BIOREACTOR SYSTEMS AND METHOD FOR OPERATING A BIOPROCESS

Abstract

A bioreactor system for receiving a disposable bioreactor bag comprises a receiving container having a container wall which defines a receiving space in which the disposable bioreactor bag is received in an operating state of the bioreactor system. A stirring system projects at least partially into the receiving space and is designed and configured to stir a biomedium present in the disposable bioreactor bag in the operating state of the bioreactor system. At least one baffle, which makes the receiving space smaller and differs from the container wall, serves to reduce a laminar flow of the biomedium. A temperature control medium flows through at least part of the at least one baffle, said temperature control medium controlling the temperature of the baffle.

Claims

1. A bioreactor system for receiving a disposable bioreactor bag, the bioreactor system comprising: a receiving container having a container wall which defines a receiving space in which the disposable bioreactor bag is received in an operating state of the bioreactor system; a stirring system which projects at least partially into the receiving space and is designed and configured to stir a biomedium present in the disposable bioreactor bag in the operating state of the bioreactor system; and at least one baffle, which makes the receiving space smaller and differs from the container wall, serving to reduce a laminar flow of the biomedium; wherein a temperature control medium flows through at least part of the at least one baffle, said temperature control medium controlling the temperature of the baffle.

2. The bioreactor system according to claim 1, wherein the at least one baffle comprises at least one baffle of a first baffle type, which rests against the container wall of the receiving container in such a way that it protrudes from the container wall and projects into the receiving space.

3. The bioreactor system according to claim 1, wherein the at least one baffle comprises at least one baffle of a second baffle type, which extends at least along a portion spaced apart from the container wall of the receiving container through the receiving space.

4. The bioreactor system according to claim 1, wherein the baffle comprises a differential temperature control channel, through which the temperature control medium flows through the baffle in two opposite directions.

5. The bioreactor system according to claim 1, wherein, within the baffle, at least one cooling bridge is arranged on at least one baffle wall, which, in the operating state of the bioreactor system, is abutted by a bag wall of the disposable bioreactor bag.

6. The bioreactor system according to claim 1, wherein the baffle penetrates the receiving space approximately completely along an approximately vertical direction.

7. The bioreactor system according to claim 1, wherein the baffle is configured so as to project from one end of the receiving space into the receiving space.

8. A bioreactor system for receiving a disposable bioreactor bag, the bioreactor system comprising: a receiving container having a container wall which defines a receiving space in which the disposable bioreactor bag is received in an operating state of the bioreactor system; a stirring system which projects at least partially into the receiving space and is designed and configured to stir a biomedium present in the disposable bioreactor bag in the operating state of the bioreactor system; and at least one baffle, which makes the receiving space smaller and differs from the container wall, serving to reduce a laminar flow of the biomedium, which abuts the container wall of the receiving container in such a way that it protrudes from the container wall and projects into the receiving space; wherein the baffle is configured so as to be rounded, such that a wall of the baffle and/or at least a transition from the container wall of the receiving container to the wall of the baffle abutting the former, which wall and/or transition is abutted by disposable bioreactor bag in the operating state, is configured so as to be substantially edgeless.

9. A bioreactor system for receiving a disposable bioreactor bag, the bioreactor system comprising: a receiving container having a container wall which defines a receiving space in which the disposable bioreactor bag is received in an operating state of the bioreactor system; a stirring system with a stirring shaft, which projects at least partially into the receiving space and is designed and configured to stir a biomedium present in the disposable bioreactor bag in the operating state of the bioreactor system; and at least one baffle, which makes the receiving space smaller and differs from the container wall, serving to reduce a laminar flow of the biomedium, which abuts the container wall of the receiving container in such a way that it protrudes from the container wall and projects into the receiving space; wherein the baffle extends in a baffle extension direction along the housing wall of the receiving container and the baffle extension direction is arranged at an angle to a stirring shaft extension direction of the stirring shaft.

10. The bioreactor system according to claim 9, wherein the baffle is configured as an internal thread of the receiving space along the baffle extension direction.

11. The bioreactor system according to claim 9, wherein the at least one baffle is formed from a material having a thermal conductivity that is greater than 10 W/mK and/or is solid in form.

12. The bioreactor system according to claim 1 comprising: at least one probe window, which allows a view into the inside of the disposable bioreactor bag in the operating state of the bioreactor system; wherein the probe window comprises at least one thermally conductive probe window cover, which is thermally conductively coupled to a cooling system of the bioreactor system.

13. The bioreactor system according to claim 1 comprising: a stirring system which projects at least partially into the receiving space and is designed and configured to stir a biomedium present in the disposable bioreactor bag in the operating state of the bioreactor system; wherein the stirring system comprises a stirring shaft, which completely penetrates the receiving space in the operating state of the bioreactor system from a first stirring shaft end to a second stirring shaft end; and at least one stirring drive of the stirring system is configured at both the first stirring shaft end and the second stirring shaft end for driving the stirring shaft.

14. The bioreactor system according to claim 13, wherein the two stirring drives arranged at the stirring shaft ends can be operated in such a way that they drive the stirring shaft simultaneously and together in the same direction of rotation.

15. The bioreactor system according to claim 13, wherein the two stirring drives arranged at the stirring shaft ends can be operated in such a way that they drive the stirring shaft in opposite directions of rotation.

16. The bioreactor system according to claim 13, having a precooling apparatus for precooling a biomedium and/or a component of the biomedium, which can be conducted into the disposable bioreactor bag during a bioprocess.

17-20. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0072] FIG. 1 schematically illustrates a perspective view, a bioreactor system for receiving a disposable bioreactor bag;

[0073] FIG. 2 schematically illustrates a perspective view, a vertical sectional view through the bioreactor system for receiving a disposable bioreactor bag;

[0074] FIG. 3A schematically illustrates a perspective view of a section of an embodiment of a temperature-controlled baffle;

[0075] FIG. 3B schematically illustrates a perspective view of an embodiment of a temperature-controlled baffle;

[0076] FIG. 3C schematically illustrates a cross-section through an embodiment of a temperature-controlled baffle;

[0077] FIG. 4A schematically illustrates a cross-section through an embodiment of a solid baffle;

[0078] FIG. 4B schematically illustrates a cross-section through an embodiment of a cavity baffle;

[0079] FIG. 5A schematically illustrates a schematic view of an embodiment of a bioreactor system, in whose receiving space a temperature-controlled baffle is arranged;

[0080] FIG. 5B schematically illustrates a schematic view of a further embodiment of a bioreactor system, in whose receiving space a temperature-controlled baffle is arranged;

[0081] FIG. 6A schematically illustrates a cross-section through a bridge baffle;

[0082] FIG. 6B schematically illustrates a cross-section through an elbow baffle;

[0083] FIG. 7A schematically illustrates a cross-section through an embodiment of a wave baffle;

[0084] FIG. 7B schematically illustrates a cross-section through an embodiment of a double wave baffle;

[0085] FIG. 8A schematically illustrates a perspective view of an embodiment of a bioreactor system having a closed probe window cover;

[0086] FIG. 8B schematically illustrates a perspective view of an embodiment of a bioreactor system having an open probe window cover;

[0087] FIG. 9A schematically illustrates a plurality of views of an embodiment of a receiving container having angular wave baffles; and

[0088] FIG. 9B schematically illustrates a plurality of views of an embodiment of a receiving container having angular, rounded bridge baffles.

DETAILED DESCRIPTION

[0089] FIG. 1 shows a perspective view of a bioreactor system 1 for receiving a disposable bioreactor bag. A similar bioreactor system is known from the document WO 2016/192824 A1 cited above. This previously known bioreactor system is designed for the cultivation of animal cells in less intensive bioprocesses. There are some structural similarities between the previously known bioreactor system and the embodiment of the bioreactor system 1.

[0090] The bioreactor system 1 comprises a receiving container 10 which can substantially have the shape of a vertically arranged cylinder, i.e. the cylinder axis of which can be arranged substantially vertically. The receiving container 10 has a container wall 11 which defines a receiving space 12 into which a disposable bioreactor bag can be inserted, which can contain a biological medium. The receiving space 12 can be designed so as to receive a disposable bioreactor bag with a volume of approximately 5 L to approximately 10,000 L. For example, common disposable bioreactor bags can hold 5 L, 10 L, 50 L, 100 L, 200 L, 500 L, 1,000 L, or 2,000 L of biomedium. The receiving space 12 is preferably designed for the simultaneous cultivation of at least approximately 100 L of biomedium, preferably of at least approximately 500 L, 1,000 L, or in particular even 10,000 L.

[0091] The biological medium in the disposable bioreactor bag is stored in the storage space of the storage container 10 for a predeterminable period of time. While the disposable bioreactor bag containing the biological medium is inside the receiving container 10, different reactions with or on the biological medium can occur. In particular, cells can be cultivated in this case.

[0092] In order to observe the biological medium, one or more view windows can be formed in the container wall 11, through which it is possible to look from the outside through the container wall 11 into the receiving space 12 of the receiving container 10. This allows the biological medium to be observed.

[0093] The bioreactor system 1 can, for example, have 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 windows 13 can substantially be designed in the form of an elongated oval, whose long oval axis is aligned substantially horizontally along the curved outer cylinder wall of the receiving container 10. The door view window 14 can be configured substantially in the form of an elongated rectangle, whose longer sides are oriented substantially vertically and can be formed approximately in the middle of a single-leaf door in the container wall of the receiving container 10.

[0094] The single-leaf door can be rotated about door hinges and is thus openable. If the single-leaf door is open, a door opening is formed in the receiving container 10 at a lateral position, through which access to the interior of the receiving container 10 is made possible. For example, the disposable bioreactor bag can be introduced through the door opening into the receiving space 12 of the receiving container 10 from a lateral direction, that is to say substantially in a horizontal direction of movement.

[0095] The bioreactor system 1 can be stored in a rollable manner so that the bioreactor system 1 can be pushed through a room. In addition to rollers, the bioreactor system 1 can have fixing feet at the lower end, which are used in order to fix and correctly align the bioreactor system 1 on uneven floors.

[0096] The receiving container 10 can be designed so as to be open at the top. Instead of a cylinder lid, the receiving container 10 can have a stirring opening at its upper end. A part of a stirring system 20 can be formed above the receiving container 10, which is open at the top, in particular a stirring drive of the stirring system 20. A stirring shaft of the stirring system 20 is not explicitly shown and can project through the stirring opening into the receiving space 12 and the disposable bioreactor bag. When operating the stirring shaft, the biomedium 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. It can be connected to the stirring system 20 via a coupling and/or linkage. The stirring system 20 can be formed centrally over the receiving container 10 and supported by a support bridge abutting an upper edge of the receiving container 10 on opposite side walls of the receiving container 10. The stirring system 20 can comprise other elements, such as another stirring drive present beneath the receiving container 10 for driving a lower end of the stirring shaft. The bioreactor system 1 can also comprise baffles which affect the flow behavior of the biomedium in the receiving space 12, which is mainly caused by the stirring system 20.

[0097] FIG. 2 shows a perspective view of a vertical section through the bioreactor system 1. For example, a disposable bioreactor bag 100 is shown in FIG. 2, more precisely a section through this disposable bioreactor bag 100, which is arranged in the receiving space 12 of the receiving container 10. In the receiving space 12 of the receiving container 10 and at the same time also in the interior of the disposable bioreactor bag 100, there is a biological medium, i.e. a biomedium 101, which can be filled to a predetermined level. The biomedium 101 extends from the bottom of the receiving container 10 up to this filling level and thus fills the entire internal volume of the receiving container 10 up to the filling level, minus the volume of the walls of the disposable bioreactor bag 100, which can be configured very [sic], e.g. from a flexible material (such as plastic) which substantially abuts the inside of the container wall 11.

[0098] The disposable bioreactor bag 100 is supported and held in shape by the container wall 11 of the receiving container 10, which extends upwards from the rounded bottom of the receiving container 10 to above the fill level. At least along the upper half, preferably along the upper two-thirds of the receiving container 10, the container wall 11 can substantially extend approximately vertically upwards in the vertical direction.

[0099] The container wall 11 can be temperature-controlled by means of a cooling system and/or a cooling apparatus. For this purpose, the container wall 11 can have a cavity, e.g. it can be designed as a double wall, and a temperature control medium (such as e.g. air) can partially flow through it.

[0100] FIG. 3A shows a perspective view of a cross-section through a first baffle 30 of a first baffle type, which is arranged in close contact with the container wall 11 of the receiving container 10 (cf. FIGS. 1 and 2). The baffle 30 of the first baffle type is formed on an inner side of the container wall 11 facing the receiving space 12 in such a way that the baffle 30 is arranged directly adjacent to and/or in physical contact with the container wall 11. The baffle 30 can, for example, extend substantially in a vertical direction from a lower to an upper end of the baffle, e.g. approximately along the entire height along the container wall 11 at least up to the predetermined filling level and/or at least in the approximately vertically arranged part of the container wall 11 (cf. FIGS. 1 and 2).

[0101] FIG. 3B shows the full length of the first baffle 30 in a perspective view. The baffle 30 is approximately elongated, and its longitudinal extension axis is approximately vertical.

[0102] The cross-section shown in FIG. 3A extends along a plane that is arranged approximately perpendicular to the container wall 11 (here, approximately horizontal) through the baffle 30 and the container wall 11. In the cross-section perpendicular to the container wall 11, the baffle 30 of the first baffle type has an approximately triangular shape. The apex of the triangle faces the receiving space 12 and can, for example, point to a center and/or central axis and/or the cylinder axis of the receiving space 12. A base facing away from this triangle apex can be convex. This base can either be formed directly by the container wall 11, which is slightly curved, for example, or it can be formed separately as a component of the baffle 30 and can be arranged in contact with the container wall 11, which is slightly curved, for example.

[0103] The baffle 30 of the first baffle type is at least partially hollow and has a differential temperature control channel 31 in its interior. A channel partition wall 32 is arranged approximately in the middle of the cavity of the baffle 30 in such a way that it mechanically separates the two subchannels of the differential temperature control channel 31 from one another. The channel partition wall 32 can extend from the container wall 11 to the apex of the triangle, which points into the interior of the receiving space 11.

[0104] FIG. 3B shows how the channel partition wall 32 can extend almost along the entire length of the baffle 30 of the first baffle type. Only at a (here, the lower) return end of baffle 30 is the channel partition wall 32 interrupted. Otherwise, the channel partition wall 32 separates the cavity of the baffle 30 of the first baffle type approximately evenly into two channel halves, namely a first and a second subchannel, which together form the differential temperature control channel 31.

[0105] At a (top) inlet end of baffle 30 of the first baffle type, at which the channel partition wall 32 strictly separates the two subchannels, a temperature control medium, for example a cold one, 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. A liquid or a gas (e.g. air) can be used as the temperature control medium. A filter screen 34 which filters the temperature control medium can be formed at this inlet end, at which the temperature control medium is introduced into the first subchannel. One or more such filter screens 34 can be arranged in the differential temperature control channel 31, in particular at the inlet end.

[0106] The temperature control medium introduced in this way runs through the first subchannel of the baffle 30 completely from the inlet end to the opposite return end. At this return end, the channel partition wall 32 is designed so as to be interrupted, and the temperature control medium can flow from the first subchannel of the differential temperature control channel 31 into the second. Along the second subchannel, it flows back from the return end to the outlet end of the baffle 30 of the first baffle type. The outlet end is formed at the same end of the baffle as the inlet end, i.e. at the upper end of the baffle in the exemplary embodiment shown.

[0107] The flow of the temperature control medium is indicated by arrows in FIGS. 3A and 3B. The temperature control medium flows through the baffle 30 of the first baffle type twice substantially completely, namely once from the inlet end to the return end and back again to the outlet end, which is arranged adjacent to the inlet end. At least at the outlet end of the differential temperature control channel 31, a ventilator unit 35 can be provided, for example a ventilator wheel, which increases and/or controls and/or regulates the flow rate of the temperature control medium.

[0108] The baffle 30 of the first baffle type provides an efficient and effective cooling and/or temperature control of the baffle 30. This enables a temperature control of the biomedium at least on the side surfaces of the baffle 30 of the first baffle type facing the receiving space 12. As a result, the temperature control (and in particular cooling) of the biomedium can be improved during the process.

[0109] The baffle 30 shown of the first baffle type does not have an independent rear wall, but rather uses the container wall 11 as a rear wall, i.e. as a side wall facing away from the receiving space 1. The transition between the baffle 30 and the container wall 11 is rounded, which will be discussed in further detail below with reference to FIGS. 6 and 7.

[0110] FIG. 3C shows a cross-section through a further embodiment of a baffle 30 of the first baffle type approximately perpendicular to the container wall 11. This is a baffle 30 which, by contrast to the baffle 30 shown in FIGS. 3A and 3B, has its own rear wall which tightly abuts the container wall 11. Just like the baffle 30 shown in FIGS. 3A and 3B, the baffle 30 shown in FIG. 3C also has a differential temperature control channel 31, by means of which the baffle 30 can be temperature-controlled.

[0111] The baffle 30 of the first baffle type not only has the channel partition wall 32 on the inside, but also one or more cooling web(s) 33. The cooling webs 33 can be arranged on an inner wall of the baffle 30, whose outer wall facing away from the inner wall is in direct physical contact with the disposable bioreactor bag in the operating position. The baffle walls of the baffle 30 thus represent a direct delimitation of the receiving space 12 of the bioreactor system 1. The cooling web 33 can be solid and projects approximately perpendicularly from the inner wall of the baffle 30 into the cavity and/or the subchannels of the baffle.

[0112] In general, the baffle 30 of the first baffle type, like the baffle of a second baffle type, is designed as an obstacle that narrows and/or delimits the receiving space 12 and serves to reduce a laminar flow in the receiving space 12. The baffles of the first baffle type differ from the baffles of the second baffle type, described in further detail below, in that they abut the container wall 11 at least in sections or even completely, while the baffles of the second baffle type run through the interior of the receiving space 12, e.g. approximately parallel and spaced apart from the container wall 11.

[0113] The cooling webs 33 of the baffle 30 of the first baffle type shown in FIG. 3C is or are preferably made of a thermally conductive material, as are the other baffle walls, for example. In particular, metallic materials such as stainless steel are particularly suitable. The cooling webs 33 can improve a heat exchange between the temperature control medium and the walls of the baffle 30 and can thus enhance the cooling effect of the baffle 30 of the first baffle type.

[0114] The baffle 30 of the first baffle type shown in FIGS. 3A and 3B can also have cooling webs 33, i.e. just like the baffle 30 of the first baffle type shown in FIG. 3C.

[0115] As an alternative to the differential temperature control channel 41, the baffle 30 can also have a single-channel temperature control channel, with which it is penetrated only once and can be temperature controlled.

[0116] FIG. 4A shows a cross-section approximately perpendicular to the container wall 11 through an embodiment of a solid baffle 50 of the first baffle type. The solid baffle 50 has an approximately triangular cross-sectional shape, similar to the baffles 30 shown in FIGS. 3A-3C. By contrast to this, however, 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, for example a metal such as aluminum.

[0117] Two outer walls of the solid baffle 50, which is triangular in cross-section, face the receiving space 12, while a third outer wall, as the rear wall, is in close thermal contact with the container wall 11 without any gaps. As a result, the rear wall of the overall thermally conductive solid baffle 50 is closely and thermally conductively coupled to the container wall 11, so that it is also temperature-controlled by a temperature control and/or cooling system of the container wall 11. As described above, the container wall 11 can be temperature-controlled. For example, the container wall 11 can be designed as a double wall, in which a temperature control medium and/or coolant circulates for temperature control and/or cooling. Due to the close thermal coupling, the solid baffle 50 benefits from the temperature control of the container wall and can pass this temperature control and/or cooling on to the biomedium present in the receiving space 12.

[0118] FIG. 4B shows an embodiment of a cavity baffle 60 of the first baffle type. The cavity baffle 60 can also be approximately triangular in the cross-section shown, approximately perpendicular to the container wall. In this case, two side walls face the receiving space 12, and a third rear side is designed without a gap and/or so that it tightly abuts the container wall 11. As a result, the cavity baffle 60 is also well coupled to the temperature control and/or cooling system of the container wall 11 and can pass this temperature control and/or cooling on to the biomedium present in the receiving space 12.

[0119] The baffles 30, 50, 60 of the first baffle types need not necessarily be triangular in cross-section, but can have other shapes, such as a wavy shape and/or a square shape. However, they can all have a rear side which tightly abuts the container wall 11 (similar to what is shown in FIGS. 3C, 4A, 4B) or is even formed by it (similar to what is shown in FIG. 3A).

[0120] FIG. 5A shows a schematic view of an embodiment of a bioreactor system 1, in whose receiving space 12 a baffle 40 of a second baffle type is arranged. The baffles of the second baffle type differ from those of the first baffle type, in that they run and/or project into and/or through the receiving space 12 spaced apart from the container wall 11 at least in sections. By contrast to this, the baffles of the first baffle type are arranged so as to tightly abut an inside of the container wall 11.

[0121] The baffle 40 of the second baffle type shown, on the other hand, is arranged spaced apart from the container wall 11 for the most part in such a way that the biomedium 101 substantially flows around it from all radial and/or horizontal directions. The baffle 40 of the second baffle type shown in FIG. 4A is a baffle 41 of the second baffle type fastened on both sides, which leads through the receiving space 12 spaced apart from the container wall 11 for the most part. The elongated baffle 41 can be fastened to the container wall 11 at both of its baffle ends and can even break through it. The baffle 41 can completely penetrate the receiving space 12 from its upper baffle end to its lower baffle end.

[0122] A temperature control medium can flow through the baffle 41 fastened on both sides along its entire length, which is indicated by arrows in FIG. 5A. For this purpose, the baffle 41 has a temperature control channel 43 which extends 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 a first fastening end of the baffle 41 to a second fastening end of the baffle 41 and optionally also beyond, e.g. from a temperature control medium source to a temperature control medium outlet.

[0123] A liquid and/or gaseous temperature control medium can flow through the temperature control channel 43, as a result of which the baffle 41 fastened on both sides is temperature controlled and provides a temperature sink in the middle of the biomedium 101.

[0124] The baffle 41 fastened on both sides can be designed as a pressurized, welded hose. The baffle 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 a temperature control medium at the fastening ends.

[0125] The temperature control in the midst of the biomedium 101 enables an effective and efficient temperature control of the biomedium. At least one wall of the baffle 41 can be transparent and can be made of a transparent plastic, for example. A luminous and/or fluorescent liquid can then be used as a temperature control medium in photobioreactors. This can make the bioreactor system 1 usable for intensive phototrophic bioprocesses.

[0126] The baffle 41 does not necessarily have to be pressurized from the outset, but can merely be designed as an initially slack hose tunnel through the interior of the disposable bioreactor bag 100. By pressurizing the at least one baffle 41 in a state of having been inserted into the receiving container 10, the disposable bioreactor can erect itself in such a way that it can be easily connected to ports of the receiving container 10 even before it is filled with the biomedium. Thus, the free baffles 41 fastened on both sides can simplify and/or facilitate assembly and/or construction of the disposable bioreactor bag 100 in the bioreactor system 1.

[0127] 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 baffles 30 shown in FIGS. 3A-3C.

[0128] FIG. 5B shows a perspective view of a further exemplary embodiment of a bioreactor system 1 having a further baffle 40 of the second baffle type. This baffle 40 is a unilaterally fastened baffle 42. This unilaterally fastened baffle 42 can, for example, hang vertically downwards into the receiving space 12 from an upper end of the receiving space 12. Alternatively, the unilaterally fastened baffle can also project into the interior of the receiving space 12 from a different direction, in particular from the side or from below. However, the unilaterally fastened baffle 42 is preferably aligned in such a way that it extends substantially parallel to an extension direction (not shown in the figures) of a stirring shaft of the stirring system of the bioreactor system 1. This can prevent the baffle 42 and the stirring shaft from interfering too much. Furthermore, the unilaterally fastened baffle 42 can then be configured as long as possible.

[0129] This extension direction approximately parallel to the stirring shaft is also advantageous for the baffle 41 shown in FIG. 5A, which is fastened bilaterally.

[0130] A temperature control medium can also flow through the unilaterally fastened baffle 42. For example, it can have an opposing temperature control channel on the inside, similar to the baffle 30, which is shown in FIGS. 3A and 3B. Alternatively, the baffle 42 can also be solid, for example, similar to the solid baffle 50 shown in FIG. 4A. In the disposable bioreactor bag 100, the baffle 42 can be designed merely as a foil insert into which a cooling finger of the bioreactor system 1 can be introduced. The cooling finger can, for example, be solid or designed as a hollow body, i.e. similar to the baffles 50 or 60 shown in FIGS. 4A and 4B. Furthermore, an opposing temperature control channel can also be arranged in the cooling finger, similar to the baffle 30 of the first baffle type (cf. FIGS. 3A to 3C).

[0131] The unilaterally fastened baffle 42 has a free end, which is arranged facing away from the fastened end and projects into the interior of the receiving space 12. The biomedium 101 can completely flow around this free end.

[0132] The baffles 41 and 42 of the second baffle type improve the temperature control of the biomedium 101 by providing a heat sink directly inside the biomedium 101, for example. This can enable the processing of intensive cell cultures, which for example require a stronger cooling capacity than conventional animal bioprocesses. The bioreactor systems 1 shown in FIGS. 5A and 5B are to be understood to be examples. A plurality of baffles 40, 41, and/or 42 can be arranged therein in order to improve the temperature control.

[0133] FIGS. 6A and 6B each show a cross-section approximately perpendicular to the container wall 11 through a bridge baffle 70 (FIG. 6A) and an angular baffle 71 (FIG. 6B). In the cross-section shown, the bridge baffle 70 is designed as a substantially rectangular bridge, which projects approximately perpendicularly from the container wall 11 into the interior of the receiving space 12. In the cross-section shown, the angular baffle 71 is designed as an angle with legs of approximately the same length, wherein the vertex of the angle points into the interior of the receiving space 12.

[0134] The baffles 70, 71 shown in FIGS. 6A and 6B have the disadvantage that they have relatively sharp edges and/or form angular transitions with the container wall 11. When inserting the disposable bioreactor bag 100, the bag wall 102 abuts the baffles 70 and 71 so unfavorably that air pockets 110 can form between the bag wall 102 on the one hand and the bridge baffle 70 or angular baffle 71 on the other hand and possibly the container wall 11.

[0135] These air pockets 110 can occur in particular at a transition between the container wall and the baffle wall of baffle 70 or 71. The baffle walls can protrude from the container wall 11 at a clearly defined angle of, for example, about 30 to about 120 degrees. The flexible bag wall 102 cannot tightly abut this transition, for which reason the air pockets 110 are created. The air pockets 110 can develop an insulating effect, which impedes and/or degrades the cooling of the biomedium 101, because they act as an insulation between the temperature-controlled container wall 11 and the biomedium 101.

[0136] FIGS. 7A and 7B show a cross-section approximately perpendicular to the container wall 11 through a wave baffle 72 and a double wave baffle 73. The wave baffles 72 and the double wave baffles 73 are much better suited for the effective cooling of the biomedium 101 than the bridge baffles 70 and the angular baffles 71 shown in FIGS. 6A and 6B. For example, the wave baffles 72 and the double wave baffles 73 are each configured as a rounded baffle of the first baffle type. The rounded baffles 72, 73 are designed so that they are free of sharp edges so that the bag wall 102 can tightly abut the baffles 72, 73 and also the container wall 11 in the operating state. As a result, insulating air pockets 110 between the bag wall 102 and the temperature-controlled container wall 11 and the baffles 72, 73 are reduced. In addition, a contact region between the container wall 11 and the baffles 72, 73 on the one hand and the bag wall 102 and thus the biomedium on the other hand can be increased. Furthermore, stress on the bag wall 102 of the disposable bioreactor bag 100 can be reduced as a result. These effects can be achieved by the outer surfaces of the baffle walls of the baffles 72, 73 sliding gently in cross-section, which allows the disposable bioreactor bag 100 to tightly abut the boundaries of the receiving space 12, in particular on and adjacent to the baffles 72, 73.

[0137] In the cross-section shown, the wave baffle 72 is designed as an approximately single-humped wave with a rounded wave crest and additionally rounded flanks, which nestle against the transition to the container wall 11 without any edges. Both the wave crest and the wave troughs adjacent to the container wall 11 form a curved shape in cross-section with a curve diameter that is preferably at least approximately 1 cm.

[0138] The same applies to the double wave baffle 73, which, in the cross-section shown, is designed similarly to the wave baffle 72 but, in contrast thereto, has a double wave as a double hump. This double wave is also rounded and additionally has rounded flanks, which nestle against the transition to the container wall 11 without any edges. Both the double wave crest and the wave troughs adjacent to the container wall 11 have a curved cross-section with a curve diameter that is preferably at least approximately 1 cm.

[0139] In an alternative embodiment, the wave baffles can have additional wave crests, e.g. as a triple or quadruple wave baffle. The crests and/or troughs of the waves can be of different heights.

[0140] Both the wave baffle 72 and the double wave 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-controlled baffle with a simple or differential temperature control channel, i.e. similar to the baffles shown in FIG. 3 or 5.

[0141] FIG. 8A shows a perspective view of a bioreactor system with a bottom view window 13 which is 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 a lower region of the receiving container 10. A probe holder 16 in the form of a handlebar can be arranged above and/or below the bottom view window 13. Probes can be fastened to the probe holder 16 and can be arranged on the bottom view window 13. Such probes can, for example, reach into the interior of the receiving space 12 and take measurements there.

[0142] Conventional bottom view windows 13 are not temperature-controlled, but are made of glass, for example. In the embodiment shown in FIG. 8A, the bottom view window 13 is covered by the view window cover 15. The view window cover 15 can be thermally conductive and/or thermally conductively coupled to a cooling system of the container wall 1. For this purpose, the view window cover 15 can be formed, for example, from a metal such as aluminum. The view window cover 17 can include one or more probe inlets 17 through which probes can be fastened to or through the bottom view window 13.

[0143] A similar view window cover can also be arranged on a side view window 14 of the bioreactor system 1 (cf. FIG. 1).

[0144] FIG. 8B shows in a 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 in such a way that they release the bottom view window 13. For this purpose, at least one hinge 19, preferably one hinge 19 for each cover flap 15A, 15B, can be provided, which serves to open and/or close the cover flaps 15A and/or 15B.

[0145] The thermally conductive view window cover(s) 15/15A/15B enable a thermal coupling of the region of the view window 13, 14 to the temperature control of the container wall 11, e.g. its temperature control by means of a temperature control medium in the double wall. This makes it possible to cool the biomedium 101 on the surface occupied by the view windows 13, 14, as well. As a result, the cooling is improved overall, and more intensive cell culture processes can be made possible.

[0146] FIG. 9A shows several views of an embodiment of a receiving container 10 having angular wave baffles 80. A view from above into the receiving space 12 of the receiving container 10 is shown on the far left in FIG. 9A. Here, a marking of a section along a vertical plane through the receiving container 10 is shown, which is shown to the right as a sectional view. The third view from the left shows a partially open perspective view of the receiving container 10, and a closed perspective view of the receiving container 10 on the far right.

[0147] A plurality of wave baffles 80 of the first baffle type are arranged in the receiving container 10, which are arranged in close contact with or adjacent to the container wall 11 of the receiving container 10. In the exemplary embodiment shown, the receiving container 10 has exactly four such angular wave baffles 80. The cross-section through the wave baffle 80 can be formed approximately like that of the wave baffle 72 shown in FIG. 7A. Alternatively, the angular wave baffle 80 can be solid (like the solid baffle 50 shown in FIG. 4A) or hollow, such as the cavity baffle 60 shown in FIG. 4B. The angular wave baffle 80 can also be a temperature control channel, e.g. similar to the baffles 30 shown in FIGS. 3A to 3C.

[0148] The angular wave baffle 80 extends from a lower end to an upper end along the container wall 11 in a roughly vertical direction. However, the upper end is offset horizontally to the lower end. Thus, the angular wave baffle 80 does not extend exactly in the vertical direction, but rather at an angle to the vertical along the inside of the container wall 11. The wave baffles 80 form a type of internal screw thread in the receiving space 12.

[0149] In particular, taken together with all of the angular wave baffles 80, a plurality of barriers are thus formed in the receiving space 12, which are all arranged approximately in the same direction and offset approximately parallel to one another at an angle to the vertical. This barrier, which is similar to an internal thread, causes the biomedium 101 to be “screwed” either upwards or downwards (depending on the direction of stirring) during the rotational mixing of the biomedium 101 through the barriers formed by the angular wave baffles 80. Due to the angular arrangement of the wave baffles 80, a vertical movement component is generated when the biomedium 101 is mixed.

[0150] The angular wave baffles 80 extend angularly to a stirring shaft (not shown in the figures) and its axis of rotation. The angle between the extension direction of the angular wave baffles 80 and the stirring shaft extension direction can be at least approximately 5° in order to generate a sufficient vertical stirring movement.

[0151] FIG. 9B shows, similar to FIG. 9A, an embodiment of a receiving container 10 with angular bridge baffles 81. Here, the angular baffles are designed as angular, rounded bridge baffles 81. They have a similar shape to the bridge baffles 70 shown in FIG. 6A, but are rounded off at least on their edge projecting into the receiving space 12 in such a way that they do not form any sharp edges there. This shape of the angular bridge baffles 81 also enables—similar to the angular wave baffles 80 shown in FIG. 9A—an additional directional and/or mixing component of the biomedium 101 in the verticals and thereby intensifies the mixing.

[0152] The embodiments of the receiving containers 10 with the angular baffles 80, 81 shown in FIGS. 9A and 9B improve and/or intensify the mixing. This can enable the realization of bioreactors for cultivating relatively viscous cells.

[0153] The baffles shown in FIGS. 3A-3C, 4A, 4B, 5A, 5B, 7A, and 7B improve the cooling of the biomedium 101, because they enable the baffles themselves to be temperature-controlled and/or allow temperature drops inside the bioreactor. This can enable the realization of bioreactors for cultivating cells that require intensive cooling.

[0154] The probe window cover 15 shown in FIGS. 5A and 5B also improves the cooling of the biomedium 101, because it increases the available temperature control surface. This can enable the realization of bioreactors for cultivating cells that require intensive cooling.

[0155] The measures outlined above can be combined with one another in order to further improve the cooling and/or mixing through combination.

[0156] According to one embodiment, a stirring system is used which is operated at a stirrer peripheral speed of up to about 6.0 m/s. As a result, the oxygenation and the mixing of the biomedium 101 can be improved.

[0157] According to one embodiment, a stirring system with a power input of up to about 11 kW/m.sup.3 is used. This enables, for example, the high stirrer peripheral speed of approximately 6 m/s.

[0158] According to one embodiment, a gassing rate of up to about 3.0 vvm (abbreviation for “vessel volume per minute”) is used. The oxygenation into the biomedium 101 can also be improved in this way. Furthermore, as a side effect of this, so to speak, the mixing effect can also be improved.

[0159] According to one embodiment, the bioreactor system 1 is optimized in order to use a La value of up to 1,000 per hour. This can be achieved as a consequence of the high stirrer peripheral speed and/or the high gassing rate.

[0160] According to one embodiment, a heating and/or cooling rate, i.e. generally a temperature control rate, of up to 90 watts per liter of the biomedium is used.

[0161] According to one embodiment, no plastic parts and/or only as few plastic parts as possible are used in the stirring drive of the stirring system. A stirring shaft made of stainless steel and/or steel can preferably be used in order to enable a high transmission of force. The stirrer itself can also be made of metal in order to enable a high transmission of force into the biomedium.

[0162] According to one embodiment, a stirrer with a geometry suitable for a power input is arranged on the stirring shaft of the stirring system. In this case, for example, stirrer geometries can be used which are known under the name Smith and, if applicable, variants. The stirrer can be designed as a hydrofoil and/or as a closed Smith stirrer. Alternatively, an elephant-ear geometry can be used, or an impeller bulletin, which is a subtype of the Smith stirrer. The stirrer can be made of stainless steel in order to be able to mix highly viscous cells (e.g. fungal cells).

[0163] According to one embodiment, a flow breaker is arranged on the stirrer, e.g. a circular disk, which surrounds the tips of the stirrer and thus achieves an improved mixing effect.

[0164] According to one embodiment, the receiving container 10 has a height at least three times its diameter. The receiving container 1 is of a substantially cylindrical design, as also shown in FIGS. 1, 2, 5A, 5B, 9A, and 9B. This relatively tall and slim design of the receiving container 10 increases the cooling surface, because a larger amount of the biomedium 101 is present on the temperature-controlled container wall 11 per volume. Furthermore, the gas dwell time can also be increased as a result.

[0165] According to one embodiment, both a gas flowing in above the biomedium 101 and/or a liquid feed for the biomedium 101 can be precooled in order to improve the overall cooling capacity.

[0166] According to one embodiment, the receiving container 10 can be designed without a door and/or without a view window. A camera for observing the biomedium 101 can be placed inside the bag holder and/or even inside the disposable bioreactor bag 100. This also increases the overall effective region of the temperature-controlled container wall 11.

[0167] According to one embodiment, the flow rates of a temperature control medium in the temperature-controlled double sheath of the container wall 11 are optimized, in particular increased, for the cooling capacity to be achieved.

[0168] Furthermore, in order to achieve a stronger stirring performance, the strength of a magnetic disk of the stirring drive can be optimized, as well as the strength, number, length, and/or quality of the magnets for coupling the stirring drive to the inside of the disposable bioreactor bag 100.

[0169] The power of the stirring system can be transferred to the interior of the disposable bioreactor bag 100 by means of a radial magnetic coupling with fine scaling. This allows the torque to be increased.

[0170] Long and strong magnets and/or more magnets overall can be used in order to improve the coupling between the stirring drive and the stirring shaft present inside the disposable bioreactor 100. In this case, current-induced magnetization can be used in order to improve the magnetic coupling.

[0171] These and other optimizations can be made in order to optimize the bioreactor system for use in bioprocesses on intensive cell cultures.

[0172] Overall, the invention provides a bioreactor system 1 and a method for operating it, in which the mixing is improved, the temperature control and/or cooling capacity is increased, and thus the cultivation of cell cultures that were previously inaccessible to the bioprocess is made possible.

LIST OF REFERENCE NUMERALS

[0173] 1 Bioreactor system [0174] 10 Receiving container [0175] 11 Container wall [0176] 12 Receiving space [0177] 13 Bottom view window [0178] 14 Side view window [0179] 15 View window cover [0180] 15A First cover flap [0181] 15B Second cover flap [0182] 16 Probe holder [0183] 17 Probe aperture [0184] 18 Probe [0185] 19 Hinge [0186] 20 Stirring system [0187] 30 Baffle of a first baffle type [0188] 31 Differential temperature control channel [0189] 32 Channel partition wall [0190] 33 Cooling bridge [0191] 34 Filter screen [0192] 35 Ventilator unit [0193] 40 Baffle of a second baffle type [0194] 41 Free bilaterally fastened baffle [0195] 42 Free unilaterally fastened baffle [0196] 43 Temperature control channel [0197] 50 Solid baffle [0198] 51 Solid baffle body [0199] 60 Cavity baffle [0200] 61 Cavity [0201] 70 Bridge baffle [0202] 71 Elbow baffle [0203] 72 Wave baffle [0204] 73 Double wave baffle [0205] 80 Angular wave baffle [0206] 81 Angular, rounded bridge baffle [0207] 100 Disposable bioreactor bag [0208] 101 Biomedium [0209] 102 Bag wall [0210] 110 Air cushion