Device for fermenting a suspension of living organisms

Abstract

The present invention relates to an apparatus (10) for fermenting a biological suspension, the apparatus comprising: a tank (4) having a feeding device (5) for supplying and discharging the biological suspension, the tank having: a first central opening (1) in the tank (4) for supplying or discharging the biological suspension; a first tube (2) extending through the central opening (1) into the tank (4) for supplying or discharging the biological suspension; a second tube (3) extending through and beyond the first tube (2) into the tank (4) for supplying or discharging the biological suspension; and a first housing (GU) whose internal space (31) is tightly fixed around the central opening (1) at the tank (4) via an upper opening, particularly at the outlet flange of the tank (4). The first tube (2) extends through the first housing in a sealed manner, wherein the first housing (GU) has an inlet (6) and a outlet (9) for the biological suspension; the second housing (GM), the internal space (32) of the second housing is tightly connected to the first tube (2) via an upper opening, and the second tube (3) extends through the second housing in a sealed manner, wherein the second housing (GM) also has an inlet (7) and an outlet (11) for the biological suspension; and the third housing (GO), the internal space (33) of the third housing is tightly connected to the second tube (3) via an opening, wherein the third housing (GO) also has an inlet (8) and an outlet (12) for the biological suspension.

Description

Technical Field

[0001] This invention relates to an apparatus for fermenting biological suspensions and the uses of such apparatus. Background Technology

[0002] Devices for fermentation are known from the prior art. Bioreactors are used to culture cells or transform substances using biocatalysts (such as enzymes, microorganisms, or plant and animal cells). The purpose of such reactors is to homogenize the contents, suspend or disperse different phases, enabling mass exchange between different phases within the bioreactor, ensuring heat exchange within the biological suspension / dispersion, and aseptically isolating the contents of the bioreactor from the environment to prevent external contamination. For this purpose, circulation must be achieved within the tank.

[0003] Existing technologies frequently utilize stirred tank reactors equipped with stirring components. A disadvantage of stirred tank reactors is that all shaft penetrations (e.g., the shaft penetration between the stirring component and the stirring mechanism drive motor) must be implemented with vapor and / or condensate barriers to ensure sterile isolation between the atmospheric environment and the product chamber. Furthermore, in large tanks, the shaft penetrations and sliding ring seals are located at the top cover of the container, resulting in limited accessibility. Additionally, large stirring mechanisms have high self-weight. In summary, corresponding solutions for circulating biological suspensions are complex and expensive.

[0004] Bubble cap reactors are also known. A disadvantage of bubble cap reactors is that a limited gas volume is required for circulation, and this limited volume may not necessarily match the gas volume needed for aeration of the tank contents. Achieving circulation using nozzles is also difficult, often generating shear forces that should be avoided for cell suspensions.

[0005] Fluidized bed reactors are only suitable for immobilized microorganisms. Furthermore, cleaning and sterilization are very complex if contamination occurs.

[0006] It is also known to achieve circulation through multiple inlets and outlets located at different height levels. However, this presents problems in terms of assembly process and sterility. Summary of the Invention

[0007] Therefore, the object of the present invention is to provide an improved apparatus for fermentation that enables better cycling in a simple, cost-effective and aseptic manner.

[0008] According to the present invention, this objective is achieved by the features described in claim 1.

[0009] Here, the apparatus includes a feeding device for supplying and discharging the biological suspension. The feeding device is designed to function as a circulation device. At least three inlet openings at different height levels are present in the tank, through which the biological suspension can be supplied or discharged. The feeding device has a first central opening in the tank for supplying or discharging the biological suspension, and a first pipe extending through the central opening into the tank, through which the biological suspension can be supplied to or discharged from the tank.

[0010] In addition, the feeding device has a second tube that passes through the first tube and extends beyond the first tube into the tank, and the biological suspension can also be supplied to or discharged from the tank via the second tube.

[0011] Furthermore, the feeding device also has a first housing, the internal space of which is tightly fixed around a central opening in the tank via an upper opening. This means that the biological suspension can flow into the tank from the internal space of the first housing through the upper opening and through the central opening. Preferably, the first housing is fixed to the outlet flange of the tank. A first pipe extends through the first housing and is sealed externally (i.e., relative to the atmospheric environment). The first housing further has an inlet opening and a outlet opening for the biological suspension. This means that the biological suspension can flow into the tank through the inlet opening, through the internal space of the first housing, through the upper opening of the housing, and through the central opening in the tank, and can also flow out of the tank through the central opening, through the upper opening, through the internal space of the first housing, and through the outlet opening in the housing. Therefore, the fact that the first pipe extends through the first housing in a sealed manner means that there is a sealed connection between the first housing and the first pipe, thereby sealing the internal space of the first housing externally. For this purpose, a seal may preferably be provided, or the first pipe may be welded to the first housing.

[0012] The device also includes a second housing, the internal space of which is sealed to the first tube via an upper opening, and the second tube extends through the second housing in a sealed manner to the outside. The second housing also has an inlet and a outlet for the biological suspension. This means that the biological suspension can flow into the internal space of the second housing through the inlet, and then into a tank through a corresponding opening between the first and second tubes. The biological suspension can also flow back from the tank to the internal space of the second housing between the first and second tubes, and then out through the outlet of the second housing. Therefore, the fact that the second tube extends through the second housing in a sealed manner to the outside implies a sealed connection between the second housing and the second tube, thus sealing the internal space of the second housing to the outside. For this purpose, a sealing element can preferably be provided, or the second tube can be welded to the second housing.

[0013] The feeding device also has a third housing, the internal space of which is sealed to the second pipe via an opening. The third housing also has an inlet and a outlet for the biological suspension. In this way, the biological suspension can enter the internal space of the third housing through the inlet, flow into the second pipe, and then into the tank through the second pipe and its opening. Similarly, the biological suspension can flow from the tank into the internal space of the third housing through the inner pipe and then exit the housing again through the outlet.

[0014] Since there are three shells (i.e., a first shell with a first central opening, a second shell with a first tube, and a third shell with a second tube) at different height levels for supplying and discharging the biological suspension, the biological suspension can be circulated through the corresponding openings (i.e., the central opening, the opening of the first tube, and the opening of the second tube) by using, for example, two shells each.

[0015] With the central opening and the central arrangement of the pipes, it is feasible to create a uniform and symmetrical flow relative to the central axis within the tank. This allows for uniform sedimentation and efficient extraction of the precipitate. This is particularly advantageous when it is necessary to concentrate cells in the bottom region of the container. Conversely, sedimentation can also be prevented by altering the flow direction using valve switching and / or pump control, thus keeping the cells in suspension. The uniform distribution of cells within the container improves mass transfer and nutrient efficiency. The flexible possibility of using the three shells specifically for circulation as feed or discharge lines makes it ideally adaptable to various processes and process steps. Since the first, second, and third shells have corresponding openings (through which they are in fluid contact with the tank interior) and each has its own feed and discharge openings, the biological suspension can be fed or discharged in a simple manner through the corresponding shells. Aseptic operation is feasible because the corresponding openings of the shells are tightly sealed externally.

[0016] According to a preferred embodiment, the corresponding discharge opening of the shell is connected to a circulation line via a corresponding aseptic discharge valve, which in turn is connected to the corresponding inlet opening of the shell via a corresponding aseptic inlet valve. The use of aseptic valves enables aseptic operation. The circulation line allows the biological suspension to circulate within the device, achieving circulation without the need for complex circulation devices such as agitators. Thus, it is feasible for the biological suspension to be guided into the tank via, for example, a first shell, and discharged from the tank via a second shell. Compared to stirred containers, the device according to the invention offers greater flexibility in terms of different filling volumes because there is no need to cover the agitator or for the agitator to dry-run.

[0017] Here, the biological suspension can only flow into the tank or circulation pipeline from the internal space of the corresponding shell, but cannot flow directly from the internal space of the corresponding shell into the internal space of another shell.

[0018] Advantageously, a sterile pump is installed in the circulation pipeline. The sterile pump enables aseptic operation.

[0019] Advantageously, the pump is a positive displacement pump. Positive displacement pumps enable low-shear delivery of biological suspensions, which is crucial for fermentation. In particular, screw pumps, hose pumps, or rotary piston pumps are suitable.

[0020] One particular implementation is characterized by the use of multiple pumps in the circulation line. Using multiple pumps makes it possible to increase the volumetric flow rate in the circulation line, which is advantageous for, for example, viscous circulating media and for achieving high circulation rates.

[0021] According to a preferred embodiment, the third housing is designed as a T-tube. This allows the second tube to be welded to the other tube first, eliminating the need for further installation or sealing. Then, for installation, the second tube can be inserted from below into the second housing and the first tube, for example.

[0022] Advantageously, the shells are detachably interconnected. This allows for easy installation of the shells, even in very large tanks with long tube lengths and relatively limited space between the bottom and central opening, and easy removal for maintenance purposes. Because the shells are detachably interconnected, the modular unit can also be expanded, allowing for the installation of further shells and / or easy adjustment of the nominal diameter and length of the tubes or shells to suit a given tank size.

[0023] Therefore, according to a preferred embodiment, the first pipe has a mounting device, particularly a mounting plate or mounting flange, formed at the first pipe. The first pipe is connected to the first housing via this mounting device. The mounting device is either arranged around the entire circumference of the pipe or extends outward on at least two sides. The first pipe can then be inserted into the tank, for example from above, and connected to the first housing, particularly, for example, by a helical engagement with the first housing from the outside. Here, the mounting device seals both relative to the internal space of the housing and externally (i.e., to the atmospheric environment) via corresponding seals, meaning that the helical engagement is particularly sealing. In this way, the device can be installed easily but still with a tight seal.

[0024] Preferably, the mounting device is fixed to the bottom of the first housing, particularly the base plate. Because the mounting device is fixed to the bottom, sufficient space is provided inside to allow the biological suspension to flow freely through the housing without significant pressure loss.

[0025] According to another embodiment, the second tube also has an installation device, specifically a thread formed on the second tube. The second tube can be connected to the second housing via the installation device (specifically the thread), particularly by screwing it in. Here, a corresponding seal ensures that the installation device (specifically the thread) is sealed both relative to the internal space of the housing and externally (i.e., to the atmospheric environment). This ensures aseptic operation and allows for easy yet still tightly sealed installation of the device.

[0026] The mounting device is preferably fixed to the bottom of the second housing, particularly the base plate, and screwed in. This allows for easy installation of the second tube by inserting it into the second housing from above or below, depending on the specific design, and tightening it. For example, if a third housing is already fixed to the second tube, it is inserted from below. Because the fixing is at the bottom (i.e., particularly the base plate), the flow path of the fluid (i.e., the biological suspension) toward the upper opening of the second housing is not obstructed.

[0027] According to another embodiment, a second mounting device is arranged at the first tube, through which the first tube is connected to the second housing. The mounting device preferably seals the interior space of the second housing and the exterior via a corresponding seal (e.g., a flush-front O-ring seal or a shaped seal made of, for example, EPDM or PTFE). Depending on the size and space, the first tube may also be tightly connected to the second housing, for example, by welding. The second housing can then be installed, for example, from below.

[0028] According to another embodiment, the first tube is welded to a first mounting device for the first housing, wherein the tube extends through the first mounting device. This eliminates the need for a first spiral joint within the first housing. The second mounting device is then arranged, for example, at the lower through end of the first tube, allowing it to be installed in the second housing. This implementation is particularly advantageous if the length of the second tube does not exceed the outlet height of the tank and therefore installation from below is feasible.

[0029] According to a preferred embodiment, the biological suspension can be introduced into the tank via an annular gap created between the first and second pipes, wherein the cross-sectional area of ​​the annular gap corresponds substantially to ±10% to 50% of the inner cross-sectional area of ​​the second pipe. That is, the hydraulic diameter is substantially constant. Here, for example, there is a deviation of 1-2 nominal diameter specifications between the pipes. This results in a considerable flow velocity and Reynolds number. This is particularly important, for example, when the biological suspension circulates between the second and third shells. The same applies to the cross-sectional area of ​​the annular gap between the central opening and the first pipe, where only the narrowest point at the flange needs to be considered (because the tank gradually widens upwards).

[0030] Furthermore, according to a preferred embodiment, the device has an aseptic filling and drain valve at the lowest point of the circulation line, thereby allowing for easy emptying of the system. As an alternative to the aseptic filling and drain valve, an aseptic valve assembly, specifically comprising multiple aseptic diaphragm valves, can also be used.

[0031] Advantageously, the device is designed such that, for mounting the housing, the first tube can be secured to the bottom of the first housing, particularly the base plate, using a mounting device disposed at the first tube, and can be tightened therein; and the second tube can be inserted through the first tube and secured to the bottom of the second housing, particularly the base plate, via the mounting device, and can be screwed in therein. Then, for example, the third housing can also be secured to the second tube, or is already secured to the second tube.

[0032] In this way, these housings can be fixed together in a simple manner via tubes and their shaped mounting devices.

[0033] According to the invention, one or more sensors may also be arranged in the circulation pipeline for measuring, for example, pH value, temperature, conductivity, turbidity, flow rate, and / or dissolved gas. The sensors in the circulation pipeline enable particularly reliable and accurate measurements.

[0034] According to a preferred embodiment, a sensor for measuring dissolved gases, particularly for quantitatively determining a specific gas (especially oxygen), is arranged in the circulation pipeline.

[0035] That is, the sensor is specifically an oxygen sensor, particularly in the form of an optical oxygen sensor or an electrochemical oxygen sensor. Preferably, an optical oxygen sensor is used because electrochemical sensors can experience measurement drift (bias) due to pressure spikes, CO2 contamination, or chemical reactions, while optical sensors do not exhibit this problem. Furthermore, optical sensors have a faster response time.

[0036] Multiple oxygen sensors can also be installed in the circulation pipeline.

[0037] Because the sensor is positioned within the circulation loop, more accurate measurements are obtained compared to when the sensor is conventionally placed on the tank wall. This is because the flow velocity at the tank wall is low, and the measured oxygen concentration does not represent the rest of the suspension. Conversely, the gases, particularly oxygen, are well dissolved in the suspension within the circulation loop area. Therefore, measurements taken here allow for representative and accurate results.

[0038] Seals, particularly sealing rings, used to seal the internal space of the respective housings are flush with the internal space of the housing for sealing. For example, in the first and second housings, a metal stop is provided specifically between the mounting device and the base plate. This ensures a defined surface pressure that prevents shear deformation of the seal.

[0039] The device according to the invention, which has a circulation mechanism rather than a stirring mechanism, has the particular advantage of simplified accessibility, thus making it easy to maintain. Furthermore, the device has fewer moving parts, and the interior of the tank is easier to clean due to its simpler structure (e.g., stirring blades and baffles in the tank).

[0040] According to a preferred embodiment, an overpressure protection device, particularly an overpressure valve or relief valve, is arranged in the circulation pipeline. When viewed along the flow direction, the overpressure protection device is preferably arranged downstream of the sterile pump or multiple sterile pumps.

[0041] Overpressure in the circulation piping can be caused by blockages or scaling within the piping itself. This can occur, for example, through erroneous valve switching or control, or through the deposition of slime-producing cell types (used in certain fermentation processes in bioreactors). In such cases, the equipment components within the circulation piping can be effectively protected.

[0042] Furthermore, according to a preferred embodiment, an aeration device for introducing gas into the circulation pipeline is arranged in the circulation pipeline. This aeration device may be additionally provided in addition to the aeration device for introducing gas into the tank. Introducing gas into the circulation pipeline improves and accelerates the mixing of gas in the suspension.

[0043] Preferably, the aeration device is located downstream of the sensor (particularly the oxygen sensor) along the flow direction, which is arranged in the circulation pipeline to obtain accurate measurement results.

[0044] According to another embodiment, a steam connection port is arranged in the circulation pipeline, particularly an inline valve body.

[0045] According to another embodiment, the circulation pipeline may be provided with an extraction port and a return port to divert liquid from the circulation pipeline and return the liquid via the return port. Preferably, the extraction port is provided with a filter device arranged upstream along the flow direction, so that the cell-free liquid is discharged through the extraction port while the cellular material remains in the device. Fresh substrate / nutrient medium can be added to the discharged cell-free liquid, for example, by introducing or re-introducing it into the device via the return port.

[0046] Dosing points for liquids and / or solids (especially micro-dosing) can be arranged in the circulation pipeline. This is particularly advantageous because thorough mixing occurs immediately upon introduction.

[0047] A temperature control unit, such as a heat exchanger, can be integrated into the circulation pipeline to regulate the temperature of the suspension.

[0048] According to the present invention, the apparatus according to at least one of claims 1 to 19 can be used for the fermentation of biological suspensions. Attached Figure Description

[0049] The invention will now be explained in more detail with reference to the accompanying drawings:

[0050] Figure 1 An embodiment of an apparatus for fermenting biological suspension according to the present invention is illustrated schematically;

[0051] Figure 2 Show Figure 2 The front view shown in the illustration;

[0052] Figure 3 A cross-section of the first housing according to the invention is shown schematically;

[0053] Figure 4 A cross-section of the second housing according to the invention is shown schematically;

[0054] Figure 5 A cross-section of the third housing according to the invention is shown schematically. Detailed Implementation

[0055] Figure 1The diagram schematically illustrates a view of a fermentation biological suspension, such as a nutrient solution containing organisms like yeast, bacteria, or other biological cell cultures, according to an embodiment of the invention. The apparatus 10 has a tank 4, which may have a lid 15 through which the tank 4 can be opened. Alternatively, the lid 15 cannot be opened, but it has a so-called manhole or inspection port. The manhole or inspection port may also be located on the side wall of the tank 4, rather than the lid 15. Alternatively or additionally, the bottom of the tank 4 may be designed to be openable. Furthermore, the lid 15 may have other connection ports, such as for lighting, venting, or other conduits for cleaning and steam delivery. The tank 4 also has a feeding device 5 for supplying and discharging the biological suspension. The feeding device 5 is designed to also enable circulation of the biological suspension. In particular, the apparatus 10 according to the invention enables flexible and directional circulation of the tank contents according to 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 has a first tube 2 that extends through a central opening 1 in the tank 4. The biological suspension can be supplied to or discharged from the tank 4 via the opening of the first tube 2, such as through... Figures 3 to 5 As shown by the arrow in the image.

[0056] Furthermore, the feeding device 5 has a second pipe 3 that extends through and beyond the first pipe 2 into the tank 4, wherein the biological suspension can also be supplied or discharged through the opening of the second pipe 3. In this way, three feeding methods (for supplying or discharging) are generated at different height levels.

[0057] Furthermore, the feeding device 5 has a first housing GU, which is connected, for example, to the outlet flange of the tank 4. Specifically, from... Figure 3 As can be seen, the first housing GU can also have a flange 17, through which the first housing GU can be flanged to the outlet flange, for example, by tightening it with one or more screws 21. However, the first housing GU can also be welded on, for example. The first housing GU has an internal space 31 with an upper opening that is tightly secured around the central opening 1 at the tank 4. The first pipe 2 extends through the first housing GU upward (i.e., toward the lid 15) into the tank. This is from Figure 2 and Figure 3 It can also be seen that the first shell GU also has a feed opening 6, through which the biological suspension can be introduced into the internal space 31 of the first shell GU, and then introduced into the tank 4 through the central opening 1. Here, as specifically from Figure 3As can be seen, an annular opening is formed between the first housing GU and the first tube 2. The first housing GU also has a discharge opening 9, through which the biological suspension can be fed from the tank 4 through the central opening 1 into the internal space 31 of the first housing GU and discharged via the discharge opening 9. Here, the first tube 2 may have a mounting device 16 fixed here, which either extends around the circumference of the first tube 2 or extends from the first tube 2 on at least two sides. The mounting device 16 may be formed, for example, at the first tube 2, particularly welded thereon. The first tube 2 is connected to the first housing GU, and here to the base plate 36, via the mounting device 16, for example, a mounting flange 16, for example, by tightening, for example, with screws 18. A hole of the nominal diameter of the first tube 2 is designed in the base plate 36, which is made so that the first tube 2 can be installed into the hole using the mounting device 16. Here, the housing GU is designed, for example, as a single piece.

[0058] To tightly isolate the internal space 31 of the first housing GU from the outside, a sealing element 19 is provided, such as a sealing ring, O-ring, or other shaped seal. This sealing element 19 seals the mounting device 16 relative to the internal space 31 of the first housing GU. Here, as specifically from... Figure 3 As can be seen, the seal 19 can be flush-fitted with the internal space 31 of the first housing GU. The mounting device 16 also utilizes a metal stop 38 to seal between the mounting device 16 and the base plate 36, thereby ensuring a defined surface pressure that prevents shear deformation of the seal 19. Additionally, the mounting device 16, particularly the mounting flange, can be configured such that a pressure relief port is provided behind the seal 19, allowing for the detection of potential failures of the seal 19 (not shown) based on leakage.

[0059] The first housing GU also has a seal 20, through which the mounting device 16 is sealed to the outside (i.e., towards the atmospheric environment). The seal 20 may also be provided here as a sealing ring (especially an O-ring) around the first tube 2 and seal between the mounting device 16 and the base plate 36, wherein a surface pressure is additionally provided between the mounting device 16 and the base plate 36 via a metal stop 38.

[0060] Connected to the inlet opening 6 and the outlet opening 9 are pipe sections 22 and 23, which can be, for example, from... Figure 2 and Figure 3 As can be seen, it is connected to the aseptic feed valve E1 and the discharge valve A1 via the connecting flange.

[0061] According to another embodiment (not shown), the lower region of the first housing GM can be implemented, for example, as a flange that can be closed relative to the internal space 31 via a corresponding seal and externally closed by a blind cover acting as an installation device. A first pipe 2 is welded into this blind cover, allowing it to extend through the blind flange into the tank 4 and connect at its lower end to the second housing GM. Particularly advantageously, the lengths of pipes 2 and 3 are characterized in such a way that installation from below is feasible. This avoids helical connections within the internal space 31, resulting in improved hygiene and reduced maintenance.

[0062] As from Figure 1 and Figure 4 As can be seen, the feeding device 5 also includes a second housing GM. The internal space 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 externally. The second housing GM also has an inlet 7 and a outlet 11 for the biological suspension. In this way, the biological suspension can flow through the annular gap between the first pipe 2 and the second pipe 3 via the inlet 7, such as... Figure 3 As indicated by the arrow, the flow proceeds to tank 4 and is introduced into tank 4. Under the corresponding valve switching state, it exits from tank 4 through the annular gap and the internal space 32 of the second housing GM, via the discharge opening 11. An installation device 24, specifically designed as a thread 24, is also designed at the second pipe 3. The second pipe 3 can be connected to the second housing GM via the thread 24, i.e., screwed in. Preferably, the second pipe 3 can be screwed into the base plate 30 of the second housing GM. The base plate 30 can either be part of the integral second housing GM, or it can be fixed to the second housing GM, for example via a clamp 37 that externally fixes the base plate 30 to the second housing GM, or via a flange connection secured with screws. The installation device 24, i.e., the thread 24, is sealed relative to the internal space 32 of the second housing GM via a seal 25. As described above regarding seal 19, seal 25 can be implemented as a sealing ring or a shaped seal that flush-fits with the internal space 32 of the second housing GM, and as previously mentioned, also has a seal achieved via metal stop 39. Additionally, seal 26 is provided that seals the mounting device 24 (here referring to thread 24) externally.

[0063] Here, the seal 26 also serves as a sealing ring surrounding the second tube 3 (i.e., the inner tube). A metal stop 39 is also formed between the second tube 3 and the base plate 30. The base plate 30 has a hole of a nominal diameter suitable for the second tube 3, with threads 24 on the inner side of the hole and the outer side of the second tube 3 for installation. The base plate 30 is connected to the second housing GM, for example, via a clamp 37, and sealed via the seal 27.

[0064] Another embodiment, not shown, makes it possible to securely connect the second pipe 3 to the base plate 30 by welding, thereby eliminating the need for the screw joints and seals 25 and 26 in the base plate 30. Particularly advantageous is that the length of the second pipe 3 does not exceed the outlet height of the container 4, making it feasible to load the entire assembly from below. It is also feasible to weld the pipe 2 to the base plate 36, thereby eliminating the need for seals 19 and 20.

[0065] Connected to the inlet opening 7 and the outlet opening 11 are pipe sections 28 and 29, which are connected to the aseptic inlet valve E2 and the aseptic outlet valve A2 via corresponding flanges, as specifically from... Figure 2 and Figure 4 It's obvious.

[0066] like Figure 5 As shown, the third housing GO can, for example, be designed as a T-tube, with the second tube 3 leading into sections 34 and 35. For this purpose, the second tube 3 can be welded in. However, the second tube 3 can also be fixed to the third housing GO and the adjacent sections 34 and 35 via corresponding seals. In this case, a shaped seal or O-ring made of, for example, EPDM or PTFE is provided. (As shown from...) Figure 2 As can be seen, pipe sections 34 and 35 can be connected to the corresponding aseptic feed valve E3 and aseptic discharge valve A3 via flanges.

[0067] As indicated by the arrow (see) Figure 5 As can be seen, the biological suspension can be introduced into the tank 4 through the feed opening 8, the internal space 33 of the third shell GO, and the second pipe 3. However, depending on the switching state of the valve, it can also be introduced from the tank 4 into the internal space 33 of the third shell GO through the second pipe 3 and discharged through the discharge opening 12.

[0068] As can be seen from the preceding description, the three housings GU, GM, and GO are tightly interconnected via pipes 2 and 3. In particular, housings GU, GM, and GO are detachably interconnected, which means that easy assembly and disassembly are possible.

[0069] The device 10 is specifically designed such that, for mounting housings GU, GM, and GO, the first tube 2 and the mounting device (here, mounting flange 16) disposed at the first tube 2 can be fixed to the bottom of the first housing GU (here, base plate 36), specifically by screws 18, and the second tube 3 can be inserted into the first tube 2 and screwed into the bottom of the second housing GM or base plate 30 via the mounting device 24 (specifically via threads 24). In this way, a connection is achieved between the first housing GU and the second housing GM in a simple manner. The third housing GO is either already fixed to the second tube 3 as a T-tube, or the third housing is fixed to the second tube 3.

[0070] All three shells, GU, GM, and GO, are implemented such that the only possible flow directions are from the corresponding internal spaces 31, 32, and 33 to tank 4 and from tank 4 to the corresponding internal spaces 31, 32, and 33, but not directly from shell to shell. That is, the shells GU, GM, and GO are sealed to each other and thus isolated from each other.

[0071] For example, specifically from Figure 1 As can be seen, the corresponding discharge openings 9, 11, and 12 of the shells GU, GM, and GO are connected to the circulation pipeline 14 via the corresponding aseptic discharge valves A1, A2, and A3. The circulation pipeline is connected to the corresponding feed openings 6, 7, and 8 of the shells GU, GM, and GO via the corresponding aseptic feed valves E1, E2, and E3.

[0072] Each housing GU, GM, GO is connected to pump 13 on both the pressure and suction sides. In this way, each sub-region of tank 4, i.e., each region where the biological suspension can be introduced or extracted via the central opening 1, the first tube 2, or the second tube 3, is connected to pump 13 on both the suction and pressure sides. This configuration makes it possible, for example, to draw the tank contents from below via the central opening 1 and then return them to tank 4 via the first tube 2 or the second tube 3, thus forming a circulation of the tank contents. It is also possible to draw the upper part of tank 4 via the second tube 3 and then return it to tank 4 via the central opening 1 or the first tube 2. It is also possible, for example, to control the first tube 2 on the suction side and then return it to tank 4 via the central opening 1 or the second tube 3.

[0073] Alternatively, the volumetric flow rate of the circulation line can be controlled via a bypass during circulation, and a fraction can be removed from the tank. Furthermore, a filtration device (e.g., having one or more particulate filters (e.g., 0.65 µm pore size) and one or more membrane filters (e.g., 0.2 µm pore size)) can be integrated into the bypass of the circulation line 14. For example, the filtration device is used to retain cells within the device 10. The characteristic of separating the volumetric flow rate by filtration makes it possible to remove cell-free and / or used nutrient media, process them, and then optionally reintroduce them into the device 10. The extracted fraction can be replaced with fresh substrate / nutrient media to provide consistent optimal growth conditions for the cells. This allows for efficient use of raw materials, increases value, and reduces process waste. Furthermore, higher cell densities can be achieved. In particular, this separation is made possible by a shut-off valve V1 between the extraction point and the introduction point. In another embodiment, not shown, this can also be achieved using an additional shut-off valve within the circulation line 14.

[0074] Furthermore, extracting portions from the container makes it possible to connect the extraction point of one tank to the inlet point of another tank, thereby enabling the establishment of fermentation cascades, for example, for continuous fermentation processes.

[0075] Pump 13 is preferably a sterile pump. Pump 13 can be designed, for example, such that the sliding ring seal is sealed or flushed with condensate or steam, or a magnetic coupler is installed between the drive motor and the impeller. Preferably, pump 13 is a low-shear delivery positive displacement pump, particularly a screw pump, hose pump, or rotary piston pump. This enables low-shear delivery of the culture medium and ensures a gentle process, which is particularly important for the fermentation of biological suspensions.

[0076] In a particular embodiment (not shown), an overpressure protection device, particularly an overpressure valve or relief valve, is located in the circulation line 14 on the pressure side of pump 13, or downstream of pump 13 along the flow direction, particularly directly downstream of pump 13. This serves to protect device 10 from overpressure, and to protect sensors S1 to Sn and valves within circulation line 14, particularly the sterile double-seat valve V1 and sterile feed valves E1, E2, E3, and sterile discharge valves A1, A2, A3. In the event of a defined overpressure, the overpressure valve is triggered, which means that circulation loop 14 is interrupted, thus preventing damage to the valves and / or sensors located downstream of pump 13 due to the increased overpressure. It is also possible to adjust the orientation of one of the feed valves E1, E2, E3 such that it opens in the flow direction into the tank and does not open in the opposite direction. With this orientation adjustment, one of the feed valves E1, E2, E3 can be used as an overpressure valve.

[0077] The overpressure that may occur in the circulation line 14 may be caused by blockage or scaling inside the circulation line 14, which may be caused, for example, by one or more incorrect valve switching or valve control, or by the deposition of slime-producing cell types (used in certain fermentation processes in bioreactors).

[0078] In addition, the device 10 has sensors S1 to Sn, for example, for measuring dissolved gas S4, pH value S3, temperature S5, conductivity S1, turbidity S2, and / or flow rate S6. The sensors are integrated in the circulation line 14. The device 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 the aseptic filling and emptying valve V1, an aseptic valve combination, particularly a valve combination with multiple aseptic diaphragm valves (not shown), can also be used. Particularly advantageously, the circulation line is implemented with a slope toward valve V1, thereby allowing the line to self-drain. For simplicity, other accessories, such as overpressure protection accessories, condensate drain accessories for cleaning, aeration, or sampling, are not shown. The same applies to the sensors; other sensors measuring different and / or the same parameters can be arranged at the same and / or different locations. Again, for simplicity, measurement, regulation, and control techniques are not shown. Pumps can, for example, be advantageously designed to be frequency controlled.

[0079] In one particular implementation, at least one sensor for measuring dissolved gas S4 is disposed in circulation line 14. This has particular advantages compared to measuring sensors (not shown) that are specifically installed directly inside container 10 or specifically near the inlet of the aeration device into the tank. By positioning the sensor in circulation line 14, the path and contact time between the dissolved gas and the liquid medium are extended, as the culture medium carried in container 4 (possibly aerated) passes through one or more pipes 2, 3 during circulation. Thus, the measurement of dissolved gas (especially dissolved oxygen) is not performed immediately after the gas enters the culture medium via the aeration device. The measurement is performed after the extended contact time, thus preventing interference from the inflow gas flow and allowing for a more precise determination of the actual dissolved percentage of gas in the circulating culture medium. Preferably, the sensor is used to measure dissolved oxygen because the percentage / quantity of dissolved oxygen corresponds to important process characteristic parameters. Measuring dissolved oxygen makes it possible to draw conclusions about organism reproduction rate, cell viability, cell growth quality, and other process characteristic parameters such as volume-dependent mass transfer coefficient (kLa value), oxygen transfer rate (OTR), and oxygen uptake rate (OUR).

[0080] One particular implementation is characterized by the coordinated adjustment of process parameters, such as the input quantity and / or volumetric flow rate of the introduced gas / gas mixture, as well as temperature and flow rate, via a control system. For example, the amount of air to be introduced and the pH value can be adjusted using measurements from installed sensors S1 to Sn via metering devices at container 4 and / or within circulation line 14. This makes it possible to adjust process parameters without significant delay, thereby enabling targeted and efficient use of feedstocks such as air and pH adjustment media (acids, alkalis). Furthermore, it facilitates feedstock conservation and continuous process optimization.

[0081] To ensure aseptic processes and maintain a sterile barrier, at least the valves communicating with the product space must be sterile valves, meaning they are constructed to ensure complete isolation from the atmospheric environment. For this purpose, sterile seat valves with bellows made of plastic, metal, or membrane, or diaphragm valves, can be used, for example.

[0082] As mentioned above, the contents of the tank can be circulated or recycled via the feeding device 5.

[0083] An annular gap is formed between the first tube 2 and the second tube 3, which are connected to the internal space 32 of the second shell GM. The annular gap has a cross-sectional area that substantially corresponds to the inner cross-sectional area of ​​the second tube 3, with a deviation of ±10% to 50%. This results in a comparable flow velocity and Reynolds number.

[0084] The cross-sectional area of ​​the annular gap between the central opening 1 and the first tube 2 is approximately ±10% to 50% of the inner cross-sectional area of ​​the second tube.

[0085] For example, to install the feeding device 5 at the tank 4, the first housing GU can be fixed to the tank outlet flange first.

[0086] Then, the first tube 2 can be inserted, for example, from above, and secured, in particular, screwed to the bottom, especially the base plate 36 of the housing GU, as described above. For this purpose, screws 18 can be screwed through the base plate 36 and the mounting device 16 from the bottom outside, which is here designed, for example, as a mounting flange or mounting plate.

[0087] Then, depending on the implementation, the second tube 3 can be inserted into the first tube 2 from above or below and fixed at the bottom plate 30 of the second housing GM, in particular by screwing it in.

[0088] Then, the clamp 37 can be used to fix the third housing GO to the bottom end of the second housing GM and the base plate 30 of the second housing GM.

[0089] If the length of the second pipe 3 exceeds the outlet height of the tank 4, it must be installed in sections through the first pipe 2, either from below or also from above. To secure the second pipe to the base plate 30, a spiral joint is provided. This spiral joint has a corresponding fitting at the lower end of the second pipe 3. After the base plate 30 is spirally joined to the second pipe 3, it can be fixed 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. Here, spiral joints are installed at the ends of each pipe section to be inserted, and these spiral joints are screwed together. The final pipe section is then connected to the base plate 30 using the spiral joints.

[0090] The housings GU, GM, and GO either already have corresponding pipe sections 22, 23, 28, 29, 34, and 35 with corresponding flanges at their inlet openings 6, 7, and 8 or outlet openings 9, 11, and 12, or these pipe sections are welded on to allow for the final transverse installation of inlet valves E1, E2, and E3 and outlet valves A1, A2, and A3. The feeding device 5 is then integrated into the circulation pipeline 14.

[0091] For small tanks 4, which have relatively short pipes 2 and 3 (length: less than 1 meter), the entire assembly can be pre-assembled and connected to tank 4 via flanges. For large tanks 4, the maximum pipe length is limited by the tank outlet height, and therefore a multi-segment structure is required, as it must be installed from both top and bottom sections or in multiple segments from the bottom. If the second pipe 3 is very long, it can be designed as a multi-segment structure and then installed into tank 4 in sections. This also makes it possible to install very long second pipes 3 from the bottom. The individual pipe segments can then be interconnected via spiral joints or welding.

[0092] The following describes a possible method using the device 10 according to the invention. In this case, the net contents of the tank can be, for example, from 200 liters to 100,000 liters, and the nominal inner diameter of the valves and circulation lines used can be, for example, in the range of 8 mm to 160 mm. First, the tank 4 can be cleaned and sterilized before operation. For example, during sterilization, steam is introduced into the tank 4 from above, and the resulting condensate can be discharged under overpressure via the filling and emptying valve V1 and the downstream condensate drain. As an alternative to the aseptic filling and emptying valve, an aseptic valve combination, particularly a valve combination with multiple aseptic diaphragm valves (not shown in the figure), can also be used. After sterilization, the tank 4 is filled with a nutrient solution via valve V1, which consists of, for example, an aqueous solution of sugars, amino acids, fatty acids, vitamins, and salts. In this case, it is feasible to completely fill the tank 4 or only partially fill it. As long as the first pipe 2 is covered, the contents can be circulated. The cells to be used can be infused into the device 10 via a sterile dosing line on the tank wall or lid, or as part of the circulation line 14. Temperature control of the contents is achieved via a double jacket on the sides and / or bottom of the container. Another embodiment (not shown) also allows for temperature control of the container contents via an external heat exchanger, which can be integrated into the circulation line 14. Alternatively, direct steam injection can also be used for temperature control of the container contents. This can be done, for example, by means of an aeration device.

[0093] The heat exchanger included in the circulation piping 14, or the heat exchange surface installed at the tank 4, can be used not only to heat the culture medium but also to cool it. This is particularly advantageous in exothermic fermentation processes. Steam or high-pressure hot water can be used as the heating medium, for example, and a glycol-water mixture, cooling tower water, or cold water can be used as the cooling medium, for example.

[0094] Once fermentation begins, the biological suspension can be introduced into tank 4, for example via first pipe 2, discharged through central opening 1, and circulated via circulation pipe 14 to create a top-down flow within tank 4, opposite to the aeration direction. In this case, the aeration device (not shown) can be implemented at tank 4 either as a pipe with defined orifices or as a sintered candle structure, which is inserted into the interior space of container 4, for example, through the bottom of tank 4. Alternatively, an aeration device (not shown) can be installed within the circulation pipe. This aeration introduces a volume of gas or a mixture of gases, such as air, CO2, O2, or N2, which is required for aeration of the organisms during fermentation. The introduced bubbles rise upwards, thus flowing against the described direction of fluid flow. Therefore, as the bubbles circulate, the flow conditions are influenced in a way that enhances mass exchange. In another embodiment (not shown), a fixed connection port for the aeration mechanism is also installed inside tank 4 in the area between the shell GU and central opening 1 or flange 17. This is particularly advantageous in the early stages of fermentation, as the cells have a high oxygen demand at this time and there are no large aggregates or cell clusters. Another embodiment, not shown, features one or more aeration devices, such as inline valve bodies, arranged in the circulation line 14. This makes it possible to aerate within the circulation line 14 or to introduce gas into the circulating culture medium, thereby extending the residence and contact time of the introduced gas in the circulating culture medium compared to introducing it within the container 4.

[0095] In another embodiment, not shown, an aeration device is present in the circulation line 14, and an additional aeration device is present in the tank 4. This is advantageous because the culture medium can be aerated, for example, at the start of fermentation using the aeration device in the tank 4, and then during subsequent fermentation using the aeration device in the circulation line 14. For example, if the oxygen demand is high in the early stages of fermentation, gas or a gas mixture can be introduced using the aeration device in the tank 4 until preliminary saturation of the culture medium is achieved. During fermentation, dissolved oxygen in the culture medium is continuously consumed or metabolized by the microorganisms. Therefore, the aeration device can be used within the circulation line 14 to achieve a sustained maximum saturation of the culture medium.

[0096] Depending on the process conditions, the amount of dissolved gas in the liquid culture medium can be increased by introducing dissolved gas into the circulation line 14, thereby optimizing the process. Typical aeration rates for biological suspensions range from 0.05 vvm to 2.00 vvm (air volume per minute per volume of liquid).

[0097] Another embodiment, not shown, is characterized by a steam connection port (not shown) provided within the circulation line 14, for example, by means of an inline valve body. This connection port makes it possible to introduce steam into the circulation loop, thereby enabling targeted temperature control, steam treatment (steaming), and steam sterilization of the device 10.

[0098] This temperature control or sterilization corresponds to a common process step, such as between cleaning and production, where sterilization is typically performed by direct top entry into container 4. The steam connection in circulation line 14 improves accessibility to the product contact surfaces and reduces the time required to reach the desired temperature.

[0099] When tank 4 is completely filled, circulation can proceed via the second tube 3 instead of the first tube 2. If cells are to be collected and emptied from tank 4, it is advantageous to first draw them in via the first tube 2 and then reintroduce them into tank 4 via the second tube 3. This circulation creates a downward flow, with no flow in the lowest part of tank 4. As a result, cells accumulate in the lower region of tank 4 and can then be transferred in concentrated form from container 4 to downstream processes, such as solid-liquid separation, using pump 13. Depending on the cell type, it may also be advantageous for transfer to homogenize the biological suspension, thereby providing a constant solids concentration for downstream solid-liquid separation throughout the separation process. It is also feasible to reverse the flow direction within the container after the cells have accumulated in the lower region of tank 4, allowing the precipitated cells to flow from the bottom to the top. This reversal of direction is achieved by switching valves E1, E2, E3, A1, A2, A3 and / or pump 13. This allows the biological suspension to circulate, while fine particles with low settling rates are carried away by the flow and fed into the precipitate from below. This also leads to cell enrichment in the lower region of tank 4, which is beneficial for cell harvesting. During the emptying process, tank 4 can be completely emptied, or only emptied up to the top of the first tube 2, and then new nutrient solution can be refilled to enable a fed-batch process.

[0100] By circulating the contents of the tank according to the device 10 and the described method, it is feasible to ensure the requirements of a bioreactor (e.g., homogenization, suspension, dispersion, mass exchange, heat exchange, and aseptic isolation) without a stirring mechanism. The quality of the measurements is improved if a sensor Sn for process monitoring is installed in the circulation line 14. In static tanks or stirred tank reactors, it is difficult to avoid different measurements due to different sensor positions. Continuous flow of the tank contents from bottom to top or top to bottom makes representative samples possible and ensures that the interpretation of measurements is unaffected by the measurement position.

[0101] As described, pump 13 and valves must be suitable for aseptic processes and must be tightly isolated from the external environment, or equipped with vapor or condensate barriers. These valve devices are made easily accessible by integrating them into the circulation line 14, compared to the agitator drive located at the top bottom of the tank (i.e., the lid).

[0102] This improves ease of maintenance and saves costs, as it eliminates the need for a large and stable platform. Alternatively, the feed material can be integrated into the circulation line 14, circulating throughout the tank without requiring top-mounted feed.

[0103] The device 10 may also include a dosing point (not shown) for micro-dosing. This dosing point is located within the circulation line 14 and is configured for dosing small amounts of substances, such as acids, alkalis, defoamers, vitamins, minerals, and other nutrients. Furthermore, the adjustment of this dosing point is coordinated with equipment installed within the circulation line 14 (e.g., sensors S1 to Sn and one or more pumps 13). The process connection of the dosing point can be made, for example, by means of an inline valve body. Therefore, dosing does not necessarily have to be performed entirely directly via the inlet tank 4. Especially when the dosing volume is extremely small, this device makes it possible to introduce the culture medium to be added in a low-loss manner and to directly mix it using the volumetric flow rate applied in the circulation line 14. If a sterile valve assembly or a sterile sampling valve is used specifically, extraction can also be performed from the circulation line 14 in addition to introducing the culture medium.

[0104] Compared to a stirring mechanism, this pump requires only the volume of the circulation tank and consumes less power because it does not require the weight of the stirring mechanism to drive it. By flexibly controlling the inlet valves and outlet valves E1, E2, E3, A1, A2, A3 on the suction or pressure side of pump 13, it is feasible to allow the pump to flow through tank 4 from bottom to top or from top to bottom in the opposite direction, or both directions at different stages of fermentation.

[0105] If the flow is from bottom to top, cell sedimentation within tank 4 can be prevented, thereby increasing cell circulation and promoting mass exchange. Depending on the cell and cell or cell cluster particle size, it is feasible to keep the cells in suspension where appropriate. If the flow is from top to bottom through tank 4, the flow direction is opposite to the rising speed of the bubbles. This increases the residence time of the introduced gas in the liquid and increases the amount of gas absorbed in the liquid. This can reduce the total amount of gas introduced, thereby improving fermentation efficiency. Furthermore, the composition of the exhaust gas can be positively affected by reducing the amount of gas or gas mixture (e.g., air, CO2, O2, or N2) entering, for example, by reducing the amount of key gas (e.g., oxygen). Therefore, additional equipment and safety devices can be omitted in the exhaust piping.

[0106] By installing a feeding device 5, which functions as a circulation system, at the lower tank outlet flange, it is feasible to modify existing tank equipment to suit fermentation corresponding to the product. For suitable tanks, this modifiability reduces the cost of using them as bioreactors, while also minimizing time investment.

[0107] The reduced number of internal components in tank 4 improves the cleanability of the bioreactor (e.g., by reducing the spray shadow area) and makes it possible to reduce the number of spray balls. Similarly, the baffles on the tank walls can be omitted.

[0108] The feeding device 5 must be implemented such that a suitable flow rate can be achieved during the process to apply the least possible shear force to the cell suspension, and sufficient flow rate can be achieved during cleaning and sterilization. The pump 13 used achieves this flow rate range, which also makes it possible for the device 10 to operate at different process stages or with different cell suspensions. This flexibility in flow rate adjustment cannot be achieved using stirred tank reactors or bubble cap reactors.

[0109] Furthermore, the flow velocity within the pipeline can be designed according to the required Reynolds number, eliminating the need for high-flow-rate nozzles. This implementation enables the smooth delivery of the biosus suspension through all equipment components and defines the process parameters to be set.

[0110] According to the present invention, it is also possible to perform feed-in batching or fed-batch processing via the first tube 2 during fermentation. If the tank 4 is only partially emptied, it is also possible to circulate the contents and monitor all process parameters.

[0111] Furthermore, thanks to the feeding device 5 and the aforementioned housings GU, GM, and GO, easy loading and unloading is possible.

[0112] When referring to “can” or “container”, the two terms should be considered synonyms.

[0113] When "sterilization" is mentioned, it can be understood as a thermal process, such as using steam, but it can also be understood as a chemical process, such as using ozone or peracetic acid, or a physical process, such as ultraviolet irradiation.

[0114] The pipe 2 can also be designed such that a volumetric body is installed above the inlet and outlet connection 1, creating a gap between the tank bottom and the pipe 2. This gap allows for directional flow within the tank, thereby preventing sedimentation at the tank bottom.

[0115] When referring to “organisms”, the following terms are specifically included: microorganisms, macroalgae, microalgae, bacteria, enzymes, yeast and other filamentous fungi, plant and animal cells, beneficial organisms (such as nematodes) or other biological cell cultures.

[0116] "Homogeneization" is understood as mixing the contents of a tank to form a uniform distribution.

[0117] When "cell-free" is mentioned, it is understood to mean filtered liquid that is as free of cells as possible, but depending on the filtration precision, it may still contain cells or cellular components.

[0118] When referring to “gas,” the term “mixed gas” is also included.

Claims

1. An apparatus (10) for fermenting biological suspensions, the apparatus comprising: A tank (4) having a feeding device (5) for supplying and discharging the biological suspension, the tank having: The first central opening (1) in the tank (4) is used to supply or discharge the biological suspension; A first tube (2) extends through the central opening (1) into the tank (4) for supplying or discharging the biological suspension; The second tube (3) passes through the first tube (2) and extends beyond the first tube (2) into the tank (4) for supplying or discharging the biological suspension; A first housing (GU) has an internal space (31) that is tightly secured around the central opening (1) at the tank (4) via an upper opening, particularly at the outlet flange of the tank (4), and a first tube (2) that extends through the first housing in an externally sealed manner, wherein the first housing (GU) has an inlet opening (6) and a outlet opening (9) for the biological suspension. The second housing (GM) has an internal space (32) that is tightly connected to the first tube (2) via an upper opening, and the second tube (3) extends through the second housing in a sealed manner to the outside, wherein the second housing (GM) also has an inlet (7) and a outlet (11) for the biological suspension. and The third housing (GO) has an internal space (33) that is tightly connected to the second tube (3) via an opening, wherein the third housing (GO) also has an inlet (8) and a outlet (12) for the biological suspension.

2. The device (10) according to claim 1, characterized in that, The corresponding discharge openings (9, 11, 12) of the housing (GU, GM, GO) are connected to the circulation pipeline (14) via the corresponding aseptic discharge valves (A1, A2, A3), and the circulation pipeline is connected to the corresponding feed openings (6, 7, 8) of the housing (GU, GM, GO) via the corresponding aseptic feed valves (E1, E2, E3).

3. The apparatus (10) according to claim 1 or 2, characterized in that, One or more sterile pumps (13) are arranged in the circulation line (14).

4. The apparatus (10) according to claim 3, characterized in that, The pump (13) is a positive displacement pump for low shear transport, particularly a screw pump, hose pump or rotary piston pump, and is especially frequency controlled.

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

6. The apparatus (10) according to at least one of claims 1 to 5, characterized in that, The housings (GU, GM, GO) are detachably connected to each other.

7. The apparatus (10) according to at least one of claims 1 to 6, characterized in that, A mounting device (16), particularly a mounting flange, is formed at the first tube (2), through which the first tube (2) is connected to the first housing (GU), particularly by a screw connection, and the mounting device (16) seals both relative to the internal space (31) of the first housing (GU) and externally via corresponding seals (19), (20). The mounting device (16) is preferably fixed to the bottom of the first housing (GU), particularly the base plate (36), and is fixed from the outside with screws.

8. The apparatus (10) according to at least one of claims 1 to 7, characterized in that, An installation device (24), particularly a thread (24), is formed at the second tube (3). The second tube (3) is connected to the second housing (GM) via the installation device, particularly by screwing it in. The installation device (24), particularly the thread (24), seals both relative to the internal space (32) of the second housing (GM) and externally via a corresponding seal. The mounting device (16) is preferably fixed to the bottom of the second housing (GM), particularly to the base plate (30), and is screwed in.

9. The apparatus (10) according to at least one of claims 1 to 8, characterized in that, Another mounting device is arranged at the first tube (2), the first tube (2) is connected to the second housing (GM) via the other mounting device, wherein the mounting device is preferably sealed relative to the internal space (32) of the second housing (GM) and to the outside via a corresponding seal, or the other mounting device (16) of the first tube is fixedly arranged at the second housing, in particular welded thereon.

10. The apparatus (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 the annular gap between the first tube (2) and the second tube (3), wherein the cross-sectional area of ​​the annular gap corresponds to + / - 10% to 50% of the inner cross-sectional area of ​​the second tube (3), and / or The cross-sectional area of ​​the annular gap between the central opening (1) and the first tube (2) is approximately ±10% to 50% of the inner cross-sectional area of ​​the second tube (3).

11. The apparatus (10) according to at least one of claims 1 to 10, characterized in that, An aseptic filling and drain valve (V1) or a combination of aseptic valves is arranged at the lowest point of the circulation line (14), and the circulation line is specifically implemented to have a slope toward the filling and drain valve (V1).

12. The apparatus (10) according to at least one of claims 1 to 11, characterized in that, The device (10) is designed such that, in order to install the housing (GU, GM, GO), the first tube (2) can be fixed to the bottom of the first housing (GU), particularly the base plate (36), by means of the mounting device (16) arranged at the first tube (2), and can be screwed in, and the second tube (3) can slide through the first tube (2) and can be fixed to the bottom of the second housing (GM), particularly the base plate (30), by means of the mounting device (24), and can be screwed in.

13. The apparatus (10) according to at least one of claims 1 to 12, characterized in that, A sensor (S4) for measuring dissolved gases is arranged in the circulation pipeline (14), particularly for quantitatively determining a specific gas, especially oxygen.

14. The apparatus (10) according to claim 7, 8 or 9, characterized in that, The seals, particularly the sealing rings, used to seal the internal spaces (31, 32, 33) of the respective housings (GU, GM, GO) are flush with the internal spaces (31, 32, 33) of the respective housings (GU, GM, GO) and additionally sealed via metal stops (38, 39), particularly between the mounting device (16) and the base plate (36, 30).

15. The apparatus (10) according to at least one of the preceding claims, characterized in that, An overpressure protection device, particularly an overpressure valve or an overflow valve, is arranged in the circulation pipeline (14). When viewed along the flow direction, the overpressure protection device is preferably arranged downstream of the sterile pump (13) or the plurality of sterile pumps (13).

16. The apparatus according to at least one of the preceding claims, characterized in that, An aeration device for introducing gas into the circulation pipeline (14) is arranged in the circulation pipeline (14), wherein, viewed along the flow direction, the aeration device is preferably arranged downstream of a sensor (S4) for measuring dissolved gas, the sensor being arranged in the circulation pipeline (14).

17. The apparatus according to at least one of the preceding claims, characterized in that, Steam connection ports are arranged in the circulation pipeline (14), especially in-line valve bodies.

18. The apparatus according to at least one of the preceding claims, characterized in that, The circulation pipeline (14) is provided with an extraction port and a return port so that liquid can be diverted from the circulation pipeline and returned to the liquid via the return port. The extraction port is preferably provided with a filter so that cell-free liquid can be discharged through the extraction port.

19. The apparatus according to at least one of claims 1 to 18, characterized in that, Dosing points for liquids and / or solids, especially micro-dosing, are arranged in the circulation pipeline (14).

20. Use of an apparatus (10) according to at least one of claims 1 to 19 for fermenting a biological suspension.

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