, the other agitation shaft end can only be attached rotatably. In contrast, the bioreactor system according to the fifth aspect comprises an agitation shaft driven by at least two agitation drives acting on different agitation shaft ends. The first agitation drive is arranged at the first agitation shaft end and the second agitation drive is arranged at the second agitation shaft end. By the two agitation drives, more agitation power can be applied than in a conventional bioreactor system. This can be, for example, an upper agitation drive and a lower agitation drive. By increasing the total available output, the bioreactor system enables thorough mixing even of very viscous cells (such as fungal cells), enabling the corresponding bioprocess.

[0052] According to one embodiment, the two stirring drive parts arranged at the end of the stirring shaft can operate so that they drive the stirring shaft together in the same rotation direction at the same time. By doing so, for example, twice the power can be introduced into the biological medium as the stirring power. As a result, the mixing is improved, and it becomes possible to culture a concentrated and / or extremely viscous biological medium. The two stirring drive parts are adjusted so that they drive the stirring shaft together integrally, synchronously, and / or at the same speed.

[0053] According to one embodiment, the two stirring drive parts arranged at the end of the stirring shaft can operate so that they drive the stirring shaft in opposite rotation directions. The stirring drive parts can be designed to drive the stirring shaft simultaneously or at different times. For example, the first stirring drive part can be designed to drive only counterclockwise, and the second stirring drive part can be designed to drive only clockwise. Depending on the operating state, either the first or the second stirring drive part drives the stirring shaft. However, in particular, an operating mode can also be provided in which the two stirring drive parts drive the stirring shaft in opposite directions at the same time. For this purpose, the stirring shaft can be made in several parts, for example, such that the first part of the stirring shaft arranged adjacent to the first stirring drive part rotates in the first rotation direction, and the second part of the stirring shaft arranged adjacent to the second stirring drive part rotates in the second opposite rotation direction. This mixing in different rotation directions can also bring about a particularly effective and strong mixing of the biological medium, and thus make available a viscous biological medium for culturing in a bioreactor.

[0054] According to one embodiment, the bioreactor system has a pre-cooling device for pre-cooling a biological medium that can be supplied to a disposable bioreactor bag during a bioprocess. In some bioprocesses, additional (e.g., fresh) biological medium and / or at least components and / or nutrients of the biological medium are introduced into the disposable bioreactor bag during the bioprocess. All of these media introduced during the bioprocess can be pre-cooled by the pre-cooling device and / or can pass through the pre-cooling device. Thus, they are introduced into the already pre-cooled bioreactor. This also improves and makes the overall cooling more effective.

[0055] All of the above bioreactor systems according to the first to fifth aspects are compatible with each other and relate to the basic problem of enabling the execution of microbial bioprocesses and / or photoautotrophic bioprocesses and / or bioprocesses using fungal cells. Thus, all of the above bioreactor systems can be designed as at least one embodiment of other bioreactor systems. Redundant descriptions are avoided above. Descriptions of corresponding features (e.g., containment vessels, containment spaces, disposable bioreactor bags, etc.) can be applied to all bioreactor systems that have these features and should thus be understood as descriptions of these bioreactor systems.

[0056] A sixth aspect is a method for operating a bioprocess in a disposable bioreactor bag, comprising the following - providing a bioreactor system according to the first, second, third, and / or fourth aspects, - inserting the disposable bioreactor bag into the containment space of the containment vessel, - agitating the biological medium present in the disposable bioreactor bag by an agitation system, and - reducing the laminar flow of the biological medium by at least one baffle.

[0057] This method relates to the operating state in a bioreactor system according to the first, second, third, and / or fourth aspects, and thus to the operation of a bioprocess. According to these aspects, the description of a bioreactor system can also be related to the method, and vice versa. The baffle is used to reduce the laminar flow of the biological medium. The baffle can be cooled and, as described in relation to the first aspect, can enable more effective cooling of the biological medium. As described in relation to the second aspect, the baffle can be rounded and can reduce the formation of insulating air pockets. The baffle can be shaped to assist and / or improve the mixing in the bioreactor, as described in relation to the third aspect. Otherwise, cooling can be enhanced by, for example, a thermally conductive probe window cover as described in relation to the fourth aspect. Thus, this method can enable the processing of intensive cell cultures, particularly microbial processes, phototrophic processes, and / or processes using fungal cells.

[0058] A seventh aspect is a method for operating a bioprocess in a disposable bioreactor bag, particularly in combination with the method according to the sixth aspect, comprising the following - providing a bioreactor system according to the fifth aspect, - inserting a disposable bioreactor bag into the accommodation space of a containment vessel, and - driving a stirring shaft by two stirring drive units such that the biological medium present in the disposable bioreactor bag is stirred.

[0059] The stirring shaft can be driven such that the stirring drive units drive the stirring shaft synchronously in the same or opposite directions. The two stirring drive units increase the total output that can be introduced into the biological medium and thus enable more effective mixing of the biological medium, even in the case of a viscous biological medium.

[0060] According to one embodiment, a pre-cooled biological medium is introduced into a disposable bioreactor bag during the bioprocess. Alternatively or additionally, only the components of the biological medium introduced during the bioprocess can be pre-cooled.

[0061] According to one embodiment, microbial cells and / or fungal cells are cultured in a biological medium during the bioprocess. This is made possible by the fact that particularly effective cooling is used, particularly high stirring forces are provided, and / or both occur. Depending on the process, corresponding complex procedures can be used to enable the cultivation of even particularly complex cells.

[0062] In the context of the present invention, the terms "substantially" and / or "approximately" can be used to include a deviation of up to 5% from the numerical value following the term and a deviation of up to 5° from the direction and / or angle following the term.

[0063] Unless otherwise specified, terms such as upper, lower, above, below, side, etc. refer to the earth's reference system in the operating position of the subject matter of the present invention.

[0064] The present invention will be described in more detail below with reference to the exemplary embodiments shown in the figures. In this case, the same or similar reference numerals can identify the same or similar features of the embodiments. The individual features shown in the figures can be implemented in other exemplary embodiments. The following is shown.

Brief Description of the Drawings

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Embodiments for Carrying Out the Invention

[0066] Figure 1 shows a perspective view of a bioreactor system 1 for accommodating a disposable bioreactor bag. A similar bioreactor system is known from the pamphlet of International Publication No. 2016 / 192824 cited above. This known bioreactor system is designed for culturing animal cells in a less intensive bioprocess. There are some structural similarities between the known bioreactor system and the embodiments of the bioreactor system 1.

[0067] The bioreactor system 1 includes a storage container 10 that can have a shape of a cylinder arranged substantially vertically, that is, its cylinder axis can be arranged substantially vertically. The storage container 10 has a container wall 11 that defines a storage space 12 into which a disposable bioreactor bag capable of storing a biological medium can be inserted. The storage space 12 can be designed to accommodate a disposable bioreactor bag having a volume of about 5L to about 10,000L. For example, a common disposable bioreactor bag can hold 5L, 10L, 50L, 100L, 200L, 500L, 1,000L, or 2,000L of biological medium. The storage space 12 is preferably designed for co-culturing at least about 100L, preferably at least about 500L, 1,000L, or particularly even 10,000L of biological medium.

[0068] The biological medium of the disposable bioreactor bag is stored in the storage space of the storage container 10 for a predetermined period. While the disposable bioreactor bag containing the biological medium is inside the storage container 10, different reactions can occur with or on the biological medium. In particular, in this case, cells can be cultured.

[0069] To observe the biological medium, one or more view windows can be formed in the container wall 11, through which the inside of the storage space 12 of the storage container 10 can be seen from the outside through the container wall 11. Thereby, the biological medium can be observed.

[0070] The bioreactor system 1 can have, for example, at least one bottom view window 13 in the lower third and / or at least one door and / or side view window 14. The bottom view window 13 can be designed substantially in the form of an elongated ellipse, and its long elliptical axis is positioned substantially horizontally along the curved outer cylindrical wall of the containment vessel 10. The door view window 14 can be configured substantially in the form of an elongated rectangle, with its long side oriented substantially vertically and formed near the center of the single leaf door of the wall of the containment vessel 10.

[0071] The single leaf door can rotate about the door hinge and is thus openable and closable. When the single leaf door is open, a door opening is formed in the containment vessel 10 in the lateral position, through which access to the inside of the containment vessel 10 becomes possible. For example, a disposable bioreactor bag can be introduced into the containment space 12 of the containment vessel 10 through the door opening from the lateral direction, i.e., the substantially horizontal movement direction.

[0072] The bioreactor system 1 can be stored rollably so that the bioreactor system 1 can be pushed across the room. In addition to the rollers, the bioreactor system 1 can have fixed legs at the lower end, which are used to fix and correctly align the bioreactor system 1 on an uneven floor.

[0073] The storage container 10 can be designed to open at the top. Instead of the lid of the cylinder, the storage container 10 can have a stirring opening at its upper end. A part of the stirring system 20 can be formed above the storage container 10 that opens at the top, particularly above the stirring drive part of the stirring system 20. The stirring shaft of the stirring system 20 is not explicitly shown and can protrude through the stirring opening into the storage space 12 and the inside of the disposable bioreactor bag. When operating the stirring shaft, the biological medium can be mixed in the disposable bioreactor bag. The stirring shaft can be designed as a disposable component and can be arranged inside the disposable bioreactor bag. This can be connected to the stirring system 20 via a coupling and / or a link mechanism. The stirring system 20 can be formed in the center above the storage container 10 and can be supported by a support bridge that abuts the upper edge of the storage container 10 on the opposing side walls of the storage container 10. The stirring system 20 can include other elements such as another stirring drive part that exists below the storage container 10 to drive the lower end of the stirring shaft. The bioreactor system 1 can also include baffles that mainly affect the flow behavior of the biological medium in the storage space 12 caused by the stirring system 20.

[0074] Figure 2 shows a perspective view of a vertical cross-section of the bioreactor system 1. For example, the disposable bioreactor bag 100, more precisely, the part passing through this disposable bioreactor bag 100 arranged in the storage space 12 of the storage container 10, is shown in Figure 2. There is a biological medium, namely the biological medium 101, that can be filled to a predetermined level in the storage space 12 of the storage container 10 and at the same time inside the disposable bioreactor bag 100. The biological medium 101 extends from the bottom of the storage container 10 to this filling level, and thus fills the volume from the entire internal volume of the storage container 10 to the filling level, minus the volume of the walls of the disposable bioreactor bag 100. This can be composed of, for example, a flexible material (such as plastic) that substantially abuts the inside of the wall 11 of the container as it is [as in the original text].

[0075] The disposable bioreactor bag 100 is supported by the container wall 11 of the containment vessel 10, retains its shape, and extends upward from the rounded bottom of the containment vessel 10 to above the fill level. Along at least the upper half, preferably along the upper two-thirds of the containment vessel 10, the container wall 11 can extend substantially vertically, almost vertically upward.

[0076] The container wall 11 can be temperature-controlled by a cooling system and / or a cooling device. For this purpose, the container wall 11 can have cavities and can be designed, for example, as a double wall, through which a temperature-control medium (such as air, etc.) can flow partially.

[0077] Figure 3A shows a perspective view of a cross-section through the first baffle 30 of the first baffle type, which is arranged in close contact with the container wall 11 of the containment vessel 10 (see Figures 1 and 2). The baffle 30 of the first baffle type is formed on the inner side of the container wall 11 facing the containment space 12 such that the baffle 30 is arranged directly adjacent to and / or in physical contact with the container wall 11. The baffle 30 can extend, for example, substantially vertically from the lower end to the upper end of the baffle, for example, along the container wall 11 up to at least a predetermined fill level and / or at least along substantially the vertically arranged portion of the container wall 11 (see Figures 1 and 2) over substantially its entire height.

[0078] Figure 3B shows a perspective view of the entire length of the first baffle 30. The baffle 30 is generally elongated, and its longitudinal extension axis is close to vertical.

[0079] The cross-section shown in FIG. 3A extends along a plane that is disposed substantially perpendicular to the wall 11 of the container (here, substantially horizontal) through the baffle 30 and the wall 11 of the container. In a cross-section perpendicular to the wall 11 of the container, the baffle 30 of the first baffle type has a shape that is close to triangular. The apex of the triangle faces the accommodation space 12 and can, for example, point towards the center and / or central axis and / or cylindrical axis of the accommodation space 12. The base facing outwards from this apex of the triangle can be convex. This base can, for example, be directly formed by the slightly curved wall 11 of the container or can be formed separately as a component of the baffle 30 and can, for example, be arranged in contact with the slightly curved wall 11 of the container.

[0080] The baffle 30 of the first baffle type is at least partially hollow and has a differential temperature control channel 31 inside it. The channel partition 32 is arranged near the center of the cavity of the baffle 30 so as to mechanically separate the two sub-channels of the differential temperature control channel 31 from each other. The channel partition 32 can extend from the wall 11 of the container to the apex of the triangle that points into the interior of the accommodation space 11.

[0081] FIG. 3B shows how the channel partition 32 can extend along substantially the entire length of the baffle 30 of the first baffle type. The channel partition 32 is interrupted only at the (here, lower) return end of the baffle 30. Otherwise, the channel partition 32 divides the cavity of the baffle 30 of the first baffle type into two channel halves that together form the differential temperature control channel 31, namely the first and second sub-channels, approximately evenly.

[0082] At the (upper) inlet end of the first baffle type baffle 30 where the channel partition 32 strictly separates the two sub-channels, a temperature control medium, for example a cryogenic medium, is introduced into the first sub-channel of the differential temperature control channel 31. This is indicated by the arrows shown in FIGS. 3A and 3B. As the temperature control medium, a liquid or a gas (for example, air) can be used. A filter screen 34 for filtering the temperature control medium can be formed at this inlet end, and at this inlet end, the temperature control medium is introduced into the first sub-channel. One or more such filter screens 34 can be arranged in the differential temperature control channel 31, particularly at the inlet end.

[0083] The temperature control medium introduced in this way flows completely through the first sub-channel of the baffle 30 from the inlet end to the opposite return end. At this return end, the channel partition 32 is designed to be blocked, and the temperature control medium can flow from the first sub-channel of the differential temperature control channel 31 to the second sub-channel. Along the second sub-channel, it flows in a reverse direction from the return end to the outlet end of the first baffle type baffle 30. The outlet end is formed at the same end of the baffle as the inlet end, that is, at the upper end of the baffle in the illustrated exemplary embodiment.

[0084] The flow of the temperature control medium is indicated by the arrows in FIGS. 3A and 3B. The temperature control medium flows substantially completely twice through the first baffle type baffle 30, that is, once from the inlet end to the return end and then back to the outlet end arranged adjacent to the inlet end. At least at the outlet end of the differential temperature control channel 31, a ventilation unit 35, for example a ventilation wheel, for increasing and / or controlling and / or adjusting the flow rate of the temperature control medium can be provided.

[0085] The first baffle type baffle 30 provides efficient and effective cooling and / or temperature control of the baffle 30. This enables temperature control of the biological medium on at least the side surface of the first baffle type baffle 30 facing the accommodation space 12. As a result, the temperature control (especially cooling) of the biological medium during the process can be improved.

[0086] The baffle 30 shown as the first baffle type does not have an independent rear wall. Instead, the wall 11 of the container is used as the rear wall, that is, as the side wall facing outward from the accommodation space 1. The transition between the baffle 30 and the wall 11 of the container is rounded, which will be described in more detail below with reference to FIGS. 6 and 7.

[0087] FIG. 3C shows a cross-section of a further embodiment of the first baffle type baffle 30 that is substantially perpendicular to the wall 11 of the container. This is a baffle 30 that has its own rear wall that abuts firmly against the wall 11 of the container, in contrast to the baffle 30 shown in FIGS. 3A and 3B. Similar to the baffle 30 shown in FIGS. 3A and 3B, the baffle 30 shown in FIG. 3C also has a differential temperature control channel 31, whereby the baffle 30 can be temperature-controlled.

[0088] The first baffle type baffle 30 not only has a channel partition 32 on the inside, but also has one or more cooling webs 33. The cooling webs 33 can be arranged on the inner wall of the baffle 30, and the outer wall facing outward from the inner wall is in direct physical contact with the disposable bioreactor bag in the operating position. Therefore, the baffle wall of the baffle 30 represents the direct limit of the accommodation space 12 of the bioreactor system 1. The cooling webs 33 may be solid and project substantially perpendicularly into the baffle cavity and / or sub-channels from the inner wall of the baffle 30.

[0089] Generally, similar to the second baffle type of baffle, the first baffle type of baffle 30 is designed as an obstacle that narrows and / or defines the limit of the accommodation space 12, and functions to reduce the laminar flow in the accommodation space 12. The first baffle type of baffle is different from the second baffle type of baffle, which will be described in more detail below, in that the second baffle type of baffle extends through the interior of the accommodation space 12, for example, substantially parallel and spaced apart from the wall 11 of the container, while at least partially or even completely abutting against the wall 11 of the container.

[0090] The cooling web 33 of the first baffle type of baffle 30 shown in FIG. 3C is, for example, similar to the walls of other baffles, made of a thermally conductive material or preferably made of a thermally conductive material. In particular, a metallic material such as stainless steel is particularly suitable. The cooling web 33 can improve the heat exchange between the temperature control medium and the wall of the baffle 30, and thus can enhance the cooling effect of the first baffle type of baffle 30.

[0091] The first baffle type of baffle 30 shown in FIGS. 3A and 3B can also have a cooling web 33, that is, it is exactly similar to the first baffle type of baffle 30 shown in FIG. 3C.

[0092] As an alternative to the differential temperature control channel 41, the baffle 30 can also have a single-channel temperature control channel that is penetrated only once and can be temperature-controlled.

[0093] FIG. 4A shows a cross-section substantially perpendicular to the wall 11 of the container through an embodiment of the solid baffle 50 of the first baffle type. The solid baffle 50 has a cross-sectional shape similar to a triangle, similar to the baffle 30 shown in FIGS. 3A - 3C. However, in contrast, the solid baffle 50 is designed with a solid baffle body 51. The solid baffle body 51 is formed entirely of a material having good thermal conductivity, such as a metal like aluminum.

[0094] The two outer walls of the solid baffle 50 with a triangular cross-section face the accommodation space 12. On the other hand, the third outer wall serving as the rear wall is in close thermal contact with the wall 11 of the container without any gap. As a result, the rear wall of the entire thermally conductive solid baffle 50 is closely and thermally conductively coupled to the wall 11 of the container, and as a result, it is also temperature-controlled by the temperature control of the wall 11 of the container and / or the cooling system. As described above, the temperature of the wall 11 of the container can be controlled. For example, the wall 11 of the container can be designed as a double wall through which a temperature control medium and / or a coolant circulate for temperature control and / or cooling. Due to the close thermal coupling, the solid baffle 50 can benefit from the temperature control of the wall of the container and transfer this temperature control and / or cooling to the biological medium present in the accommodation space 12.

[0095] Figure 4B shows an embodiment of the cavity baffle 60 of the first baffle type. The cavity baffle 60 may also be approximately triangular and nearly perpendicular to the wall of the container in the illustrated cross-section. In this case, the two side walls face the accommodation space 12, and the third rear side is designed to abut against the wall 11 of the container without a gap and / or firmly. As a result, the cavity baffle 60 is also well-coupled to the temperature control and / or cooling system of the wall 11 of the container, and this temperature control and / or cooling can be passed to the biological medium present in the accommodation space 12.

[0096] The baffles 30, 50, 60 of the first baffle type do not necessarily have to have a triangular cross-section and can have other shapes such as wavy and / or square. However, they can all have a rear side, which abuts firmly against the wall 11 of the container (similar to that shown in FIGS. 3C, 4A, 4B) or is formed by it (similar to that shown in FIG. 3A).

[0097] FIG. 5A shows a schematic view of an embodiment of a bioreactor system 1 in which a second baffle type baffle 40 is disposed in the accommodation space 12. The second baffle type baffle, unlike the first baffle type baffle, extends at least partially into, and / or projects into, and / or extends through the accommodation space 12 spaced from the wall 11 of the container. In contrast, the first baffle type baffle is arranged to be in close contact with the inner side of the wall 11 of the container.

[0098] On the other hand, the illustrated second baffle type baffle 40 is arranged mostly spaced from the wall 11 of the container such that the biological medium 101 flows substantially around it from all radial and / or horizontal directions. The second baffle type baffle 40 shown in FIG. 4A is a second baffle type baffle 41 fastened on both sides, and mostly passes through the accommodation space 12 spaced from the wall 11 of the container. The elongated baffle 41 can be fastened to the wall 11 of the container at both of its baffle ends, and even penetrate it. The baffle 41 can completely penetrate the accommodation space 12 from its upper baffle end to its lower baffle end.

[0099] The temperature control medium can flow through the baffle 41 fastened on both sides along its entire length, which is indicated by the arrow in FIG. 5A. For this purpose, the baffle 41 has a temperature control channel 43 extending as a cavity along the extension between the baffle ends of the baffle 41 fastened on both sides. The temperature control channel 43 can extend at least from the first fastening end of the baffle 41 to the second fastening end of the baffle 41, and optionally, for example, beyond the temperature control medium outlet from the temperature control medium source.

[0100] The liquid and / or gaseous temperature control medium can flow through the temperature control channel 43, as a result, the baffle 41 fastened on both sides is temperature-controlled, providing a temperature sink at the center of the biological medium 101.

[0101] The baffles 41 fastened on both sides can be designed as pressurized welding hoses. The baffles 41 can be designed as an integral part of the disposable bioreactor bag 100. During assembly, the temperature control channel 43 can be connected to one or more channels of the temperature control medium at the fastening end.

[0102] By controlling the temperature in the middle of such a biological medium 101, effective and efficient temperature control of the biological medium becomes possible. At least one wall of the baffle 41 can be made transparent, for example, made of transparent plastic. Then, a light-emitting and / or fluorescent liquid can be used as the temperature control medium in the photobioreactor. This enables the bioreactor system 1 to be used for intensive photoautotrophic bioprocesses.

[0103] The baffle 41 does not necessarily have to be pressurized initially and can simply be designed as a hose tunnel that initially loosens and passes through the interior of the disposable bioreactor bag 100. By pressurizing at least one baffle 41 while it is inserted into the storage container 10, the disposable bioreactor can stand upright on its own so that it can be easily connected to the port of the storage container 10 even before being filled with the biological medium. Therefore, the free baffle 41 fastened on both sides can simplify and / or facilitate the assembly and / or construction of the disposable bioreactor bag 100 of the bioreactor system 1.

[0104] As an alternative to the single-channel temperature control channel 43, the baffle 41 can be penetrated by a differential temperature control channel, similar to the baffle 30 shown in FIGS. 3A - 3C.

[0105] FIG. 5B shows a perspective view of a further exemplary embodiment of the bioreactor system 1 having a further baffle 40 of the second baffle type. This baffle 40 is a baffle 42 fastened on one side. This baffle 42 fastened on one side can, for example, hang vertically downward into the accommodation space 12 from the upper end of the accommodation space 12. Alternatively, the baffle fastened on one side can also protrude into the interior of the accommodation space 12 from different directions, in particular laterally or downward. However, the baffle 42 fastened on one side is preferably aligned so as to extend substantially parallel to the extending direction (not shown) of the stirring shaft of the stirring system of the bioreactor system 1. Thereby, it is possible to prevent the baffle 42 and the stirring shaft from interfering too much. Furthermore, the baffle 42 fastened on one side can be configured as long as possible at this time.

[0106] This extending direction substantially parallel to the stirring shaft is also advantageous for the baffle 41 shown in FIG. 5A fastened on both sides.

[0107] The temperature control medium can also flow through the baffle 42 fastened on one side. For example, this can have temperature control channels facing inward, similar to the baffle 30 shown in FIGS. 3A and 3B. Alternatively, the baffle 42 can be solid, similar to the solid baffle 50 shown in FIG. 4A, for example. In the disposable bioreactor bag 100, the baffle 42 can only be designed as a foil insert that can introduce the cooling fingers of the bioreactor system 1. The cooling fingers can, for example, be solid or designed as a hollow body, that is, similar to the baffles 50 or 60 shown in FIGS. 4A and 4B. Furthermore, similar to the baffle 30 of the first baffle type (see FIGS. 3A to 3C), opposing temperature control channels can also be arranged in the cooling fingers.

[0108] The baffle 42 fastened on one side is arranged so as to face outward from the fastened end and has a free end protruding into the interior of the accommodation space 12. The biological medium 101 can flow completely around this free end.

[0109] The second baffle-type baffles 41, 42 improve the temperature control of the biological medium 101, for example, by providing a heat sink directly inside the biological medium 101. This can enable, for example, intensive cell culture processes that require a stronger cooling capacity than conventional animal bioprocesses. The bioreactor system 1 shown in FIGS. 5A and 5B should be understood as an example. To improve temperature control, a plurality of baffles 40, 41, and / or 42 can be arranged therein.

[0110] FIGS. 6A and 6B each show a cross-section substantially perpendicular to the wall 11 of the container through the bridge baffle 70 (FIG. 6A) and the angled baffle 71 (FIG. 6B). In the illustrated cross-section, the bridge baffle 70 is designed as a substantially rectangular bridge that projects substantially perpendicularly from the wall 11 of the container into the interior of the accommodation space 12. In the illustrated cross-section, the angled baffle 71 is designed as an angle with legs of substantially the same length, and the angled top tapers into the interior of the accommodation space 12.

[0111] The baffles 70, 71 shown in FIGS. 6A and 6B have the disadvantage that they have relatively sharp edges and / or form an angled transition with the wall 11 of the container. When inserting the disposable bioreactor bag 100, the wall 102 of the bag abuts against the baffles 70 and 71, so that, undesirably, an air pocket 110 can be formed between the wall 102 of the bag on the one hand and the bridge baffle 70 or the angled baffle 71 on the other hand, and in some cases also between the wall 102 of the bag and the wall 11 of the container.

[0112] These air pockets 110 can occur, in particular, at the transition between the wall of the container of the baffle 70 or 71 and the wall of the baffle. The wall of the baffle can protrude from the wall 11 of the container at a clearly defined angle, for example, of about 30° to about 120°. The flexible bag wall 102 cannot abut firmly against this transition, and thus, the air pocket 110 is formed. Since the air pocket 110 acts as insulation between the temperature-controlled wall 11 of the container and the biological medium 101, it can exhibit an insulating effect that prevents and / or deteriorates the cooling of the biological medium 101.

[0113] Figures 7A and 7B show cross-sections substantially perpendicular to the wall 11 of the container through the corrugated baffle 72 and the double-corrugated baffle 73. The corrugated baffle 72 and the double-corrugated baffle 73 are much more suitable for the effective cooling of the biological medium 101 than the bridge baffle 70 and the angled baffle 71 shown in Figures 6A and 6B. For example, the corrugated baffle 72 and the double-corrugated baffle 73 are each configured as a rounded baffle of the first baffle type. The rounded baffles 72, 73 are designed so that in the operating state, the bag wall 102 can abut firmly against the baffles 72, 73 and the wall 11 of the container without sharp edges. As a result, the insulating air pockets 110 between the bag wall 102 and the wall 11 of the temperature-controlled container and the baffles 72, 73 are reduced. Furthermore, the contact area between, on the one hand, the wall 11 of the container and the baffles 72, 73 and, on the other hand, the bag wall 102, and thus the biological medium, can be increased. Furthermore, as a result, the stress on the bag wall 102 of the disposable bioreactor bag 100 can be reduced. These effects can be achieved by the outer surface of the baffle wall of the baffles 72, 73 sliding gently in the cross-section, thereby enabling the disposable bioreactor bag 100 to abut firmly against the boundary of the accommodation space 12, particularly adjacent to the baffles 72, 73.

[0114] In the illustrated cross-section, the corrugated baffle 72 is designed as a wave approximating a single bump having a rounded wave crest and additionally rounded sides, which nests into the transition to the wall 11 of the container without any edges. Both the wave crest and the wave trough adjacent to the wall 11 of the container preferably form a curved shape in a cross-section having a curved diameter of at least about 1 cm.

[0115] The same applies to the double corrugated baffle 73, which in the illustrated cross-section is designed similarly to the corrugated baffle 72, but in contrast has a double wave as a double hump. This double wave is also rounded and furthermore has rounded sides, which nests into the transition to the wall 11 of the container without any edges. Both the crest of the double wave and the trough of the wave adjacent to the wall 11 of the container preferably have a curved cross-section with a curved diameter of at least about 1 cm.

[0116] In an alternative embodiment, the corrugated baffle can have additional wave crests, for example as a three- or four-wave baffle. The wave crests and / or troughs can be of different heights.

[0117] Both the corrugated baffle 72 and the double corrugated baffle 73 can be configured as a cavity baffle (similar to the cavity baffle 60 shown in FIG. 4B), as a solid baffle (similar to the solid baffle 50 shown in FIG. 4A), and / or as a temperature control baffle having simple or differential temperature control channels, i.e., similar to the baffle shown in FIG. 3 or 5.

[0118] Figure 8A shows a perspective view of a bioreactor system having a bottom view window 13 covered by a view window cover 15. As shown in FIG. 1, the bottom view window 13 can be formed in the container wall 11 in the lower region of the containment vessel 10. A probe holder 16 in the form of a handle bar can be arranged above and / or below the bottom view window 13. The probe can be fastened to the probe holder 16 and arranged in the bottom view window 13. Such a probe can reach, for example, into the interior of the accommodation space 12 where measurements can be taken.

[0119] The conventional bottom view window 13 is not temperature-controlled and is made of glass or the like. In the embodiment shown in FIG. 8A, the bottom view window 13 is covered by a view window cover 15. The view window cover 15 is thermally conductive and / or can be thermally conductively coupled to the cooling system of the container wall 1. For this purpose, the view window cover 15 can be formed of a metal such as aluminum, for example. The view window cover 17 can include one or more probe inlets 17 through which a probe can be fastened to or through the bottom view window 13.

[0120] A similar view window cover can also be arranged on the side view window 14 of the bioreactor system 1 (see FIG. 1).

[0121] Figure 8B shows in perspective view that the view window cover 15 can be opened. More specifically, the view window cover 15 has a first cover flap 15A and a second cover flap 15B. These can be folded away from the bottom view window 13 so as to remove the bottom view window 13. For this purpose, at least one hinge 19 can be provided which functions to open and close the cover flap 15A and / or 15B, preferably one hinge 19 for each cover flap 15A, 15B.

[0122] The thermally conductive view window covers 15 / 15A / 15B enable thermal coupling of the regions of the view windows 13, 14 to the temperature control of the wall 11 of the container, such as by temperature control of a double wall with a temperature control medium. Thereby, it is also possible to cool the biological medium 101 on the surface occupied by the view windows 13, 14. As a result, cooling is improved overall, making it possible to have a more intensive cell culture process.

[0123] FIG. 9A shows some views of an embodiment of the containment vessel 10 having angled corrugated baffles 80. The view from above into the containment space 12 of the containment vessel 10 is shown at the left end of FIG. 9A. Here, markings of a cross-section along a vertical plane through the containment vessel 10 are shown, which are shown on the right as a cross-sectional view. The third view from the left shows a partially open perspective view of the containment vessel 10 and a closed perspective view of the containment vessel 10 on the far right.

[0124] A plurality of corrugated baffles 80 of a first baffle type are arranged in the containment vessel 10, and these are arranged in close contact with or adjacent to the wall 11 of the container of the containment vessel 10. In the illustrated exemplary embodiment, the containment vessel 10 has exactly four such angled corrugated baffles 80. The cross-section through the corrugated baffle 80 can be formed in substantially the same way as the cross-section of the corrugated baffle 72 shown in FIG. 7A. Alternatively, the angled corrugated baffle 80 can be solid (like the solid baffle 50 shown in FIG. 4A) or hollow, like the cavity baffle 60 shown in FIG. 4B. The angled corrugated baffle 80 can also have temperature control channels similar to the baffle 30 shown in FIGS. 3A - 3C, for example.

[0125] The angled corrugated baffle 80 extends in a generally vertical direction from the lower end to the upper end along the wall 11 of the container. However, the upper end is horizontally offset with respect to the lower end. Thus, the angled corrugated baffle 80 does not extend exactly vertically, but rather extends at an angle to the vertical along the inside of the wall 11 of the container. The corrugated baffle 80 forms a kind of internal thread in the containment space 12.

[0126] In particular, in consideration with all the angled corrugated baffles 80, the plurality of barriers are formed in the accommodation space 12 in such a manner that all are arranged in substantially the same direction, angled with respect to the vertical and offset from each other in a substantially parallel manner. This barrier, similar to a female screw, "screws" the biological medium 101 either upward or downward (depending on the stirring direction) during the mixing by the rotation of the biological medium 101 through the barriers formed by the angled corrugated baffles 80. Due to the arrangement angle of the corrugated baffles 80, a vertical movement component is generated when the biological medium 101 is mixed.

[0127] The angled corrugated baffles 80 extend at an angle with respect to the stirring axis (not shown in the figure) and its axis of rotation. The angle between the extending direction of the angled corrugated baffles 80 and the extending direction of the stirring axis can be at least about 5° in order to produce a sufficient vertical stirring motion.

[0128] FIG. 9B shows, similar to FIG. 9A, an embodiment of the accommodation container 10 having angled bridge baffles 81. Here, the angled baffles are designed as angled rounded bridge baffles 81. They have a similar shape to the bridge baffles 70 shown in FIG. 6A, but are rounded at least at their edges protruding into the accommodation space 12, whereby they do not form any sharp edges at this location. This shape of the angled bridge baffles 81 also enables an additional directional and / or mixing component of the biological medium 101 in the vertical direction, similar to the angled corrugated baffles 80 shown in FIG. 9A, thereby enhancing the mixing.

[0129] The embodiments of the accommodation container 10 provided with the angled baffles 80, 81 shown in FIGS. 9A and 9B improve and / or enhance the mixing. This enables the realization of a bioreactor for culturing relatively highly viscous cells.

[0130] The baffles shown in FIGS. 3A - 3C, 4A, 4B, 5A, 5B, 7A, and 7B enable the baffle itself to be temperature - controlled and / or enable a reduction in temperature inside the bioreactor, thus improving the cooling of the biological medium 101. This makes it possible to realize a bioreactor for culturing cells that require intensive cooling.

[0131] The probe window covers 15 shown in FIGS. 5A and 5B also increase the available temperature - control surface area, thus improving the cooling of the biological medium 101. This makes it possible to realize a bioreactor for culturing cells that require intensive cooling.

[0132] The means outlined above can be combined with each other to further improve cooling and / or mixing by combination.

[0133] According to one embodiment, an agitation system operating at an agitator peripheral speed of up to about 6.0 m / s is used. As a result, the oxygenation and mixing of the biological medium 101 can be improved.

[0134] According to one embodiment, an agitation system is used that is accompanied by a power input of up to about 11 kW / m 3 This enables, for example, a high agitator peripheral speed of about 6 m / s.

[0135] According to one embodiment, a gas generation rate of up to about 3.0 vvm (abbreviation for "volume per minute of the vessel") is used. This can improve the oxygenation of the biological medium 101. Also, as a secondary effect, it can improve the so - called mixing effect.

[0136] According to one embodiment, the bioreactor system 1 is optimized to use values of up to 1,000 k L a per hour. This can be achieved as a result of a high agitator peripheral speed and / or a high gas generation rate.

[0137] According to one embodiment, a heating and / or cooling rate of up to 90 watts per liter of biological medium, i.e., generally a temperature control rate, is used.

[0138] According to one embodiment, no plastic parts are used in the stirring drive part of the stirring system and / or only as few plastic parts as possible are used. In order to enable high-power transmission, a stirring shaft made of stainless steel and / or steel can preferably be used. The stirrer itself may also be made of metal in order to enable high-power transmission to the biological medium.

[0139] According to one embodiment, a stirrer having a shape suitable for power input is arranged on the stirring shaft of the stirring system. In this case, for example, the geometric shape of a stirrer known by the name of Smith and, where applicable, its deformed forms can be used. The stirrer can be designed as a hydrofoil and / or a closed Smith stirrer. Alternatively, the shape of an elephant ear or an impellability, which is a subtype of the Smith stirrer, can be used. The stirrer can be made of stainless steel in order to enable the mixing of highly viscous cells (e.g., fungal cells).

[0140] According to one embodiment, the flow breaker is arranged on the stirrer, such as a circular disk, which surrounds the tip of the stirrer and thus achieves an improved mixing effect.

[0141] According to one embodiment, the containment vessel 10 has a height that is at least three times its diameter. The containment vessel 1 is also of a substantially cylindrical design as shown in FIGS. 1, 2, 5A, 5B, 9A, and 9B. This relatively tall and slender design of the containment vessel 10 increases the cooling surface because a greater amount of biological medium 101 per unit volume is present on the temperature-controlled vessel wall 11. As a result, the residence time of the gas can also be lengthened.

[0142] According to one embodiment, in order to improve the overall cooling capacity, both the gas flowing above the biological medium 101 and / or the liquid supply for the biological medium 101 can be precooled.

[0143] According to one embodiment, the containment vessel 10 can be designed without a door and / or without a viewing window. A camera for observing the biological medium 101 can be placed inside the bag holder and / or even inside the disposable bioreactor bag 100. This also increases the overall effective area of the wall 11 of the temperature-controlled vessel.

[0144] According to one embodiment, the flow rate of the temperature control medium in the temperature-controlled double sheath of the wall 11 of the vessel is optimized for the cooling capacity to be achieved and is particularly increased.

[0145] Furthermore, in order to achieve a stronger stirring capacity, the strength of the magnetic disk of the stirring drive unit, as well as the strength, number, length, and / or mass of the magnets for coupling the stirring drive unit inside the disposable bioreactor bag 100 can be optimized.

[0146] The power of the stirring system can be transmitted inside the disposable bioreactor bag 100 by magnetic coupling in the radial direction with fine scaling. Thereby, the torque can be increased.

[0147] In order to improve the coupling between the stirring drive unit and the stirring shaft present inside the disposable bioreactor 100, overall longer and stronger magnets and / or more magnets can be used. In this case, current-induced magnetization can be used to improve the magnetic coupling.

[0148] These and other optimizations can be made to optimize the bioreactor system for use in bioprocesses for intensive cell culture.

[0149] As a whole, the present invention provides a bioreactor system 1 and a method for operating the same, which have improved mixing, enhanced temperature control and / or cooling capabilities, and thus enable the cultivation of cell cultures that were previously inaccessible in bioprocesses.

Explanation of reference numerals

[0150] 1 Bioreactor system 10 Containment vessel 11 Wall of the vessel 12 Containment space 13 Bottom view window 14 Side view window 15 View window cover 15A First cover flap 15B Second cover flap 16 Probe holder 17 Probe opening 18 Probe 19 Hinge 20 Stirring system 30 First baffle type baffle 31 Differential temperature control channel 32 Channel partition 33 Cooling bridge 34 Filter screen 35 Ventilation unit 40 Second baffle type baffle 41 Baffle freely fastened on both sides 42 Baffle freely fastened on one side 43 Temperature control channel 50 Solid baffle 51 Solid baffle body 60 Hollow baffle 61 Hollow 70 Bridge baffle 71 Elbow baffle 72 Corrugated baffle 73 Double corrugated baffle 80 Angled corrugated baffle 81 Angled and rounded bridge baffle 100 Disposable bioreactor bag 101 Biological medium 102 Bag wall 110 Air cushion

Claims

1. A bioreactor system (1) for accommodating a disposable bioreactor bag (100), comprising: - a containment vessel (10) having a vessel wall (11) defining a containment space (12) in which the disposable bioreactor bag (100) is accommodated in the operating state of the bioreactor system (1); - a stirring system (14) at least partially protruding into the containment space (12) and designed and configured to stir a biological medium (101) present in the disposable bioreactor bag (100) in the operating state of the bioreactor system (1); - at least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) different from the vessel wall (11) that reduces the laminar flow of the biological medium (101) and serves to make the containment space (12) smaller; a temperature control medium flowing through at least a part of the at least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81), the temperature control medium controlling the temperature of the baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81); the at least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) comprising at least one baffle (40, 41, 42) of a second baffle type extending at least along a part spaced apart from the vessel wall (11) of the containment vessel (10) through the containment space (12); the baffle (40, 41, 42) of the second baffle type at least partially protruding into the disposable bioreactor bag (100), the bioreactor system (1).

2. The at least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) comprises at least one baffle (30; 50; 60; 72; 73; 80; 81) of a first baffle type that is made to lean towards the vessel wall (11) of the containment vessel (10), protrudes from the vessel wall (11), and protrudes into the containment space (12), the bioreactor system (1) according to claim 1.

3. The bioreactor system (1) according to claim 1, wherein the baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) comprises a differential temperature control channel (31) through which the temperature control medium flows in two opposite directions through the baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81).

4. The bioreactor system (1) according to claim 1, wherein at least one cooling bridge (33) is arranged on the wall of at least one baffle within the baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) and is abutted by the bag wall (102) of the disposable bioreactor bag (100) in the operating state of the bioreactor system (1).

5. The bioreactor system (1) according to claim 1, wherein the baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) penetrates the accommodation space (12) almost completely along a substantially vertical direction.

6. The bioreactor system (1) according to claim 1, wherein the baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) is configured to protrude into the accommodation space (12) from one end of the accommodation space (12).

7. A bioreactor system (1) for accommodating the disposable bioreactor bag (100) according to claim 1, - comprising at least one baffle (30; 50; 60; 72; 73; 80; 81) that is different from the wall (11) of the container, reduces the laminar flow of the biological medium (101), abuts against the wall (11) of the container of the accommodation container (10), protrudes from the wall (11) of the container, and protrudes into the accommodation space (12) to reduce the size of the accommodation space (12). The baffle (30; 50; 60; 72; 73; 80; 81) is A bioreactor system (1) configured to be rounded, so that a transition from the wall of the baffle (30; 50; 60; 72; 73; 80; 81) and / or at least the wall (11) of the container of the containment container (10) to the wall of the baffle (30; 50; 60; 72; 73; 80; 81) that abuts the former is configured such that the wall and / or the transition is abutted by a disposable bioreactor bag (100) in the operating state and is substantially edge-free.

8. A bioreactor system (1) for containing the disposable bioreactor bag (100) according to claim 1, - a stirring system (20) comprising a stirring shaft designed and configured to project at least partially into the containment space (12) and to stir a biological medium (101) present in the disposable bioreactor bag (100) in the operating state of the bioreactor system (1); - at least one baffle (80; 81) that abuts against the wall (11) of the containment container (10) and projects from the wall of the container so as to project into the containment space (12), The baffle (80; 81) extends along the wall (11) of the containment container (10) in a baffle extension direction, and the baffle extension direction is arranged at an angle with respect to the extension direction of the stirring shaft. A bioreactor system (1).

9. The bioreactor system (1) according to claim 8, wherein the baffle (80; 81) is configured as an internal thread of the containment space (10) along the baffle extension direction.

10. The bioreactor system (1) according to claim 1, wherein the at least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81) is formed from a material having a thermal conductivity exceeding 10 W / mK and / or in solid form.

11. A bioreactor system (1) for containing the disposable bioreactor bag (100) according to claim 1, - comprising at least one probe window (13; 14) that enables viewing inside the disposable bioreactor bag (100) in the operating state of the bioreactor system (1). The bioreactor system (1), wherein the probe window (13; 14) includes at least one thermally conductive probe window cover (15) thermally conductively coupled to a cooling system of the bioreactor system (1).

12. A bioreactor system (1) for accommodating the disposable bioreactor bag (100) according to Claim 1, - The stirring system (20) includes a stirring shaft that completely penetrates the accommodation space (12) from a first stirring shaft end to a second stirring shaft end in the operating state of the bioreactor system (1), - At least one stirring drive part of the stirring system (20) is configured at both the first stirring shaft end and the second stirring shaft end to drive the stirring shaft, the bioreactor system (1).

13. The bioreactor system (1) according to Claim 12, wherein the two stirring drive parts arranged at the stirring shaft ends can operate so that they drive the stirring shaft simultaneously in the same rotation direction.

14. The bioreactor system (1) according to Claim 12 or 13, wherein the two stirring drive parts arranged at the stirring shaft ends can operate so that they drive the stirring shaft in opposite rotation directions.

15. The bioreactor system (1) according to Claim 1, having a pre-cooling device for pre-cooling a biological medium (101) and / or components of the biological medium (101) that can be introduced into the disposable bioreactor bag (100) during a bioprocess.

16. A method for operating a bioprocess (1) with a disposable bioreactor bag (100), comprising the following - providing the bioreactor system (1) according to Claim 1; - inserting the disposable bioreactor bag (100) into the accommodation space (12) of the accommodation container (10); - stirring the biological medium (101) present in the disposable bioreactor bag (100) by the stirring system (20); - reducing the laminar flow of the biological medium (101) by the at least one baffle (30; 40, 41, 42; 50; 60; 72; 73; 80; 81).

17. A method for operating a bioprocess (1) with a disposable bioreactor bag (100) according to claim 16, comprising the following - providing a bioreactor system (1) according to claim 12; - inserting the disposable bioreactor bag (100) into the accommodation space (12) of the accommodation container (10); - driving the stirring shaft with the two stirring drive units so that the biological medium (101) present in the disposable bioreactor bag (100) is stirred.

18. A method for operating a bioprocess with a disposable bioreactor bag (100) according to claim 16, wherein a pre-cooled biological medium (101) is introduced into the disposable bioreactor bag (100) during the bioprocess.

19. A method for operating a bioprocess with a disposable bioreactor bag (100) according to claim 16, wherein microbial cells and / or fungal cells are cultured in the biological medium (101) during the bioprocess.

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