Apparatus for fermenting a biological suspension

Abstract

The invention relates to an apparatus (10) for fermenting a biological suspension, comprising a tank (4) with a feed device (5) for feeding and discharging the biological suspension, the feed device comprising: a first central opening (1) in the tank (4) for feeding or discharging the biological suspension, a first pipe (2) which extends through the central opening (1) into the tank (4) in order to feed or discharge the biological suspension, a second pipe (3) which extends through the first pipe (2) and beyond the first pipe (2) into the tank (4) in order to feed or discharge the biological suspension, a first housing (GU), the interior (31) of which is tightly fastened, by means of an upper opening, to the tank (4), in particular to an outlet flange of the tank (4), around the central opening (1) and through which, with sealing with respect to the outside, the first pipe (2) extends, the first housing (GU) having an inlet opening (6) and an outlet opening (9) for the biological suspension, a second housing (GM), the interior (32) of which is tightly connected, by means of an upper opening, to the first pipe (2) and through which, with sealing with respect to the outside, the second pipe (3) extends, the second housing (GM) additionally having an inlet opening (7) and an outlet opening (11) for the biological suspension, and a third housing (GO), the interior (33) of which is tightly connected, by means of an opening, to the second pipe (3), the third housing (GO) additionally having an inlet opening (8) and an outlet opening (12) for the biological suspension.

Description

[0001] Device for fermenting a biological suspension

[0002] The invention relates to a device for fermenting a biological suspension and the use of such a device.

[0003] Fermentation devices are already known from the state of the art. Bioreactors are used for the cultivation of cells or for material conversion with the help of biocatalysts such as enzymes, microorganisms, or animal and plant cells. The purpose of such reactors is to homogenize the contents, suspend or disperse different phases, enable mass transfer between the different phases in the bioreactor, ensure heat exchange within the biological suspension / dispersion, and sterilely separate the contents of the bioreactor from the environment, thus preventing external contamination. This requires circulation within the tank.

[0004] Stirred tank reactors equipped with a stirrer are commonly used in the state of the art. Stirred tank reactors have the disadvantage that all shaft feedthroughs, such as those between the stirrer and the drive motor of the agitator, must be equipped with a vapor and / or condensate barrier to ensure sterile separation between the atmosphere and the product chamber. Furthermore, in large tanks, the shaft feedthrough and the mechanical seal are located on the top lid of the vessel, resulting in limited accessibility. Large agitators also have a high deadweight. Overall, a suitable solution for circulating biological suspensions is complex and expensive.

[0005] Bubble column reactors are also known. Bubble column reactors have the disadvantage that a defined gas volume is required for circulation, which does not necessarily correspond to the gas volume required for aeration of the tank contents. Circulation using nozzles is also difficult, as shear forces often occur, which are to be avoided with cell suspensions.

[0006] Fluidized-bed reactors are only suitable for immobilized microorganisms. Furthermore, cleaning and sterilization in the event of contamination are very complex. Circulation through multiple inlets and outlets at different heights is also already known. However, this poses problems with assembly and sterility.

[0007] Based on this, the present invention is based on the object of providing an improved device for fermentation which enables improved circulation in a simple, cost-effective and sterile manner.

[0008] According to the invention, this object is achieved by the features of claim 1.

[0009] The device comprises a feed device for supplying and discharging the biological suspension. This feed device is designed to function as a circulation device. There are at least three inlet openings at different heights in the tank through which the biological suspension can be supplied or discharged. The feed device comprises a first central opening in the tank for supplying or discharging the biological suspension and a first pipe extending through this central opening into the tank and through which the biological suspension can be supplied or discharged into the tank.

[0010] Furthermore, the feed device has a second pipe which extends through the first pipe and beyond the first pipe into the tank and via which the biological suspension can also be fed into or discharged from the tank.

[0011] The feed device further comprises a first housing, the interior of which is attached to the tank via an upper opening in a sealed manner around the central opening, i.e. the biological suspension can flow via the upper opening from the interior of the first housing and through the central opening into the tank. The first housing is preferably attached to an outlet flange of the tank. The first pipe extends through the first housing and is sealed to the outside, i.e. to the atmosphere. The first housing further comprises an inlet opening and an outlet opening for the biological suspension. This means that biological suspension can flow via the inlet opening through the interior of the first housing, via the upper opening of the housing and the central opening in the tank into the tank, but can also flow out of the tank through the central opening, via the upper opening and the interior in the first housing and via the outlet opening in the housing.The fact that the first tube extends through the first housing, sealed to the outside, therefore means that there is a tight connection between the first housing and the first tube, such that the interior of the first housing is sealed to the outside. For this purpose, a seal can preferably be provided, or the first tube can be welded to the first housing.

[0012] The device further comprises a second housing, the interior of which is tightly connected to the first tube via an upper opening and through which the second tube extends, sealed to the outside, wherein the second housing also has an inlet opening and an outlet opening for the biological suspension. This means that biological suspension can flow via the inlet opening into the interior of the second housing and can flow between the first and second tubes into the tank via a corresponding opening and can also flow from the tank between the first and second tubes back into the interior of the second housing and flow out via the outlet opening of the second housing. The fact that the second tube extends through the second housing, sealed to the outside, therefore means that there is a tight connection between the second housing and the second tube, such that the interior of the second housing is sealed to the outside.For this purpose, a seal can preferably be provided or the second tube can be welded to the second housing.

[0013] The feed device further comprises a third housing, the interior of which is tightly connected to the second tube via an opening. The third housing also has an inlet opening and an outlet opening for the biological suspension. Thus, the biological suspension can flow through the inlet opening into the interior of the third housing, into the second tube, and through the second tube into the tank via its upper opening. It can also flow from the tank via the inner tube into the interior of the third housing, leaving the housing again via the outlet opening.

[0014] Since there are three housings for supplying and discharging the biological suspension at different height levels - ie, the first housing with the first central opening, the second housing with the first pipe and the third housing with the second pipe -, for example, two housings can be used for circulating the biological suspension via the corresponding opening, ie the central opening, the opening of the first pipe and the second pipe.

[0015] The central arrangement of the central opening and the pipes allows the flow to develop evenly and symmetrically to the central axis in the tank. This allows sediment to settle homogeneously and be easily removed. This is particularly advantageous if the cells are to be concentrated in the lower area of ​​the tank. Conversely, deposition can be counteracted by reversing the direction using the valve circuit and / or the pump control, so that the cells can be kept in suspension. The homogeneous distribution of the cells within the tank improves mass transfer and nutrient availability. The flexible option of using the three housings as either inlet or outlet lines, particularly for circulation, enables ideal adaptation to various processes and process steps.Since the first, second, and third housings have a corresponding opening through which they are in fluid contact with the interior of the tank, as well as an inlet and outlet opening, biological suspension can be easily added or removed through the corresponding housings. Because the corresponding openings in the housings are hermetically sealed to the outside, sterile operation is possible.

[0016] According to a preferred embodiment, the respective outlet openings of the housings are connected via respective aseptic outlet valves to a circulation line, which are connected via respective aseptic inlet valves to the respective inlet openings of the housings. The use of aseptic valves enables sterile working. The circulation line makes it possible for the biological suspension to circulate and be circulated in the device without the need for a complex circulating device such as an agitator. It is thus possible for the biological suspension to be fed into the tank via a first housing, for example, and out of the tank via a second housing. In contrast to a stirred tank, the device according to the invention results in greater flexibility with regard to different fill levels, since no agitating elements have to be covered or can run dry.

[0017] The biological suspension can only flow from the interior of the respective housing into the tank or into the circulation line but not from the interior of the respective housing directly into the interior of another housing.

[0018] An aseptic pump is advantageously installed in the circulation line. This aseptic pump allows for sterile work.

[0019] The pump is advantageously a positive displacement pump. Positive displacement pumps enable low-shear conveyance of the biological suspension, which is essential for fermentation. A screw pump, a peristaltic pump, or a rotary lobe pump are particularly suitable. A special embodiment is characterized by the use of multiple pumps in the circulation line. The use of multiple pumps enables an increase in the volume flow in the circulation line, which is advantageous, for example, with viscous circulation media and for achieving high circulation rates.

[0020] According to a preferred embodiment, the third housing is designed as a T-piece. Thus, the second pipe can already be welded to another pipe, eliminating the need for further assembly or sealing. The second pipe can then be inserted, for example, from below into the second housing and the first pipe.

[0021] Advantageously, the housings are detachably connected to one another. This has the advantage that the housings can be easily assembled and disassembled for maintenance purposes, even in very large tanks with long pipe lengths and comparatively little space between the floor and the central opening in the tank. Because the housings are detachably connected to one another, the modular system can also be scaled, meaning that additional housings can be added, and / or the nominal diameters of the pipes, or the housings and pipe lengths, can be easily adapted to the given tank size.

[0022] For this purpose, according to a preferred embodiment, the first tube has a mounting means, in particular a mounting plate or mounting flange, which is formed on the first tube. The first tube is connected to the first housing via this mounting means. The mounting means is either arranged around the entire circumference of the tube or extends outwards on at least two sides. The first tube can then, for example, be pushed through the tank from above and connected to the first housing, in particular screwed to the first housing, e.g. from the outside. The mounting means is sealed by appropriate seals both from the interior of the housing and from the outside, i.e., to the atmosphere, i.e., in particular, the screw connection is sealed. The device can therefore be mounted simply yet hermetically sealed.

[0023] Preferably, the mounting means is fastened to the floor, in particular a floor plate of the first housing. Because the mounting means is fastened to the floor, sufficient space remains in the interior for the biological suspension to flow freely through the housing without major pressure losses. According to a further exemplary embodiment, the second tube likewise has a mounting means, in particular a thread formed on the second tube. The second tube can be connected to the second housing, in particular screwed in, via the mounting means, in particular the thread. Here, too, the mounting means, in particular the thread, is sealed off from the interior of the housing and from the outside, i.e., from the atmosphere, by means of appropriate seals. In this way, sterile working can be guaranteed and the device can be mounted simply yet hermetically sealed.

[0024] The mounting means is preferably fastened, in particular screwed, to the base, in particular a base plate of the second housing. Thus, the second tube can be easily fastened by inserting it into the second housing from above or below, depending on the specific design, and screwing it tight. If, for example, the third housing is already attached to the second tube, it is inserted from below. Because the attachment is made to the base, i.e., in particular to the base plate, the flow path for the fluid, i.e., the biological suspension, towards the upper opening of the second housing is not disrupted.

[0025] According to a further embodiment, a further mounting means is arranged on the first tube, via which the first tube is connected to the second housing. Preferably, the mounting means is sealed to the interior of the second housing and to the outside via appropriate seals, such as flush-mounted O-ring seals or profile seals made of, for example, EPDM or PTFE. Depending on the size and space, the first tube can also be firmly connected to the second housing, e.g., welded. In this case, the second housing can be attached, for example, from below.

[0026] According to a further embodiment, the first pipe is firmly welded to the first mounting means for the first housing, with the pipe extending through the first mounting means. This eliminates the need for the first screw connection within the first housing. The additional mounting means is then arranged, for example, at the lower end of the first pipe, so that it can be mounted on the second housing. This design is particularly advantageous if the length of the second pipe does not exceed the outlet height of the tank, thus allowing installation from below.

[0027] According to a preferred embodiment, the biological suspension can be introduced into the tank via the resulting annular gap between the first pipe and the second pipe, wherein the cross-sectional area of ​​the annular gap essentially corresponds to the cross-sectional area of ​​the second pipe ± 10 to 50%. This means that the hydraulic diameter is essentially constant. Here there is, for example, a deviation of 1-2 nominal diameter steps between the pipes. This results in comparable flow velocities and Reynolds numbers. This is important if, for example, the biological suspension circulates between the second housing and the third housing. The same applies to the cross-sectional area of ​​the annular gap between the central opening and the first pipe, whereby only the narrowest point on the flange needs to be taken into account here (since the tank widens towards the top).

[0028] Furthermore, according to a preferred embodiment, the device has an aseptic filling and draining valve at the lowest point of the circulation line, so that the system can be easily drained. As an alternative to an aseptic filling and draining valve, an aseptic valve combination, in particular comprising several aseptic diaphragm valves, can also be used.

[0029] Advantageously, the device is designed such that, for mounting the housing, the first tube can be fastened, in particular screwed, to the floor, in particular the floor plate of the first housing, using the mounting means arranged on the first tube, and the second tube can be pushed through the first tube and fastened, in particular screwed, to the floor, in particular a floor plate of the second housing, via a mounting means. The third housing can then, for example, still be fastened to the second tube or is already fastened to the second tube.

[0030] This allows the housings to be easily attached to each other using the tubes and their integral mounting hardware.

[0031] According to the present invention, one or more sensors can also be arranged in the circulation line, for measuring, for example, pH, temperature, conductivity, turbidity, flow, and / or dissolved gases. Sensors in the circulation line allow for particularly reliable and precise measurements.

[0032] According to a preferred embodiment, a sensor for measuring dissolved gases, in particular a sensor for quantitatively determining a specific gas, in particular oxygen, is arranged in the circulation line.

[0033] The sensor is therefore, in particular, an oxygen sensor, particularly in the form of an optical oxygen sensor or an electrochemical oxygen sensor. An optical oxygen sensor is preferred because electrochemical sensors can cause drift (= deviation) in the measured values ​​due to pressure peaks, CO2 fouling, or chemical reactions, which does not occur in optical sensors. Furthermore, optical sensors also have a faster response time.

[0034] Several oxygen sensors can also be provided in the circulation line.

[0035] By locating the sensor in the circulation line, a more precise measurement result is obtained compared to a sensor located on the inside of the tank, as is generally the case. This is because the flow velocity at the tank wall is low and the measured oxygen concentration is not representative of the rest of the suspension. In contrast, the gas, especially the oxygen, has already dissolved well in the suspension in the area of ​​the circulation line. Thus, measuring at this location enables a representative and precise result.

[0036] The seal for sealing the interior of the respective housing, in particular a sealing ring, seals flush with the interior of the housing. In the first and second housings, for example, a metal stop is provided between the mounting device and the base plate. This ensures a defined surface pressure, which can prevent shearing of the seal.

[0037] The device according to the invention, which uses a circulation device instead of an agitator, has the particular advantage of simplified accessibility and is thus easier to maintain. Furthermore, the device has few moving parts and is also easier to clean inside the tank due to fewer complex structures, such as the agitator blades and the baffles in the tank.

[0038] According to a preferred embodiment, a device for overpressure protection, in particular a pressure relief valve or an overflow valve, is arranged in the circulation line, which is preferably arranged, viewed in the flow direction, after the aseptic pump or after the aseptic pumps.

[0039] A potential overpressure in the circulation line can be triggered by a blockage or fouling within the circulation line, which can be caused, for example, by one or more faulty valve circuits or valve control, or by deposits of mucus-forming cell types (which are used in certain fermentation processes in bioreactors). In such a case, the system components in the circulation line can be effectively protected.

[0040] Furthermore, according to a preferred embodiment, an aeration device for introducing gas into the circulation line is arranged in the circulation line. This can be provided in addition to a aeration device for introducing gas into the tank. The introduction of gas into the circulation line results in improved and faster mixing of the gas in the suspension.

[0041] Preferably, this ventilation device is located downstream of a sensor arranged in the circulation line, in particular an oxygen sensor, in order to obtain an exact measurement result.

[0042] According to a further embodiment, a connection for steam, in particular an in-line valve housing, is arranged in the circulation line.

[0043] According to a further embodiment, a withdrawal port and a return port can be provided in the circulation line to divert liquid from the circulation line and return liquid via the return port. Preferably, the withdrawal port is provided with a filter device upstream in the flow direction, so that cell-free liquid is discharged via the withdrawal port and the cell mass remains within the device. The discharged cell-free liquid can, for example, be provided with fresh substrate / nutrient medium and fed or re-fed to the device via the return port.

[0044] A dosing point for liquids and / or solids, especially for small dosages, can be arranged in the circulation line. This is particularly advantageous because thorough mixing occurs immediately upon introduction.

[0045] A temperature control unit, for example a heat exchanger, can be integrated into the circulation line to control the temperature of the suspension.

[0046] According to the invention, the device according to at least one of claims 1 to 19 can be used for the fermentation of biological suspensions. The present invention is explained in more detail below with reference to the following figures:

[0047] Fig. 1 shows schematically an embodiment of a device for fermenting a biological suspension according to the present invention,

[0048] Fig. 2 shows the representation shown in Fig. 2 from the front,

[0049] Fig. 3 shows schematically a section through a first housing according to the present invention,

[0050] Fig. 4 shows schematically a section through a second housing according to the present invention,

[0051] Fig. 5 shows schematically the section through a third housing according to the present invention.

[0052] Fig. 1 shows a schematic view of an embodiment according to the present invention for fermenting a biological suspension, such as a nutrient solution with organisms such as yeasts, bacteria or other biological cell cultures. The device 10 has a tank 4, which can have a lid 15 via which the tank 4 can be opened. Alternatively, the lid 15 can not be opened, but the lid 15 has a so-called manhole or an inspection opening. The manhole or the inspection opening can also be located in the side wall of the tank 4 instead of in the lid 15. Alternatively or additionally, the bottom of the tank 4 can be designed such that it can be opened. Furthermore, the lid 15 can have further connections for, for example, lighting, exhaust air lines or further supply lines for, for example, cleaning and steam.The tank 4 further comprises a feed device 5 for supplying and discharging the biological suspension. The feed device 5 is designed such that it also enables circulation of the biological suspension. In particular, the device 10 according to the invention enables flexible circulation of the tank contents, directed towards the corresponding cells. A central opening 1 is provided at the lower end of the tank 4 for supplying or discharging the biological suspension. Furthermore, the device 10 comprises a first pipe 2 extending through the central opening 1 in the tank 4. Biological suspension can be supplied to or discharged from the tank 4 via the pipe opening of the first pipe 2, as shown by the arrow in Figures 3 to 5.Furthermore, the feed device 5 has a second pipe 3 that extends through the first pipe 2 and projects beyond the first pipe 2 into the tank 4. The biological suspension can also be added or removed via the opening of the second pipe 3. This provides three feed options (for adding or removing) at different heights.

[0053] Furthermore, the feed device 5 has a first housing Gil, which is connected, for example, to the outlet flange of the tank 4. As can be seen in particular from Fig. 3, the first housing GU can also have a flange 17, via which the first housing GU can be flange-connected to the outlet flange, for example, by screwing it tight using one or more screws 21. However, the first housing GU can also be welded, for example. The first housing GU has an interior space 31 with an upper opening that is attached to the tank 4 so as to be tightly around the central opening 1. The first pipe 2 extends upwards through the first housing GU (i.e., in the direction of the lid 15) into the tank. The same can also be seen from Figs. 2 and 3. The first housing GU further has an inlet opening 6, via which the biological suspension can be introduced into the interior space 31 of the first housing GU and, via the central opening 1, into the tank 4.This creates an annular opening between the first housing GU and the first pipe 2, as can be seen in particular from Fig. 3. The first housing GU also has a drain opening 9, wherein the biological suspension can be discharged from the tank 4 through the central opening 1 into the interior 31 of the first housing GU via the drain opening 9. The first pipe 2 can have a mounting means 16 attached thereto, which either extends around the circumference of the first pipe 2 or protrudes from the first pipe 2 on at least two sides. The mounting means 16 can, for example, be formed onto the first pipe 2, in particular welded. The first pipe 2 is connected to the first housing GU, here to the base plate 36, via the mounting means 16, here e.g. a mounting flange 16, e.g. screwed tight using screws 18.A bore of the nominal diameter of the first pipe 2 is formed in the base plate 36, which is designed so that the first pipe 2 can be attached to this bore using the mounting means 16. Here, for example, the GU housing is formed as a single piece.

[0054] To hermetically separate the interior 31 of the first housing GU from the outside, a seal 19 is provided, here for example a sealing ring, O-ring, or profile seal. This seal 19 seals the mounting means 16 from the interior 31 of the first housing GU. The seal 19 can be flush with the interior 31 of the first housing GU, as can be seen in particular from Fig. 3. The mounting means 16 further seals with a metallic stop 38 between the mounting means 16 and the base plate 36, so that a defined surface pressure is ensured, which can prevent shearing of the seal 19. In addition, the mounting means 16, in particular the mounting flange, can be designed such that the space behind the seal 19 is provided with a relief bore, so that a possible failure of the seal 19 can be detected by means of a leak (not shown).

[0055] The first housing GU also has a seal 20, by means of which the mounting means 16 is sealed to the outside, i.e., to the atmosphere. The seal 20 can also be provided as a sealing ring, in particular an O-ring, around the first tube 2 and seals between the mounting means 16 and the base plate 36. Here, too, a surface pressure is additionally provided via a metallic stop 38 between the mounting means 16 and the base plate 36.

[0056] Pipe sections 22 and 23 are connected to the inlet opening 6 and the outlet opening 9, which, for example, as shown in Fig. 2 and 3, can be connected to an aseptic inlet valve E1 and outlet valve A1 via a connecting flange.

[0057] According to another embodiment (not shown), for example, the lower region of the first housing GU can be designed as a flange, which can be closed via a respective seal to the interior 31 and to the outside, with a blind cover that serves as an assembly means, into which the first pipe 2 is welded so that it projects through the blind flange into the tank 4 and is connected at the lower end to the second housing GM. This is particularly advantageous if the lengths of the pipes 2 and 3 are such that installation from below is possible. This avoids the need for screwing in the interior 31, which leads to improved hygiene and reduced maintenance.

[0058] The feed device 5 further provides a second housing GM, as can be seen from Fig. 1 and Fig. 4. The interior 32 of the second housing GM is tightly connected to the first pipe 2 via an upper opening. The second pipe 3 extends through the second housing GM and is also sealed to the outside. The second housing GM also has an inlet opening 7 and an outlet opening 11 for the biological suspension. Thus, the biological suspension can flow via the inlet opening 7 through the annular gap between the first pipe 2 and the second pipe 3, as shown by the arrows in Figure 3, towards the tank 4 and be introduced into the tank 4. From the tank 4, it can leave the second housing GM via the annular gap and the interior 32 of the second housing GM, with the valves switched accordingly, via the outlet opening 11. A mounting means 24 is also formed on the second pipe 3, here in particular as a thread 24.The second tube 3 can be connected to the second housing GM via the thread 24, i.e. screwed in. Preferably, the second tube 3 can be screwed into a base plate 30 of the second housing GM. The base plate 30 can either be part of the one-piece second housing GM or the base plate 30 can be fastened to the second housing GM, for example via a clamp 37 which fastens the base plate 30 to the second housing GM from the outside or via a flange connection which is fastened with screws. The mounting means 24, i.e. the thread 24, is sealed off from the interior 32 of the second housing GM via the seal 25. As previously described in connection with the seal 19, the seal 25 can be designed as a sealing ring or profile seal which is flush with the interior 32 of the second housing GM and, as previously described, also has a seal via a metallic stop 39.Furthermore, a seal 26 is provided which seals the mounting means 24, here the thread 24, to the outside.

[0059] Here, too, the seal 26 is provided as a sealing ring around the second tube 3, i.e., the inner tube. Here, too, a metallic stop 39 is formed between the second tube 3 and the base plate 30. The base plate 30 has a bore for the nominal diameter of the second tube 3, which is equipped with a thread 24 on the inside of the bore and the outside of the second tube 3 for assembly. The base plate 30 is connected to the second housing GM by, for example, a clamp 37 and sealed by a seal 27.

[0060] Another embodiment (not shown) allows the second pipe 3 to be permanently welded to the base plate 30, thus eliminating the need for the screw connection in the base plate 30 and the seals 25 and 26. This is particularly advantageous if the second pipe 3 is no longer than the outlet height of the container 4, allowing installation of the entire device from below. It is also possible to weld pipe 2 to the base plate 36, thus eliminating the need for the seals 19 and 20.

[0061] Pipe sections 28, 29 are connected to the inlet opening 7 and the outlet opening 11 and are connected to the aseptic inlet valve E2 and aseptic outlet valve A2 via a corresponding flange, as can be seen in particular from Figs. 2 and 4.

[0062] The third housing GO, shown in Fig. 5, can be designed, for example, as a T-piece, with the second pipe 3 opening into pipe sections 34 and 35. For this purpose, the second pipe 3 can be welded in. However, the second pipe 3 can also be fastened to a third housing GO with the adjoining pipe sections 34 and 35 via a corresponding seal. In this case, a profile seal or an O-ring made of, for example, EPDM or PTFE is provided. As can also be seen from Fig. 2, the pipe sections 34 and 35 can be connected to the corresponding aseptic inlet valve E3 and aseptic outlet valve A3 via flanges.

[0063] The biological suspension can, as indicated by the arrow (see Figure 5), be fed into the tank 4 via the inlet opening 8, the interior space 33 of the third housing GO and the second pipe 3, but can also be drained from the tank 4 via the second pipe 3 into the interior space 33 of the third housing GO and via the outlet opening 12, depending on the switching of the valves.

[0064] As can be seen from the previous description, the three housings Gil, GM, and GO are tightly connected to each other via tubes 2 and 3. In particular, the housings Gil, GM, and GO are detachably connected to each other, allowing for easy assembly and disassembly.

[0065] The device 10 is particularly designed such that, for mounting the housings GU, GM, GO, the first pipe 2 can be fastened to the base, here the base plate 36 of the first housing GU, using the mounting means arranged on the first pipe 2, here the mounting flange 16, in particular can be screwed tight using the screws 18, and the second pipe 3 can be pushed through the first pipe 2 and screwed into the base or base plate 30 of the second housing GM using a mounting means 24, in particular using the thread 24. This results in a good connection between the first and second housings GU, GM in a simple manner. The third housing GO is either already attached to the second pipe 3 as a T-piece or is attached to the second pipe 3.

[0066] All three housings GU, GM, GO are designed in such a way that only one flow direction is possible from the respective interior space 31, 32, 33 in the direction of the tank 4 and from the tank 4 into the respective interior space 31, 32, 33, but not directly from housing to housing, i.e. the housings GU, GM, GO are sealed from each other and thus separated.

[0067] As can be seen in particular from Fig. 1, the respective outlet opening 9, 11, 12 of the housings GU, GM, GO is connected via respective aseptic outlet valves A1, A2, A3 to a circulation line 14, which is connected via respective aseptic inlet valves E1, E2, E3 to the respective inlet openings 6, 7, 8 of the housings GU, GM, GO. Each housing GU, GM, GO is connected on the pressure side and suction side to the pump 13. Thus, each sub-area of ​​the tank 4, i.e. each area where biological suspension can be introduced or removed via the central opening 1, the first pipe 2 or the second pipe 3, is also connected on the suction side and pressure side to the pump 13. This configuration makes it possible, for example, to draw off the tank contents from below via the central opening 1 and to convey them back into the tank 4 via the first pipe 2 or the second pipe 3, thereby creating a circulation of the tank contents.It is also possible to suction the upper part of the tank 4 via the second pipe 3 and to convey it back into the tank 4 via the central opening 1 or the first pipe 2. It is also possible, for example, to control the first pipe 2 on the suction side and to convey it back into the tank 4 via the central opening 1 or the second pipe 3.

[0068] Furthermore, during circulation, it is possible to direct the volume flow of the circulation line through a bypass and remove a portion from the tank. Furthermore, a filter device, for example with one or more particle filters (for example, 0.65 pm pore size) and one or more membrane filters (for example, 0.2 pm pore size), can be integrated into this bypass of the circulation line 14. For example, the filter device is used to retain the cells within the device 10. The described feature of separating the volume flows with filtration enables the removal of cell-free and / or used nutrient medium, its processing, and subsequent, optional reintroduction into the device 10. The removed portion can be replaced with fresh substrate / nutrient medium in order to consistently provide the cells with optimal growth conditions.This allows for the effective use of raw materials, their value being enhanced, and process waste to be reduced. Furthermore, a higher cell density can be achieved. The separation is made possible, in particular, by a shut-off valve V1 between the extraction point and the introduction point. In another embodiment (not shown), an additional shut-off valve within the circulation line 14 can also be used for this purpose.

[0069] In addition, the removal of a partial quantity from the container also enables the connection of the removal point of one tank with the introduction point of another tank, so that a fermentation cascade can be set up, for example for a continuous fermentation process.

[0070] The pump 13 is preferably an aseptic pump. The pump 13 can, for example, be designed such that a mechanical seal is sealed or flushed with condensate or steam, or a magnetic coupling is installed between the drive motor and the impeller. The pump 13 is preferably a positive displacement pump for low-shear conveyance, in particular a screw pump, a peristaltic pump, or a rotary lobe pump. This enables low-shear conveyance of the medium and ensures a gentle process, which is particularly important for the fermentation of a biological suspension.

[0071] In a particular embodiment not shown, an overpressure protection device, in particular a pressure relief valve or an overflow valve, is located in the circulation line 14 on the pressure side of the pump 13 or in the flow direction downstream of the pump 13, in particular directly downstream of the pump 13. This serves to protect the device 10 against overpressure and to protect the sensors S1 to Sn and valves within the circulation line 14, in particular the aseptic double-seat valve V1 and the aseptic inlet valves E1, E2, E3 as well as the aseptic outlet valves A1, A2, A3. The pressure relief valve is triggered at a defined overpressure, which means that the circulation circuit 14 is interrupted, whereby the valves and / or sensors downstream of the pump 13 in the flow direction cannot be damaged by increasing overpressure.It is also possible to align one of the inlet valves E1, E2, or E3 so that it opens in the direction of flow into the tank rather than against it. In this orientation, one of the inlet valves E1, E2, or E3 can be used as a pressure relief valve.

[0072] The trigger for a possible overpressure in the circulation line 14 can be a blockage or fouling within the circulation line 14, which can arise, for example, due to one or more faulty valve circuits or valve control, or due to deposits of mucus-forming cell types (which are used in certain fermentation processes in bioreactors).

[0073] Furthermore, the device 10 has sensors S1 to Sn, for example for measuring dissolved gases S4, the pH value S3, the temperature S5, the conductivity S1, the turbidity S2 and / or the flow rate S6. The sensors are integrated in the circulation line 14. The system is filled or emptied via an aseptic filling or emptying valve V1, which is connected to the lowest point of the circulation line 14. As an alternative to an aseptic filling and emptying valve V1, an aseptic valve combination, in particular with several aseptic diaphragm valves, can also be used (not shown). The circulation line is particularly advantageously designed such that it has a gradient towards the valve V1, so that the line is self-draining. Other fittings, such as those provided for overpressure protection, for draining condensate for cleaning, ventilation or sampling, are not shown for the sake of simplicity.The same applies to sensors; additional sensors can be arranged at the same and / or different positions, measuring different and / or identical parameters. Also for simplicity, the measurement and control technology is not shown. Pumps, for example, can advantageously be designed with frequency control.

[0074] In a special embodiment, at least one sensor for measuring dissolved gases S4 is present in the circulation line 14. This offers a particular advantage over measuring sensors that are mounted directly in the container 10 or, in particular, near the inlet of the aeration device into the tank (not shown). By positioning the sensors in the circulation line 14, the distance and thus the contact time between dissolved gas and liquid medium is extended, which the medium carried in the container 4, which may be aerated, travels during circulation via one or more pipes 2, 3. The measurement of dissolved gases, in particular dissolved oxygen, therefore does not take place directly after the gases enter the medium via the aeration device.The measurement is taken after an extended contact time so that the measurement cannot be distorted by the incoming gas stream and the actual dissolved fraction of the gases in the circulating medium can be defined with increased accuracy. A sensor for measuring dissolved oxygen is preferably used, as the proportion / quantity of dissolved oxygen corresponds to an essential process parameter. By measuring dissolved oxygen, conclusions can be drawn about the reproduction rates of organisms, the vitality of cells, the quality of cell growth, and other process parameters such as the volume-related mass transfer coefficient (kLa value), the oxygen transfer rate (OTR), and the oxygen uptake rate (OUR).

[0075] A particular embodiment is characterized in that process parameters, such as the input quantity and / or volume flow of the introduced gas / gas mixture, as well as temperature and flow rate, are regulated in coordination with one another by means of a control system. For example, both the amount of air to be introduced and the adjustment of the pH value can be regulated by a dosing device on the container 4 and / or in the circulation line 14 using the measured values ​​of the installed sensors S1 to Sn. This allows process parameters to be adjusted without significant delay, thus allowing raw materials such as air and pH adjustment media (acid, alkali) to be used in a targeted and effective manner. Furthermore, the savings of raw materials and continuous process optimization are enabled.To ensure a sterile process and maintain a sterile barrier, at least the valves connected to the product chamber must be aseptic valves, i.e., they must be designed to provide hermetic separation from the atmosphere. For this purpose, aseptic seat valves with plastic or metal bellows, diaphragms, or diaphragm valves can be used.

[0076] As already mentioned, the tank contents can be circulated or recirculated via the feed device 5.

[0077] An annular gap is formed between the first tube 2, which is connected to the interior 32 of the second housing GM, and the second tube 3. The annular gap has a cross-sectional area that essentially corresponds to the inner cross-sectional area of ​​the second tube 3, with a deviation of ± 10 to 50%. This results in comparable flow velocities and Reynolds numbers.

[0078] The cross-sectional area of ​​the annular gap between the central opening 1 and the first tube 2 also essentially corresponds to the inner cross-sectional area of ​​the second tube ± 10 to 50%.

[0079] To mount the feed device 5 on the tank 4, for example, the first housing GU can first be attached to the tank outlet flange.

[0080] The first tube 2 can then be inserted, for example, from above, and fastened, in particular screwed, to the base, in particular to the base plate 36 of the GU housing, as described above. For this purpose, as described above, the screws 18 can be screwed from below and outside through the base plate 36 and the mounting means 16, which here is designed, for example, as a mounting flange or mounting plate.

[0081] Then, depending on the design, the second tube 3 can be inserted through the first tube 2 from above or below and fastened, in particular screwed, to the base plate 30 of the second housing GM.

[0082] The third housing GO can then be fastened to the base plate 30 of the housing GM at the lower end of the second housing GM using a clamp 37. If the second pipe 3 is longer than the outlet height of the tank 4, it must be installed in several sections from below or from above through the first pipe 2. In order to fasten it to the base plate 30, the latter is provided with a screw connection. This screw connection has a corresponding counterpart at the lower end of the second pipe 3. After the base plate 30 has been screwed to the second pipe 3, it can be fastened to the lower end of the second housing GM. This embodiment also allows several sections of the first pipe 2 to be inserted into the tank 4 from below. A screw connection is attached to each end of the pipe sections to be inserted, which are then screwed together. The last pipe section is then connected to the screw connection on the base plate 30.

[0083] The GU, GM, and GO housings either already have the corresponding pipe sections 22, 23, 28, 29, 34, and 35 with a respective flange at their inlet openings 6, 7, and 8 and outlet openings 9, 11, and 12, respectively, or these are welded on to allow the inlet valves E1, E2, and E3 and outlet valves A1, A2, and A3 to be mounted laterally. The feed device 5 is then integrated into the circulation line 14.

[0084] For smaller tanks 4, which have relatively short pipes 2 and 3 (length: less than 1 meter), the entire assembly can also be pre-assembled and flanged to the tank 4. For large tanks 4, a multi-part construction is necessary because the tank outlet height limits the maximum pipe length and the assembly must therefore be inserted partially from above and below or in multiple parts from below. If the second pipe 3 is very long, the second pipe 3 can be designed in multiple parts and inserted into the tank 4 in multiple parts. This also allows the installation of very long second pipes 3 from below. The individual pipe sections can then be connected to one another using a screw connection or welded together.

[0085] A possible method using the device 10 according to the invention is described below. The net tank capacity can be, for example, 200 liters to 100,000 liters, and nominal diameters for the inner diameter of the valves used and the circulation line can, for example, be in the range of 8 millimeters to 160 millimeters. First, the tank 4 can be cleaned and sterilized before operation. During sterilization, steam is introduced into the tank 4 from above, for example, and the resulting condensate can be discharged via the filling and emptying valve V1 and a downstream condensate drain with overpressure. As an alternative to an aseptic filling and emptying valve, an aseptic valve combination, in particular with several aseptic diaphragm valves (not shown), can be used. After sterilization, the tank 4 is filled with nutrient solution from, for example,an aqueous solution of sugar, amino acids, fatty acids, vitamins, and salts. It is possible to fill the tank 4 completely or only partially. The contents can also be circulated, at least long enough to cover the first pipe 2. The device 10 can be inoculated with the cells used via a sterile dosing line on the tank wall or the tank lid, or as part of the circulation line 14. The temperature of the contents is controlled via a double jacket on the tank body and / or the tank base. A further embodiment (not shown) also allows the temperature of the tank contents to be controlled via an external heat exchanger, which can be integrated into the circulation line 14. Alternatively, direct steam injection can also be used to control the temperature of the tank contents. This can be done, for example, using the ventilation device.

[0086] The heat exchanger contained in the circulation line 14 or the heat transfer surfaces attached to the tank 4 can be used not only to heat the medium but also to cool it. This is particularly advantageous in exothermic fermentation processes. Steam or high-pressure hot water, for example, can be used as the heating medium, while a glycol-water mixture, cooling tower water, or cold water can be used as the cooling medium.

[0087] Once fermentation has started, the biological suspension in tank 4 can be introduced, for example, via the first pipe 2 and discharged via the central opening 1 and circulated via the circulation line 14 to create a flow in tank 4 from top to bottom in the opposite direction to aeration. The aeration device (not shown) can be designed, for example, on the tank 4 either as a pipe with defined bores or as a sintered candle, which are introduced, for example, through the lower base of the tank 4 into the interior of the container 4. In addition, the aeration device (not shown) can be installed within the circulation line. Through this aeration, a defined volume of gas or a mixture of gas, for example air, CO2, O2 or N2, is metered, which is required to aerate the organisms during fermentation.The introduced gas bubbles rise upwards and thus against the described flow direction of the fluid. This influences the flow conditions when flowing around the bubbles in such a way that the mass transfer can be intensified. In a further embodiment (not shown), the fastening connections of the aeration devices within the tank 4 are also arranged in an area between the housing GU and the central opening 1, or the flange 17. This is particularly advantageous at the beginning of a fermentation when the cells have a high oxygen demand and no large agglomerates or cell clusters are yet present. A further embodiment (not shown) is characterized in that one or more aeration devices are arranged in the circulation line 14, for example by means of an in-line valve housing. This enables aeration orIntroduction of gases into the circulating medium within the circulation line 14, whereby the residence time and contact time of the introduced gas(es) in the circulating medium is extended in contrast to introduction within the container 4.

[0088] In a further embodiment not shown, an aeration device is located in the circulation line 14 and an additional aeration device in the tank 4. This has the advantage that, for example, the medium is aerated at the beginning of the fermentation by means of the aeration device in the tank 4 and later in the fermentation the aeration device in the circulation line 14 is used. For example, if there is a high demand for oxygen at the beginning of the fermentation, the aeration device in the tank 4 can be used to introduce the gas or gas mixture until a preliminary saturation of the medium is reached. During the course of fermentation, the dissolved oxygen in the medium is increasingly consumed or metabolized by the organism. Thus, the aeration device within the circulation line 14 can be used to achieve continuous maximum saturation of the medium.

[0089] Depending on the process conditions, the amount of dissolved gas(es) in the liquid medium can be increased and thus optimized by introducing it within the circulation line 14. Typical aeration rates for biological suspensions are 0.05–2.00 vvm (volume of air per volume of liquid per minute).

[0090] Another embodiment, not shown, is characterized in that a connection for steam (not shown) is provided within the circulation line 14, for example, by means of an inline valve housing. This connection enables the introduction of steam into the circulation circuit, so that targeted temperature control, steam exposure (steaming), and steam sterilization of the device 10 can be carried out.

[0091] This temperature control or sterilization corresponds to a common process step, for example between cleaning and production, whereby sterilization usually takes place from above directly into the container 4. The steam connection in the circulation line 14 improves the accessibility of the product-contacting surfaces and reduces the time until the desired temperature is reached. When the tank 4 is completely full, circulation can take place via the second pipe 3 instead of the first pipe 2. If the cells are to be harvested and emptied from the tank 4, it is advantageous to first suck in via the first pipe 2 and then feed the second pipe 3 back into the tank 4. This circulation creates a downward flow, whereby the lowest part of the tank 4 has no flow through it.As a result, the cells collect in the lower region of tank 4 and can then be transferred in concentrated form from the container 4 to a downstream process, such as a solid-liquid separation, using the pump 13. Depending on the cell type, it may also be advantageous for a transfer to be carried out if the biological suspension is homogenised so that a constant solid concentration is supplied to the downstream solid-liquid separation throughout the entire separation process. It is also possible, after the cells have collected in the lower region of tank 4, to reverse the flow direction within the container so that the sedimented cells are flowed through from bottom to top. The reversal of direction is achieved using the valve circuit E1, E2, E3, A1, A2, A3 and / or the pump 13.This allows the biological suspension to flow around, and small particles with a low sedimentation velocity are carried along by the flow and introduced into the sediment from below. This also leads to an enrichment of cells in the lower region of tank 4, which is beneficial for cell harvesting. During emptying, tank 4 can be emptied completely or only to just above the first tube 2 and then refilled with new nutrient solution to enable a fed-batch process.

[0092] By circulating the tank contents through the device 10 according to the invention and the described method, it is possible to ensure the requirements of a bioreactor (such as homogenization, suspension or dispersion, mass transfer, heat exchange, sterile isolation) without an agitator. If the sensors Sn for process monitoring are installed in the circulation line 14, the quality of the measured values ​​is improved. In static tanks or stirred-tank reactors, different measured values ​​cannot always be avoided depending on the position of the sensors. A continuous flow through the tank contents from bottom to top or vice versa enables a representative sample and makes the interpretation of the measured values ​​independent of the measuring location.

[0093] As described, pump 13 and valves must be suitable for sterile processes and either hermetically sealed from the environment or equipped with vapor or condensate barriers. By integrating the valves into the circulation line 14, they are easily accessible compared to an agitator drive at the top (i.e., lid) of the tank. This increases ease of maintenance and can save costs, as large and stable platforms are eliminated. It is also possible to integrate dosages into the circulation line 14, which are circulated throughout the tank and do not have to be introduced from above.

[0094] The device 10 can also contain a dosing point (not shown) for small dosages. This is arranged within the circulation line 14 and is intended for the dosing of small quantities such as acid, alkali, antifoam, vitamins, minerals, and other nutrients. Furthermore, the control of this dosing point is coordinated with the equipment installed within the circulation line 14, such as sensors S1 to Sn and one or more pumps 13. The process connection of the dosing point can be established, for example, via an in-line valve housing. Dosing therefore does not have to be carried out exclusively via direct introduction into the tank 4. Especially when dosing very small quantities, this device enables low-loss introduction of the medium to be dosed and direct mixing via the applied volume flow in the circulation line 14.If, in particular, an aseptic valve combination or an aseptic sampling valve is used, in addition to the introduction of a medium, a withdrawal from the circulation line 14 can also take place.

[0095] Compared to an agitator, the pump only needs to circulate the tank volume and requires less electrical power than an agitator, since the agitator's own weight does not need to be set in motion. The flexible control of the inlet and outlet valves E1, E2, E3, A1, A2, A3 on the suction or pressure side of pump 13 makes it possible to flow through tank 4 from bottom to top or in the opposite direction from top to bottom, or both at different times during a fermentation.

[0096] If the flow is from bottom to top, sedimentation of the cells within tank 4 can be counteracted, which leads to an increased flow around the cells and thus promotes mass transfer. Depending on the cell and particle size of the cells or cell clusters, it is possible to keep the cells in suspension. If the flow is from top to bottom through tank 4, the flow is in the opposite direction to the bubble ascent velocity. This extends the residence time of introduced gases in the liquid and increases gas uptake into the liquid. This can reduce the total amount of gases introduced, which leads to an increase in fermentation efficiency. In addition, the composition of the exhaust air can be positively influenced by the reduced input of gas or mixed gas (e.g. air, CO2, O2 or N2), for example by reducing the input of critical gases such as oxygen.This means that additional equipment and safety devices in the exhaust air duct are no longer required.

[0097] By installing the feed device 5, which acts as a circulation device, on the lower tank outlet flange, it is possible to convert existing tank systems so that they are suitable for fermentation processes appropriate to the product. This retrofit capability reduces the costs and time required for use as bioreactors, provided the tanks are suitable.

[0098] Due to the reduced number of internal components in tank 4, the cleanability of the bioreactor is improved (e.g., by reducing spray shadows) and a reduction in spray balls is possible. Flow breakers on the tank wall are also eliminated.

[0099] The feed device 5 must be designed in such a way that suitable flow rates are achieved during the process to exert the lowest possible shear forces on the cell suspension, as well as sufficient flow rates during cleaning and sterilization. The pump 13 used allows this range, which also makes it possible to operate the device 10 in different process stages or with different cell suspensions. This flexibility in adjusting the flow rate is not possible with stirred tank or bubble column reactors.

[0100] In addition, the flow velocity within the pipeline can be designed to the required Reynolds number, eliminating the need for nozzles with increased flow velocity. This design enables gentle conveyance of the biological suspension through all system components and allows for defined, adjustable process parameters.

[0101] The embodiment according to the invention also enables a fed-batch or supplementary feeding process during fermentation through the first pipe 2. If the tank 4 is only partially emptied, it is still possible to circulate the contents and monitor all process parameters.

[0102] Furthermore, the design of the feed device 5 with the previously described housings GU, GM, GO enables simple assembly and disassembly.

[0103] When referring to tanks or containers, these two terms should be considered synonymous. Sterilization can refer to a thermal process, such as steam, but also to chemical processes using ozone, peracetic acid, or physical methods such as UV rays.

[0104] Pipe 2 can also be designed such that a solid body is mounted above the inlet and outlet connection 1 in such a way that a gap is created between the tank bottom and pipe 2. This gap enables a targeted flow into the tank, thus counteracting deposits on the tank bottom.

[0105] When we talk about organisms, we particularly include the following terms: microorganisms, macroalgae, microalgae, bacteria, enzymes, yeasts and other mycelium-forming organisms (fungi), animal and plant cells, beneficial organisms such as nematodes (roundworms) or other biological cell cultures.

[0106] The term “homogenization” or “homogenized” or “homogenization” refers to the mixing of the tank contents to produce a homogeneous distribution.

[0107] When we talk about “cell-free”, we mean a filtered liquid that is as cell-free as possible, but may still contain cells or cell components depending on the filtration sharpness.

[0108] When we talk about “gas”, this also includes the term mixed gas.

Claims

Claims 1. A device (10) for fermenting a biological suspension, comprising: a tank (4) with a feed device (5) for supplying and discharging the biological suspension, having a first central opening (1) in the tank (4) for supplying or discharging the biological suspension, a first pipe (2) extending through the central opening (1) into the tank (4) for supplying or discharging the biological suspension, a second pipe (3) extending through the first pipe (2) and beyond the first pipe (2) into the tank (4) for supplying or discharging the biological suspension, a first housing (Gil), the interior (31) of which is fastened to the tank (4), in particular to an outlet flange of the tank (4), via an upper opening, tightly around the central opening (1), and through which the first pipe (2) extends, sealed to the outside, wherein the first housing (GU) has an inlet opening (6) and an outlet opening (9) for the biological suspension,a second housing (GM), the interior (32) of which is tightly connected to the first tube (2) via an upper opening and through which the second tube (3) extends, sealed to the outside, the second housing (GM) further comprising an inlet opening (7) and an outlet opening (11) for the biological suspension, and a third housing (GO), the interior (33) of which is tightly connected to the second tube (3) via an opening, the third housing (GO) further comprising an inlet opening (8) and an outlet opening (12) for the biological suspension.

2. Device (10) according to claim 1, characterized in that the respective outlet openings (9, 11, 12) of the housings (GU, GM, GO) are connected via respective aseptic outlet valves (A1, A2, A3) to a circulation line (14), which are connected via respective aseptic inlet valves (E1, E2, E3) to the respective inlet openings (6, 7, 8) of the housings (GU, GM, GO).

3. Device (10) according to claim 1 or 2, characterized in that one or more aseptic pumps (13) are arranged in the circulation line (14).

4. Device (10) according to at least claim 3, characterized in that the pump (13) is a positive displacement pump for low-shear conveyance, in particular a screw pump, a hose pump or a rotary piston pump, which is in particular frequency-controlled.

5. Device (10) according to at least one of claims 1 to 4, characterized in that the third housing (GO) is designed as a T-piece.

6. Device (10) according to at least one of claims 1 to 5, characterized in that the housings (GU, GM, GO) are detachably connected to one another.

7. Device (10) according to at least one of claims 1 to 6, characterized in that a mounting means (16), in particular a mounting flange, is formed on the first tube (2), via which the first tube (2) is connected, in particular screwed, to the first housing (GU), and the mounting means (16) is sealed via corresponding seals (19), (20) both to the interior (31) of the first housing (GU) and to the outside, wherein the mounting means (16) is preferably fastened to the base, in particular to a base plate (36) of the first housing (GU), in particular screwed on from the outside.

8. Device (10) according to at least one of claims 1 to 7, characterized in that a mounting means (24), in particular a thread (24), is formed on the second tube (3), via which the second tube (3) is connected to the second housing (GM), in particular is screwed in, wherein the mounting means (24), in particular the thread (24), is sealed both to the interior (32) of the second housing (GM) and also to the outside via corresponding seals, wherein the mounting means (16) is preferably fastened, in particular screwed in, to the base, in particular to a base plate (30) of the second housing (GM).

9. Device (10) according to at least one of claims 1 to 8, characterized in that a further mounting means is arranged on the first tube (2), via which the first tube (2) is connected to the second housing (GM), wherein preferably the mounting means is sealed via corresponding seals to the interior (32) of the second housing (GM) and to the outside or the further mounting means (16) of the first tube is fixedly arranged on the second housing, in particular is welded.

10. Device (10) according to at least one of claims 1 to 9, characterized in that the biological suspension can be introduced into the tank (4) via an annular gap between the first tube (2) and the second tube (3), the cross-sectional area of ​​the annular gap corresponding to the inner cross-sectional area of ​​the second tube (3) + / - 10 to 50% and / or the cross-sectional area of ​​the annular gap between the central opening (1) and the first tube (2) essentially corresponding to the inner cross-sectional area of ​​the second tube (3) ± 10 to 50%.

11. Device (10) according to at least one of claims 1 to 10, characterized in that an aseptic filling and emptying valve (V1) or an aseptic valve combination is arranged at the lowest point of the circulation line (14) and the circulation line is designed in particular with a gradient towards the filling and emptying valve (V1).

12. Device (10) according to at least one of claims 1 to 11, characterized in that the device (10) is designed such that for mounting the housings (GU, GM, GO) the first tube (2) can be fastened, in particular screwed, to the bottom, in particular a bottom plate (36) of the first housing (GU) using the mounting means (16) arranged on the first tube (2), and the second tube (3) can be pushed through the first tube (2) and can be fastened, in particular screwed, to the bottom, in particular a bottom plate (30) of the second housing (GM) via a mounting means (24).

13. Device (10) according to at least one of claims 1 to 12, characterized in that a sensor for measuring dissolved gases (S4), in particular a sensor for quantitatively determining a specific gas, in particular oxygen, is arranged in the circulation line (14).

14. Device (10) according to claim 7, 8 or 9, characterized in that the seal for sealing the interior (31, 32, 33) of the respective housing (GU, GM, GO), in particular a sealing ring, seals flush with the interior (31, 32, 33) of the respective housing (GU, GM, GO) and additionally a seal is provided via a metallic stop (38, 39), in particular between the mounting means (16) and the base plate (36, 30).

15. Device (10) according to at least one of the preceding claims, characterized in that in the circulation line (14) a device for overpressure protection tion, in particular a pressure relief valve or an overflow valve is arranged, which is preferably arranged, viewed in the flow direction, after the aseptic pump (13) or after the aseptic pumps (13).

16. Device according to at least one of the preceding claims, characterized in that an aeration device for introducing gas into the circulation line (14) is arranged in the circulation line (14), wherein the aeration device is preferably arranged, viewed in the direction of flow, after a sensor for measuring dissolved gases (S4) arranged in the circulation line (14).

17. Device according to at least one of the preceding claims, characterized in that a connection for steam, in particular an in-line valve housing, is arranged in the circulation line (14).

18. Device according to at least one of the preceding claims, characterized in that a withdrawal connection and a return connection are provided in the circulation line in order to branch off liquid from the circulation line (14) and to return liquid via the return connection, wherein preferably the withdrawal connection is provided with a filter device in such a way that cell-free liquid can be discharged via the withdrawal connection.

19. Device according to at least one of claims 1 to 18, characterized in that a dosing point for liquids and / or solids, in particular for small dosage, is arranged in the circulation line (14).

20. Use of a device (10) according to at least one of claims 1 to 19 for the fermentation of biological suspensions.

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