Centrifuge system for separating cells in a suspension

Abstract

An apparatus for separating cell suspension material into centrifugal filtrate and concentrate includes a single-use structure (178, 240, 250, 370, 414) releasably positioned within a cavity in a solid-walled rotatable centrifuge drum (172). The drum and portions of the single-use structure rotate about an axis (174, 428). A fixed inlet feed pipe (184, 430), a centrifugal filtrate discharge pipe (212, 436), and a concentrate discharge pipe (230, 448) extend along the axis of the rotating single-use structure. A centrifugal filtrate centrifugal pump (208, 438) is fluidly connected to the centrifugal filtrate discharge pipe. A concentrate centrifugal pump (216, 450) is fluidly connected to the concentrate discharge pipe. At least one concentrate channel (380, 454) and a concentrate centrifugal pump chamber (376, 452) are structurally configured to facilitate the flow of cell concentrate.

Description

Technical Field

[0001] This disclosure relates to the centrifugation of materials. An exemplary arrangement relates to an apparatus for separating cells from a suspension by centrifugation. Background Technology

[0002] Apparatus and methods for centrifuging cells in suspensions are useful in many technological settings. Such apparatus and methods can benefit from improvements. Summary of the Invention

[0003] The exemplary arrangements described herein include apparatus and methods for centrifuging cells in large-scale cell cultures with high cell concentrations using pre-sterilized, single-use fluid path components. The exemplary centrifuges discussed herein can be solid-wall centrifuges using pre-sterilized, single-use components and can be capable of handling cell suspensions with high cell concentrations.

[0004] Exemplary arrangements utilize rotary-fixed feed and discharge components. Single-use components typically include a flexible membrane mounted on a rigid frame comprising a core with an enlarged diameter. Single-use components may also include at least one centripetal pump. The single-use structure can be supported within a reusable rigid drum having an internal frustoconical shape. These structures allow the exemplary system to maintain sufficiently high angular velocities to produce settling velocities suitable for efficiently processing highly concentrated cell culture streams. Features that minimize feed turbidity, along with other features that allow continuous or semi-continuous discharge of cell concentrate, increase overall productivity beyond achievable rates. The exemplary structures and methods provide efficient operation and reduce the risk of contamination. Attached Figure Description

[0005] Figure 1 This is a schematic diagram of an exemplary arrangement of a centrifuge system including single-use and multi-use components.

[0006] Figure 2 yes Figure 1 A close-up view of the upper flange area of ​​a centrifuge, showing a method of sealing flexible chamber material to the surface of the flange.

[0007] Figure 3 yes Figure 1 An isometric sectional view of the core and upper flange of a single-use component in the centrifuge system.

[0008] Figure 4 yes Figure 1 The schematic diagram shows an arrangement in which the pump chamber of the centrifuge system includes accelerator blades.

[0009] Figure 5 yes Figure 4An isometric view of the top of the pump chamber in an example arrangement of a centrifuge system shown.

[0010] Figure 6 It is an isometric sectional view of the core, upper flange, and lower flange of a single-use centrifuge system with an enlarged core diameter (to produce a shallow-pool centrifuge) and a feed accelerator.

[0011] Figure 7 yes Figure 6 An isometric view of the feed accelerator.

[0012] Figure 8 It is an isometric cross-sectional view of the core and upper flange of a single-use centrifuge system with a standard core diameter and a feed accelerator having curved blades and an elliptical drum.

[0013] Figure 9 yes Figure 8 An isometric view of the feed accelerator.

[0014] Figure 10 This is a schematic diagram of a part of a continuous concentrate discharge centrifuge system.

[0015] Figure 11 This is a schematic diagram of another arrangement that includes a continuous concentrate discharge centrifuge system.

[0016] Figure 12 This is a schematic diagram of a centrifuge system with a continuous concentrate discharge function that includes diluent injection.

[0017] Figure 13 This is a schematic diagram of another example arrangement of a continuous concentrate discharge system with a throttling mechanism for a centrifugal pump.

[0018] Figure 14 It is an isometric sectional view of the core and upper flange of a single-use centrifuge system with a core and a feed accelerator having straight blades.

[0019] Figure 15 yes Figure 14 An isometric view of the feed accelerator.

[0020] Figure 16 This is an isometric sectional view of an alternative continuous concentrate discharge centrifuge system.

[0021] Figure 17 This is an isometric exploded view of an alternative centripetal pump.

[0022] Figure 18 It is an isometric view of the plate of the alternative centripetal pump, which includes the volute channel.

[0023] Figure 19This is a schematic diagram of a centrifuge system that operates to ensure positive pressure is maintained within the centrifuge chamber.

[0024] Figure 20 It shows the result of Figure 19 A schematic diagram of a simplified exemplary logic flow executed by at least one control circuit of the system shown.

[0025] Figure 21 This is a schematic cross-sectional view of an alternative continuous centrifugal centrifuge system for discharging centrifuge media and concentrate.

[0026] Figure 22 This is a schematic cross-sectional view of an alternative continuous centrifugal filter and concentrate discharge centrifuge system.

[0027] Figure 23 This is a schematic cross-sectional view of an alternative continuous centrifugal filter and concentrate discharge centrifuge system.

[0028] Figure 24 This is a schematic diagram of a control system for an exemplary continuous centrifugal filter and concentrate discharge centrifuge system.

[0029] Figure 25 Is with Figure 24 A schematic representation of the logical flow associated with an exemplary control system.

[0030] Figure 26 This is an exemplary upper cross-sectional view of a single-use centrifuge structure, which includes a concentrate dam and a centrifuge filter dam located in a separation chamber.

[0031] Figure 27 This is an exemplary upper cross-sectional view of a single-use structure, which includes blades located in a centrifugal filter pump chamber and a concentrate pump chamber to control the radial position of the air / liquid interface.

[0032] Figure 28 This is a perspective view of the chamber surface of an exemplary concentrate pump chamber or centrifugal filter pump chamber, the chamber surface including a plurality of chamber blades.

[0033] Figure 29 It is similar to Figure 27 The axial cross-sectional view of the exemplary upper part of the single-use structure shown illustrates the location of the air / liquid interface.

[0034] Figure 30 This is an axial cross-sectional view of an exemplary upper portion of a single-use structure, which includes an air passage for retaining pressurized air in a cavitation.

[0035] Figure 31This is a schematic diagram of an exemplary system for controlling a centrifuge system, which includes centrifugal filter return pressure control.

[0036] Figure 32 This is an axial schematic cross-sectional view of another alternative continuous centrifugal filter and concentrate discharge centrifuge system.

[0037] Figure 33 yes Figure 32 The diagram shows a cross-sectional view of the upper part of the system.

[0038] Figure 34 It is similar to Figure 32 A schematic cross-sectional view, but the system is in operation and has a ring-shaped cell concentrate area in the separation chamber.

[0039] Figure 35 This is another alternative single-use centrifuge structure, with an external front top perspective view.

[0040] Figure 36 yes Figure 35 The cross-sectional view of the single-use structure shown.

[0041] Figure 37 yes Figure 35 An exploded view of the upper disc-shaped portion of the single-use structure shown.

[0042] Figure 38 yes Figure 35 A perspective view of the lower component of the upper disc-shaped portion of the structure shown. Detailed Implementation

[0043] In the field of cell culture used in biopharmaceutical processes, it is necessary to separate cells from a fluid medium (e.g., the fluid in which cells grow). The intended product from the cell culture can be a type of molecule secreted into the medium by the cells, a type of molecule retained within the cells, or it can be the cells themselves. At a production scale, the initial stages of the cell culture process are typically carried out in a bioreactor, which can operate in batch or continuous mode. Variations can also be implemented, such as repeating batch processes. The intended product must typically be ultimately separated from other process components before final purification and product formulation. Cell harvesting is a general term used to describe these separations of cells from other process components. Clarification is a term used to describe cell separation where the goal is a cell-free supernatant (or centrifuged filtrate). Cell recovery is a term generally used to describe separations targeting cell concentrates. The exemplary arrangement described herein relates to cell harvesting separation in a large-scale cell culture system.

[0044] Methods for cell harvesting and separation include batch, intermittent, continuous, and semi-continuous centrifugation, tangential flow filtration (TFF), and depth filtration. Historically, centrifuges used for harvesting large quantities of cell cultures at production scale were complex, reusable systems requiring cleaning-in-situ (CIP) and steam-in-situ (SIP) technologies to provide a sterile environment to prevent microbial contamination. Smaller systems can be used in laboratory-scale and continuous cell harvesting processes. A system manufactured by Pneumatic Scale Corporation is described in published application US2010 / 0167388. A centrifuge system, the entire disclosure of which is incorporated herein by reference, successfully processes batches of cultures for cell harvesting at rates ranging from 3 to 30 liters per minute, up to approximately 2000 liters. Also incorporated herein in their entirety are U.S. Patent Nos. 10,384,216 and 9,222,067, which are also owned by the assignee of this application, Pneumatic Scale Corporation. Batch processing typically requires periodically stopping the rotation of the centrifuge drum and the feed flow to discharge the concentrate. This method generally works well with low-concentration, high-viability cultures, where large batches can be processed and the cell concentrate is discharged relatively quickly and completely.

[0045] Sometimes it is necessary to harvest cells from cell cultures with high concentrations and / or low viability, which contain high concentrations of cells and cell debris in the feed material; this is sometimes referred to as a "high-turbidity feed." In some centrifugation systems, this high-turbidity feed can slow down the processing rate because:

[0046] 1. A slower feed flow rate is required to provide an increased residence time in the centrifuge in order to separate small cell debris particles, and

[0047] 2. High concentrations of cells and cell debris may cause the drum to fill rapidly with cell concentrate, requiring the drum to be stopped to drain the concentrate.

[0048] These combined factors can lead to reduced net productivity and unacceptably long cell harvesting processing times. In addition to the potential increase in costs associated with longer processing times, the increased time spent in the centrifuge can also result in higher levels of product contamination and losses when harvesting low-viability cell cultures.

[0049] High concentrations of cells and cell debris in the feed material can also result in very high viscosity of the cell concentrate. This can make it more difficult to completely remove the cell concentrate from the centrifuge, even with extended discharge cycles. In some cases, additional buffered rinsing cycles may be added to achieve adequate and complete discharge of the concentrate. The need for any or both of these adjustments to the discharge cycle further increases processing time, which can complicate and increase the cost of processing large volumes of cell cultures.

[0050] Proportionally increasing the system size by increasing the drum size to increase the length of the feed section in the batch processing cycle is sometimes impractical, as this also results in a proportionally longer discharge cycle for the cell concentrate. Another limitation that may prevent simple geometric scaling is the proportional variation of relevant hydrodynamic factors. The maximum processing rate of any centrifuge depends on the settling velocity of the separated particles. The settling velocity is given by a modification of Stokes' law as defined by Equation 1:

[0051]

[0052] Where v = settling velocity, Δρ is the solid-liquid density difference, d is the particle diameter, r is the radial position of the particle, ω is the angular velocity, and μ is the liquid viscosity. With respect to the scaled-up geometry, changing the drum radius alters the maximum radial position r that the particles can occupy. Therefore, if the other parameters in Equation 1 remain constant, for a given separation efficiency, increasing the drum radius leads to an increase in both the average settling velocity and the throughput. However, as the radius increases, maintaining the drum's angular velocity becomes more difficult due to the potentially increased material strength and other engineering constraints. If the decrease in angular velocity is greater than the square root of the proportional increase in radius, both the gain in average settling velocity and throughput (which is proportional to the radius) decreases.

[0053] One engineering limitation that must be considered is that the angular velocity required to rotate a larger drum may not be practical to achieve due to the need for a larger and more expensive centrifuge drive platform.

[0054] Furthermore, if the angular velocity remains constant with increasing radius, the force pushing the cells against the centrifuge wall also increases. When the drum rotates at a sufficiently high angular velocity to produce the desired processing efficiency, both the container walls and the cells accumulated there are subjected to increased stress. For the cells, this can cause cell damage by encapsulating them at excessively high concentrations. Cell damage is a disadvantage in applications where maintaining cell viability is crucial and can lead to contamination of the solution with products present in the centrifuged filtrate. The higher viscosity resulting from excessively high cell concentrations is also sometimes a drawback to the complete removal of the cell concentrate.

[0055] Exemplary arrangements include apparatus and methods for continuously or semi-continuously centrifuging low-viability cell suspensions containing high concentrations of cells and cell debris at rates suitable for commercial-scale processing of large volumes of cell suspensions. Some exemplary centrifuges are pre-sterilized, single-use designs and capable of processing such cell suspensions at flow rates exceeding 20 liters per minute. For a 2000-liter bioreactor, this flow capacity allows for total run times in the range of 2 to 3 hours. Exemplary arrangements of single-use centrifuge systems may be able to process approximately 300 to 2000 liters of fluid while operating at a rate of approximately 2 to 40 liters per minute.

[0056] Figure 1 A single-use centrifuge structure 1000 is disclosed. The centrifuge structure 1000 includes a core structure 1500 (in...). Figure 3 (Best shown in the diagram), it includes a core 1510, an upper flange 1300, a lower flange 1200, and a flexible gasket 1100 sealing both the upper flange 1300 and the lower flange 1200. The centrifuge structure 1000 also includes a centrifugal pump 1400, which includes a pair of stationary scraper discs 1410 and a rotary mechanical seal 1700 in a rotary pump chamber 1420.

[0057] The centrifuge structure 1000 also includes a feeding / discharging assembly 2000. Assembly 2000 includes a rotation axis 1525 about the centrifuge 1000 (in... Figure 12 Multiple concentric tubes (marked in the middle). The innermost part of the feed / discharge assembly 2000 includes a feed pipe 2100. Multiple additional tubes concentrically surround the feed pipe 2100 and may include a tube or fluid passage 2200 that allows the discharge of centrifuged filter material, and a tube or fluid passage 2500 that allows the discharge of concentrate (e.g., see...). Figure 12 ) or a pipe or fluid passage that allows the supply of diluent 5000 (e.g., see Figure 12 Each part of the feed / discharge connection may be fluidly connected to a portion of the interior of the centrifuge 1000 via a suitable fluid connection, and to a collection or feed chamber (not shown), and may include additional tubing fluidly connected to concentric tubes to remove centrifuged filter material, concentrate or diluent from the system or add it to the system.

[0058] like Figure 1 As shown, the upper flange 1300 and the lower flange 1200 include a conical drum that is axially aligned with and recessed toward the core 1510. The core 1510 includes a generally cylindrical body with a hollow cylindrical center that is large enough to receive a core having an axis 1525 (in Figure 12The feed tube 2100 (marked in the middle). The upper flange 1300, core 1510, and lower flange 1200 may be an integral structure to provide a stronger support structure for the flexible liner 1100, which is also referred to herein as a membrane. In other arrangements, the core structure 1500 may be formed from multiple component parts. In yet another arrangement, the core 1510 and upper flange 1300 may comprise a single component, wherein the lower flange 1200 comprises a separate component, or the core 1510 and lower flange 1200 may comprise a single component, wherein the upper flange 1300 comprises a separate component.

[0059] Figure 3 An exemplary arrangement of the integral core 1510 and the upper flange 1300 is shown. This integral component engages with the lower flange 1200 to create an internal support structure 1500 for the single-use component of the centrifuge 1000. This structure anchors the flexible liner 1100 around the fixed internal rigid or semi-rigid support structure 1500 at the top and bottom. When the centrifuge system is in use, the flexible liner 1100 is also externally supported by the walls and cover of the drum of the reusable structure 3000.

[0060] The exemplary separation chamber 1550 is an open chamber, generally cylindrical in shape, and is generally defined by the outer surface 1515 of the core 1510 and the flexible liner 1100, and by the upper surface 1210 of the lower flange 1200 and the lower surface 1310 of the upper flange 1300. The separation chamber 1550 is fluidly connected to the feed pipe 2100 via an aperture 1530 extending from the central cavity 1520 of the core 1510 to the outer surface 1515 of the core 1510. The separation chamber 1550 is also fluidly connected to the pump chamber 1420 via a similar aperture 1540 passing through the core structure 1500. In this example, the aperture 1540 is angled upward toward the pump chamber 1420 and opens into the separation chamber 1550 directly below the junction between the core 1510 and the upper flange 1300. Figure 12 As shown, orifices 1420 or 4420 can enter the pump chamber at angles other than upward, including horizontally or downward. Additionally, in some arrangements, orifices 1420 and 4420 can be replaced by slots or gaps between accelerator blades.

[0061] Figure 1 Also shown is a feed / discharge assembly 2000, which includes a feed pipe carrier 2300 through which a feed pipe 2100 extends to... Figure 3The location shown is near the bottom of the centrifuge structure 1000. In this location, the feed tube 2100 can perform feeding and discharging functions without moving. By carefully designing the gap between the nozzle 2110 of the feed tube 2100 and the upper surface 1210 of the lower flange 1200, the diameter of the nozzle 2110 of the feed tube 2100, and the angular velocity of the centrifuge, shear forces during the feeding process can be minimized. The disclosure describes how to select appropriate relationships to minimize shear forces by referencing U.S. Patent No. 6,616,590, which is incorporated herein by reference in its entirety. Other suitable feed tube designs known to those skilled in the art for minimizing the shear forces associated with feeding liquid cell cultures into a rotary centrifuge can also be used.

[0062] Figure 1 It also includes a centrifugal pump 1400 for discharging centrifugal filter material through the centrifugal filter material discharge passage 2200. Figure 1 In the arrangement shown, the centrifugal filter pump 1400 is located above the upper flange 1300 in the pump chamber 1420. The pump chamber 1420 is a cavity defined by the upper surface 1505 of the core 1510 and the inner surfaces 1605, 1620 of the centrifuge cover 1600. The centrifuge cover 1600 may include a cylindrical wall 1640 and a shape similar to a generally disc-shaped ( Figure 5 The centrifuge cover 1600 (as shown) is a mating cover portion 1610. The centrifuge cover 1600 can be formed as a single unit or as a separate component.

[0063] As discussed in more detail below, in other arrangements, the shape and position of the centrifugal filter pump chamber 1420 can be varied. The chamber 1420 is typically an axisymmetric chamber near the upper end of the core structure 1500, fluidly connected to the separation chamber 1550 via an orifice or slit 1530 extending from near the exterior of the core 1515 into the centrifugal filter pump chamber 1420. In some arrangements, such as... Figure 11 and Figure 12 As most clearly shown, the centrifugal filter pump chamber 1420 can be located in a recess within the chamber 1550.

[0064] An exemplary centrifugal filter pump 1400 includes a pair of scraper discs 1410. The scraper discs 1410 are two thin discs (plates) axially aligned with the axis 1525 of the core structure 1500. Figures 1 to 5 In the arrangement shown, the scraper disc 1410 is kept fixed relative to the centrifuge structure 1000, and the scraper disc passes through a fixed gap 1415 (in Figure 10The scraper discs 1410 (marked 1415) are separated from each other. The gap 1415 between the scraper discs 1410 forms part of a fluid connection for removing centrifugal filter material from the centrifuge 1000, which allows the centrifugal filter material to flow between the scraper discs 1410 into a hollow cylindrical centrifugal filter material discharge passage 2200 surrounding the feed tube carrier 2300, which terminates at the centrifugal filter material outlet 2400.

[0065] An exemplary single-use centrifuge structure 1000 is contained within a multi-use centrifuge structure 3000. Structure 3000 includes a drum 3100 and a cover 3200. The walls of the centrifuge drum 3100 support a flexible liner 1100 of the centrifuge structure 1000 during rotation of the centrifuge 1000. To do this, the external structure of the single-use structure 1000 and the internal structure of the multi-use structure are adapted to each other. Similarly, the upper surface of the upper flange 1200, the outer portion of the upper part of the core 1510, and the lower portion of the wall 1640 of the centrifuge cover 1600 are adapted to the inner surface of the multi-use drum cover 3200, which is also adapted to provide support during rotation. Features of the multi-use drum 3100 and drum cover 3200 (discussed in more detail below) are designed to ensure that shear forces do not tear the liner 1100 from the single-use centrifuge structure 1000. In some cases, an existing multi-use structure 3000 can be retrofitted for single-use processing by selecting a suitable single-use structure 1000. In other cases, the multi-use structure 3000 can be specifically designed for use with the single-use structure insert 1000.

[0066] Figure 2 A portion of an exemplary structure for the upper flange 1300, the plastic gasket 1100, and the cap 3200 of the reusable centrifuge structure 3000 is shown to illustrate the seal of the flexible gasket 1100 to the upper flange 1300. The flexible gasket 1100 may be a thermoplastic elastomer, such as polyurethane (TPU), or other stretchable, tough, tear-resistant, biocompatible polymer, while the upper flange 1300 and lower flange 1200 may be made of rigid polymers, such as polyetherimide, polycarbonate, or polysulfone. The flexible gasket 1100 is a thin sleeve or sash that extends between and seals to the upper flange 1300 and lower flange 1200, forming the outer wall of the separation chamber 1550. The composition of the gasket 1100, the upper flange 1300, the lower flange 1200, and the core 1510 described herein are merely exemplary. Those skilled in the art may substitute suitable materials having properties similar to those of the proposed properties that are known or may become known.

[0067] Thermal bonding adhesion process can be used for bonding Figure 2Different materials are shown in the region. The thermally bonded portion 1110 is formed by preheating the flange material, placing the elastomeric polymer on top of the heated flange, and applying heat and pressure to the elastic membrane gasket 1100 at a temperature above the membrane's softening point. The plastic gasket 1100 is bonded to the lower flange 1200 in the same manner. While the thermally bonded portion 1110 is described herein, it is merely exemplary. Other methods can be used to create a similar strong, relatively permanent bond between the flexible membrane and the flange material, such as by temperature, chemicals, adhesives, or other bonding methods.

[0068] The exemplary single-use components are pre-sterilized. These heat-bonded sections 1110 remain sterile within the single-use chamber during removal of these components from their protective packaging and installation into the centrifuge. When in use, the stretchable flexible liner 1100 adapts to the walls of the reusable drum 3100. The reusable drum 3100 provides sufficient support, and the flexible liner 1100 is sufficiently resilient to allow the single-use structure 1000 to withstand increased rotational forces generated when the centrifuge 1000, with its larger radius, is filled with liquid cell cultures or other cell suspensions and rotates at a sufficient angular velocity to achieve a settling velocity that allows processing at a rate of approximately 2 to 40 liters per minute.

[0069] In addition to the heat-bonded section 1110, a sealing ridge or "piece" 3210 may be present on the drum cover 3200 to press the thermoplastic membrane against the rigid upper flange 1300, thus forming an additional seal. The same compression seal can also be used at the bottom of the drum 3100 to seal the thermoplastic membrane against the rigid lower flange 1200. These compression seals support the heat-bonded area 1110 by isolating it from shear forces generated by the hydrostatic pressure produced during centrifugation when the chamber is filled with liquid. The combination of the heat-bonded section 1110 and the compression piece 3210 seal has been tested at 3000x g, corresponding to a hydrostatic pressure of 97 psi at the drum wall. The gasket should be thick enough and compressible to allow the piece 3210 to compress and clamp the flexible gasket 1100 while minimizing the risk of tearing near the heat-bonded section 1110 or the compression piece 3210. In one instance setup, a 0.010-inch thick flexible TPU liner was sealed without tearing or leaking.

[0070] Tested inside a 5.5-inch diameter drum. Figures 1 to 2 The diagram shows the corresponding arrangement. Under 2000 times gravity, it has a hydraulic capacity of >7 liters per minute and successfully separates mammalian cells with an efficiency of 99% at a rate of 3 liters per minute.

[0071] In most cases, the upper flange 1300 and the lower flange 1200 can have the same characteristics as... Figure 1 The shapes shown are similar, but in some cases, the upper surface of a single-use centrifuge structure can have different shapes, such as... Figure 10 and Figure 11 As shown. In Figure 10 and Figure 11 In the arrangement shown, instead of a generally conical drum cover 3200 adapted to a generally conical upper flange 1300, both the upper flange and the drum cover are relatively disc-shaped. Those skilled in the art will be able to adapt the sealing techniques described herein to sealing surfaces of various shapes.

[0072] Figures 4 to 5 An example arrangement featuring improved efficiency of the centripetal pump 1400 is shown. For example... Figure 5 As detailed in the text, it is used for similar purposes. Figure 1 and Figure 2 This arrangement of the internal structure of the single-use component shown includes a plurality of radial blades 1630 on the inner surface 1620 of the cap 1610 of the pump chamber 1420. Figure 5 The inner surface 1620 of the cap 1610 of the centrifuge cover 1600 is shown. Radial vanes 1630 may be thin, generally rectangular radial plates extending perpendicularly from the inner surface 1620 of the cap 1610. In this exemplary arrangement, six (6) vanes 1630 are shown, but other arrangements may include fewer or more vanes 1630. In this arrangement, the vanes 1630 form part of the inner surface of the cap 1620, but in other arrangements, the upper surface 1620 of the pump chamber 1420 may be included, taking a different form than the cap 1610. When the centrifuge system 1000 is in use, the vanes 1630 are positioned above the scraper disc 1410 of the centrifugal pump 1400 within the chamber 1420. These vanes 1630 transmit the angular rotation of the centrifuge 1000 to the centrifuged filter within the pump chamber 1420.

[0073] This increases the efficiency of the centrifugal pump 1400, stabilizes the gas-liquid interface in the pump chamber 1420 above the scraper disc 1410, and increases the size of the gas barrier. The gas barrier is a generally cylindrical column of gas extending outward from the outside of the feed / discharge mechanism 2000 into the pump chamber 1420 to reach the inner surface of the rotating centrifugal filter media. This increase in barrier size also occurs because the increased angular velocity of the centrifugal filter media forces it toward the centrifuge wall. Friction generated when the rotating centrifugal filter media contacts the stationary scraper disc 1410 within the pump chamber 1420 could reduce the efficiency of the pump 1400. The addition of multiple radial vanes 1630, which rotate at the same angular velocity as the centrifugal filter media, overcomes any velocity reduction that might otherwise result from collisions between the rotating centrifugal filter media and the stationary scraper disc 1410.

[0074] Figure 6 An exemplary arrangement of a core structure 1500 for high-turbidity feed is shown. The core structure 1500 includes a core 1510, an upper flange 1300, and a lower flange 1200. The core 1510 has a cylindrical central cavity 1520 adapted to allow a feed tube 2100 to be inserted into the central cavity 1520. The distance from the central axis 1525 to the outside of the core 1515 (core width, by...) is... Figure 6 The dashed line 6000 in the text indicates that it is greater than... Figure 3 The corresponding distances in the arrangement shown. The larger diameter core 1510 reduces the depth of the separation chamber 1550 (indicated by the dashed line 6010), allowing the centrifuge 1000 to operate as a shallow-pool centrifuge. The depth 6010 of the separation chamber 1550 is typically within... Figure 1 and Figure 12 The distance between the outer edge of the core 1510 (marked in the center) and the flexible liner 1100. A shallow-pool centrifuge is a centrifuge with a depth of 6010 that is smaller than its diameter. (As can be...) Figure 12 As seen in the exemplary arrangement, the shallow pool depth 6010 varies from shallower at the bottom of the separation chamber 1550 to slightly deeper at the top of the separation chamber 1550 to facilitate the removal of cell concentrate. In some arrangements shown herein, the ratio of the average separation pool depth 6010 to the core width is 1:1 or less. An example of a shallow pool centrifuge is as shown by Pneumatic Scale Corporation. Available as an optional model of the centrifuge system. The advantage of a shallow-pool centrifuge is that it enables separation at higher feed flow rates. This is achieved through a higher average gravity for a given inner drum diameter, which results in a higher settling velocity at a given angular velocity. The enhanced separation performance is beneficial when separating highly turbid feeds containing a high concentration of cell debris.

[0075] Figure 6The illustrated core structure 1500 also includes an accelerator blade 1560 as part of a lower flange 1200. The accelerator blade 1560 (e.g.) Figure 12 (as shown) (not the hole 1530 through the solid core 1510) Figures 10 to 11 The diagram shows an alternative arrangement for the fluid connection between the central cavity 1520 and the separation chamber 1550 of the core 1510.

[0076] exist Figure 6 In the exemplary arrangement of the core structure 1500 shown, the accelerator blade 1560 includes a plurality of radially, generally rectangular, spaced-apart thin plates 1580 extending upward from the upper tapered surface of the lower flange 1200. The plates 1580 extend upward perpendicular to the base of the core 1510. The plates 1580 extend radially outward generally from near the axis 1525 of the core 1510. In the exemplary arrangement, as... Figure 7 The most clearly shown arrangement has 12 plates 1580. In other arrangements, there may be fewer or more than 12 plates 1580. Additionally, in other arrangements, the plates 1580 may be bent in the direction of rotation of the centrifuge 1000, such as... Figure 9 The exemplary arrangement is shown in the figure. The inner surface of the lower flange 1200 may be modified to form an elliptical accelerator drum 1590, from which curved plates extend upward. These arrangements are intended to be exemplary, and those skilled in the art may combine them in different ways, or may modify these arrangements to further benefit from the reduction in turbidity of these plates and the shape produced by the lower flange 1200 and / or the embedded accelerator drum.

[0077] Other features of the exemplary arrangement of the single-use centrifuge 1000 designed for continuous or semi-continuous operation are as follows: Figures 10 to 12 As shown in the image. Figure 10 The exemplary arrangement shown includes a second centripetal pump 4400 for removing cell concentrate. The centripetal pump 4400 for removing cell concentrate is positioned above the centripetal pump 1400 for removing centrifugal filter media. The centripetal pump 4400 includes a pump chamber 4420 and a scraper disc 4410. A plurality of orifices or continuous slits 4540 extend from the upper outer circumference of the separation chamber 1550 into the pump chamber 4420, providing fluid connection from the outside of the separation chamber 1550 to the second pump chamber 4420. Like the pump chamber 1400, the pump chamber 4400 may have the same... Figures 10 to 12The shapes shown may differ, but they will generally be axially symmetrical chambers located near the upper end of the core structure 1500, which is fluidly connected to the separation chamber 1550. Like the pump chamber 1400, the pump chamber may be partially or completely recessed within the core structure 1500. If the centrifugal filter pump chamber 1400 is located near the upper end of the core structure 1500, the cell concentrate pump chamber 4400 will be located approximately above it. The pump chamber 4400 for removing the cell concentrate will be fluidly connected to the separation chamber 1550 via a hole or slit 4540 extending from near the outer upper wall of the separation chamber 1550 to collect the heavier cell concentrate propelled there by centrifugal force.

[0078] exist Figure 10 In the arrangement shown, the radius of the scraper disc 4410 for the concentrate discharge pump 4400 is approximately the same as the radius of the scraper disc for the centrifugal filter discharge pump 1400, and is rotatably fixed. In other arrangements, for example... Figure 11 As shown in the arrangement, the scraper disc 4410 in the concentrate discharge pump 4400 can have a larger radius than that in the centrifugal filter discharge pump 1400, resulting in a correspondingly larger pump chamber 4420. Various intermediate diameter scraper discs can also be used. The optimal diameter will depend on the properties of the cell concentrate to be discharged. Larger diameter scraper discs offer higher pumping capacity but generate greater shear.

[0079] exist Figure 1 , Figure 4 and Figure 10 In the arrangement shown, the scraper disc 4410 in the concentrate discharge pump 4400 is rotatably fixed. In other arrangements, for example... Figure 11 As shown in the arrangement, the scraper disc 4410 can be adapted to rotate at an angular velocity between zero and the angular velocity of the centrifuge 1000. The desired angular velocity can be controlled by a variety of mechanisms known to those skilled in the art. One example of a control device is an external slip clutch, which allows the scraper disc 4410 to rotate at an angular velocity that is a fraction of the angular velocity of the centrifuge 1000. Other devices for controlling the angular velocity of the scraper disc will be apparent to those skilled in the art.

[0080] exist Figure 1 , Figure 4 , Figures 10 to 12 In the arrangement shown, the gaps 1415 and 4415 between the scraper discs 1410 and 4410 are fixed. In other arrangements, for example... Figure 13In the arrangement shown, the gaps 1415, 4415 between scraper discs 1410 and 4410 can be adjustable to control the flow rate at which centrifugal filter material or concentrate is removed from centrifuge 1000. One of each pair of scraper discs 1410 and 4410 is attached to a vertically movable throttling tube 6100. The throttling tube 6100 can move up or down to narrow or widen the gaps 1415, 4415 between each pair of scraper discs 1410 and 4410. Additionally, an external peristaltic pump 2510 (not shown) can be added to the concentrate removal line 2500 (not shown) to assist in the removal of concentrate. This pump 2510 can be controlled by a sensor 4430 in pump chamber 4420. The sensor 4430 (not shown) can also be used to control the diluent pump 5150 to synchronize the removal of concentrate with the addition of diluent.

[0081] Figure 13 An arrangement is also shown in which the centrifugal filter pump 1400 is located at the base of the centrifuge 1000. Figure 13 In the illustrated arrangement, a centrifugal filter well 1555 is formed between the pump chamber 1420 and the flexible liner 1100. An orifice 1530 extends from the core 1510 into the centrifugal filter well 1555 below the pump chamber 1420. Additionally, in the illustrated exemplary arrangement, an orifice 1540 extends from the separation chamber 1550 into the pump chamber 1420 adjacent to the outer surface 1515 of the core 1510 to allow removal of the centrifugal filter using a centrifugal filter pump 1400. An orifice 4540 may also extend from between the separation chambers 1550 into the pump chamber 4420 adjacent to the outer upper surface of the separation chamber to allow cell concentrate to flow into the pump chamber 4420 for removal using a centrifugal pump 4400.

[0082] As described above, in the illustrated exemplary arrangement, the gaps 1415, 4415 between scraper discs 4410 and 1410 can be adjusted using a throttle tube 6100 connected to one of each pair of scraper discs 4410, 1410. The throttle tube 6100, and one of the attached scraper discs in each pair of scraper discs 4410, 1410, can be moved up or down to narrow or widen the gaps 1415, 4415. In the illustrated exemplary arrangement, the throttle tube 6100 is attached to the lower and upper scraper discs of the scraper disc pairs 4410, 1410, respectively. In other arrangements, this attachment can be reversed, and can be used to throttle a single centripetal pump, or to throttle both in parallel (instead of as shown). Figure 13 (The opposite of what is shown).

[0083] If available Figures 10 to 12As seen in the illustrated arrangement, the walls of the solid reusable drum 3100 are thicker at the base than at the top, creating an internal frustoconical shape to support the single-use centrifuge structure 1000, which has a smaller radius at the lower end than at the upper end. This larger radius at the upper end of the separation chamber 1550 causes the denser cell concentrate to move towards the upper outer part of the separation chamber 1550 and into the centripetal pump chamber 4420. In the illustrated arrangement, this frustoconical shape is created by the reusable drum 3100, which has walls thicker at the base than at the top. Those skilled in the art will recognize that the reusable drum 3100 with an internal frustoconical shape can also include walls of uniform thickness, and other variations can exist to produce the desired internal shape of the reusable drum 3100.

[0084] exist Figures 10 to 12 In the exemplary arrangement shown, the feed mechanism 2000 also includes additional pathways for removing cells or cell concentrates. Figure 1 In the arrangement shown, the cylindrical passage 2200 surrounding the feed pipe 2100 is used to remove centrifugal filter media. Figures 10 to 12 The arrangement shown also includes a concentric cylindrical passage for removing cells or cell concentrate, referred to as the cell discharge tube 2500. The cell discharge tube 2500 surrounds the centrifuge filter removal passage 2200. If the centrifuge is designed for use with concentrates that are expected to be very viscous, an additional concentric cylindrical fluid passage 5000 can be added around the feed tube 2100 to allow diluent to be introduced into the cell concentrate pump chamber 4420 to reduce the viscosity of the concentrate. Figure 12 In the exemplary arrangement shown, the diluent passage 5000 includes a concentric tube surrounding the cell discharge passage and, at its lower end, opens to a thin, disc-shaped fluid passage 5100 above the scraper disc 4410, discharging near the outer edge of the scraper disc 4410 to provide fluid communication with the pump chamber 4420. Injecting the diluent at this location in this manner limits its mixing with the concentrate and discharge with it, rather than introducing it into the centrifuged filter, which may be undesirable in some applications. In an alternative arrangement, the diluent may be introduced directly onto the upper surface of the scraper disc and allowed to expand radially outward, or introduced onto a separate disc located above the scraper disc.

[0085] The choice of diluent will depend on the purpose of the separation process and the nature of the cell concentrate to be diluted. In some cases, a simple isotonic buffer or deionized water can be used as a diluent. In other cases, a diluent specific to the properties of the cell concentrate may be advantageous. For example, in production-scale batch cell cultures operating at low cell viability, flocculants are often added to the cultures when they are fed to a centrifuge to cause cells and cell debris to flocculate or aggregate into larger particles, which facilitates separation by increasing their settling rate. Since both cells and cell debris carry a negative surface charge, compounds used as flocculants are typically cationic polymers carrying multiple positive charges, such as polyethyleneimine. Due to their multiple positive charges, such flocculants can bind negatively charged cells and cell debris into large aggregates. An undesirable result of using such flocculants is that they further increase the viscosity of the cell concentrate. Therefore, a diluent particularly useful in this application is an antiflocculator that disrupts the binding that increases the viscosity of the cell concentrate. Examples of antiflocculators include high-salt buffers, such as sodium chloride solutions, at concentrations of 0.1 M to 1.0 M. Other antiflocculating agents that can be used to reduce the viscosity of cell concentrates are anionic polymers, such as polymers of acrylic acid.

[0086] In cases where cell concentrates are intended to maintain cell viability, a diluent that is a shear protectant, such as dextran or Pluronic F-68, can be selected. Using a shear protectant, combined with isotonic buffer, will enhance cell survival and viability upon discharge from the centrifuge.

[0087] Figure 4 The exemplary centrifuge shown operates as described below. During the feed cycle, the feed suspension flows into the rotating drum assembly through the feed pipe 2100. When the feed suspension enters the central cavity 1520 of the core 1510 near the lower flange 1200, it is pushed outward along the upper surface of the lower flange 1200 by centrifugal force, passes through the hole 1530 in the core 1510, and enters the separation chamber 1550.

[0088] Centrifugal filter media are collected in separation chamber 1550, specifically, a hollow, generally cylindrical space below the upper flange 1300 of core 1510. The centrifugal filter media flows upward into the separation chamber from its inlet through orifice 1530 until it encounters orifice 1540 located between separation chamber 1550 and pump chamber 1420 adjacent to core 1410 in the upper part of separation chamber 1550. Particles with a density higher than the liquid density move towards the outer wall of separation chamber 1550, away from orifice 1530, through sedimentation (particle concentrate). When centrifuge 1000 stops rotating, the particle concentrate moves downward under gravity to nozzle 2110 of feed pipe 2100 for removal via combined feed / discharge mechanism 2000.

[0089] During rotation, the centrifugal filter material enters the centrifugal filter pump chamber 1420 through the orifice 1540. Inside the pump chamber 1420, the rotating centrifugal filter material encounters a fixed scraper disc 1410, which converts the kinetic energy of the rotating liquid into pressure. This pressure pushes the upward-discharged centrifugal filter material through the centrifugal filter discharge passage 2200 within the feed / discharge mechanism 2000 and discharges it through the centrifugal filter discharge pipe 2400.

[0090] The efficiency of the centrifugal pump 1400 is increased by adding radial vanes 1630 to the inner surface 1620 of the cap 1610 of the rotary pump 1400. These vanes 1630 transfer the angular momentum of the rotating assembly to the centrifugal filter media in the pump chamber 1420, which may be further slowed down due to friction when the rotating centrifugal filter media encounters the stationary scraper discs 1410. Due to the gas-liquid interface within the pump chamber 1420, the centrifugal pump 1400 provides an improved method of centrifugal filter media discharge at the mechanical seal. The rotating seal 1700 isolates the gas within the pump chamber 1420 from contamination by the external environment. Because the centrifugal filter media discharged between the scraper discs 1410 does not come into contact with air during the feeding or discharging process, it avoids the excessive foaming that often occurs when air is introduced into the cell culture during the discharge process.

[0091] exist Figures 4 to 5 In the arrangement of the centrifuge 1000 shown, cell concentrate is discharged by periodically stopping the drum rotation and feed flow and subsequently pumping out the cell concentrate already collected along the outer wall of the separation chamber 1550. This process is referred to as batch processing. When the volumetric capacity of the separation chamber 1550 is reached, centrifugal rotation is stopped. The cell concentrate moves downward toward the nozzle 2110 of the feed pipe 2100, where it is drawn out by pumping the concentrate out through the feed pipe 2100. Appropriate valves (not shown) outside the centrifuge 1000 are used to guide the concentrate into a collection container (not shown). If the entire bioreactor batch has not been completely processed, drum rotation and feed flow are resumed, followed by additional feed and discharge cycles until the entire batch has been processed.

[0092] As described above, the process slows down when cell cultures are concentrated or contain a large amount of cell debris because the residence time must be increased to capture small debris particles. This necessitates a slower feed flow rate and rapid filling of the centrifuge chamber 1550, and frequent and repeated stopping of the rotation for each culture batch. Additionally, cell concentrates tend to be more viscous, so gravity cannot effectively flush the concentrate to the bottom of the centrifuge 1000, resulting in longer processing times, and in some cases, washing may be required to remove remaining cells.

[0093] like Figures 6 to 13The improvements in the exemplary arrangement shown allow the centrifuge to produce a higher average sedimentation velocity without increasing angular velocity in a single use, allowing the centrifuge 1000 to operate continuously or semi-continuously, and allowing diluent to be added to the cell concentrate during the cell removal process, making cell removal easier and more complete.

[0094] Figures 6 to 12 The single-use centrifuge structure 1000 shown operates as described herein. The feed suspension enters the single-use centrifuge structure 1000 via the feed pipe 2100. When the feed suspension encounters the accelerator blades 1560, the blades 1560 impart an angular velocity to the feed suspension close to the angular velocity of the single-use centrifuge 1000. Using blades 1560 instead of orifices 1530 provides a larger volume of feed suspension to enter the separation chamber 1550 at a slower radial velocity, avoiding the jetting that occurs when the feed suspension is forced through orifices 1530, which have a smaller cross-sectional opening than the opening between the blades 1560. This reduction in feed flow velocity as the feed flow enters the separation zone or tank minimizes disruption of the liquid contents in the tank, allowing for more efficient sedimentation.

[0095] When centrifuge 1000 rotates, particles denser than the centrifuged material are pushed towards the outside of separation chamber 1550, leaving particle-free centrifuged material near the core 1510. The centrifuge drum 3100 has an inverted frustoconical shape, with a wider radius at the upper end than the lower end. Centrifugal force causes particles to collect in the upper part and outside of the chamber. Centrifuge 1000 can operate in a semi-continuous manner to discharge the concentrate. Centrifuged material discharge is typically as described in the reference... Figure 4 The cell concentrate discharge operates similarly, wherein the cell concentrate is collected near the upper outer wall of the separation chamber 1550 and enters the concentrate discharge pump chamber 4400 via a hole 4540 near the upper outer wall of the separation chamber 1550.

[0096] Sensors (including, but not limited to, vibration sensor systems, such as those described in U.S. Patent No. 9,427,748, which is incorporated herein by reference in its entirety) can be used to monitor the supply rate and rotational angular velocity of the suspension. Such a sensor system allows the centrifuge to be filled at a lower rate until the sensor arrangement indicates that the centrifuge is nearly full, and then the supply rate and angular velocity are appropriately adjusted in response to this information. Typically, once the centrifuge is nearly full, the supply rate is reduced or stopped, and the angular velocity is increased to increase the settling velocity, and this cycle is repeated once settling and discharge are substantially complete. If the additional features described herein are used to optimize the system to reduce the need for process interruptions, the system can be operated continuously or nearly continuously at the angular velocity required for settling.

[0097] In the case of semi-continuous concentrate discharge, a concentrate pump 4400, operating intermittently to remove concentrate, continuously supplies the suspension to the centrifuge 1000. The operation of the concentrate pump 4400 can be controlled by an optical sensor in the concentrate discharge line, indicating the presence or absence of discharged concentrate. Instead of the concentrate pump 4400, a controller and sensors can be used to electronically manage the discharge cycle, determining when to open and close valves for most efficient treatment of the fluid suspension.

[0098] The average discharge rate can be further controlled by using a centrifuge 1000 with an adjustable gap between scraper discs 4410 and 1410. It should be noted that it may be desirable or necessary for only one set of scraper discs 4410 and 1410 to be adjustable. The gap between scraper discs 4410 and 1410 (which forms part of the fluid passage exiting the centrifuge 1000) can be opened to allow flow or closed to cut off flow, thus acting as an internal valve. It may also be useful to widen or narrow the gap 4415 between scraper discs 4410 and 1410 depending on the desired product or the characteristics of the product. Changing the gap affects the pumping and shearing rates associated with the scraper discs.

[0099] It can be used Figures 4 to 13 Several features of the exemplary arrangement shown further control the rate at which concentrate and centrifugal filter media are removed from centrifuge 1000, as well as the viability of the removed concentrate. Accelerator vanes 4630, similar to those in centrifugal filter media pump chamber 1420, can be added to concentrate pump chamber 4420. The addition of accelerator vanes 4630 increases the rate at which concentrate can be removed by overcoming some of the deceleration caused by friction between the moving concentrate and scraper disc 4410. In addition to the accelerator vanes 4630 in the upper surface of pump chamber 4420, such vanes 4630 can also be added to the lower surface of pump chamber 4420 to increase its effectiveness. Another feature could be replacing the holes 1540, 4540 with slits, which minimizes shear on the material entering pump chambers 1420, 4420.

[0100] If the viability of the concentrate is important, a rotatable scraper disc 4410 may be included in the pump chamber 4420, which reduces the shear force applied to the concentrate when it contacts the surface of the scraper disc 4410. The rotational rate of the scraper disc 4410 can be adjusted to a rate between a fixed value and the rotational rate of the separation chamber 1550 to balance the concentrate viability and discharge rate. The desired angular velocity can be controlled by a variety of mechanisms known to those skilled in the art. One example of a control device is an external slip clutch, which allows the scraper disc to rotate at an angular velocity that is a fraction of the centrifuge's angular velocity. The use of slip clutches is well known to those skilled in the art. Alternatively, there may be other means, different from slip clutches, to adjust the angular velocity, which will be apparent to those skilled in the art.

[0101] The peristaltic pump 2510 can also be used to make the removal of concentrates more efficient and reliable, especially for highly concentrated feed suspensions. Using the peristaltic pump 2510 allows the user to control the flow rate of the concentrate from the centrifuge 1000 more precisely than could possibly rely solely on the centrifugal pump 4400, because the rate of the centrifugal pump is not as easily adjustable as the rate of the peristaltic pump 2510.

[0102] Additionally, to reduce the viscosity of the concentrate, a diluent such as sterile water or a buffer solution can be pumped through the diluent passage 5000 into the concentrate pump chamber 4420 using a diluent pump 5150. A more comprehensive and useful discussion of diluents can be found above. The operating rate of either or both of the peristaltic pump 2510 or the diluent pump 5150 can be controlled by an automatic controller (e.g., discussed later) in response to a concentration sensor 4430 located in the concentrate discharge connection 2500. The controller can be programmed to start, stop, or change the pumping rate for diluent addition and concentrate removal in response to the particle concentration in the concentrate (independently in response to the concentration sensor 4430, in conjunction with a standard feed / discharge cycle, or as a combination).

[0103] Figure 16 An alternative example arrangement of a core for use in conjunction with a centrifuge providing continuous separation processing to produce a continuous supply of concentrate and centrifugal filter media is shown. Core 10, similar to those previously discussed, is configured to be positioned within a rotatable drum of the centrifuge. During processing, the centrifuge drum and the core rotate about axis 12. The apparatus includes a stationary assembly 14 and a rotatable assembly 16.

[0104] As described above, the stationary assembly 14 includes a feed pipe 18. The feed pipe 18 is coaxial with axis 12 and terminates in an opening 20 at the bottom of the separation chamber or cavity 22 adjacent to the core. The stationary assembly also includes a centrifugal filter pump 24, an exemplary arrangement of which, as described in more detail below, includes an inlet 26 and an annular outlet 28. The annular outlet is in fluid connection to the centrifugal filter tube 30. The centrifugal filter tube extends coaxially around the feed pipe 18.

[0105] In this exemplary arrangement, the centrifugal filter centrifugal pump 24 is positioned within the centrifugal filter pump chamber 32. The centrifugal filter pump chamber is defined by a wall that is part of a rotatable assembly, and this wall provides an inlet 26 for the centrifugal filter centrifugal pump to expose the pool of liquid centrifugal filter during operation.

[0106] This exemplary arrangement also includes a concentrate centrifugal pump 34. The concentrate centrifugal pump 34 of this exemplary arrangement may also have a configuration similar to that discussed in detail later. In the exemplary arrangement, the concentrate centrifugal pump 34 includes an inlet 36 located in a wall defining an annular periphery of the centrifugal pump. It should be noted that the concentrate centrifugal pump 34 has a peripheral diameter larger than the peripheral diameter of the centrifugal filter pump. The concentrate pump also includes an annular outlet 38. The annular outlet 38 is in fluid connection to a concentrate outlet pipe 40. The concentrate outlet pipe extends coaxially around the centrifugal filter pipe 30.

[0107] In this exemplary arrangement, the inlet 36 of the centripetal pump for the concentrate is positioned within the concentrate pump chamber 42. The concentrate pump chamber is defined by the wall of the rotatable assembly 16. During operation, the inlet 36 of the centripetal pump for the concentrate is exposed to concentrate within the concentrate pump chamber 42. The concentrate pump chamber 42 is vertically defined by a top 44. At least one fluid seal 46 extends between the outer circumference of the outlet pipe 40 and the top 44. The exemplary seal 46 is configured to reduce the risk of fluid escaping from the interior of the separation chamber and to prevent contaminants from being introduced from the outer region of the core therein.

[0108] During centrifuge operation, the drum and the core, including the chamber or separation chamber, rotate about axis 12 in the rotational direction. Rotation in the rotational direction is operable to separate the cell suspension introduced through feed tube 18 into centrifuged filter material discharged through centrifuge filter tube 30 and concentrate discharged through concentrate outlet tube 40.

[0109] The cell suspension enters separation chamber 22 through a tube opening 20 at the bottom of the separation chamber. The cell suspension moves outward by centrifugal force and multiple accelerator blades 48. As the suspension moves outward through the accelerator blades, centrifugal force acts on the cell suspension material, causing it to move outward toward the annular conical wall 50 that defines the outside of the separation chamber. As shown, the concentrated cell material is pushed outward and upward against the conical wall 50 and through multiple concentrate tanks 52. The concentrated material moves upward past the concentrate tanks and enters the concentrate pump chamber 42, from which the concentrate is discharged by a centripetal concentrate pump 34.

[0110] In the exemplary arrangement, during operation, the cell-free centrifugal filter is positioned close to the vertical annular wall 54 defining the interior of the separation chamber 22. The centrifugal filter material moves upward through centrifugal filter orifices 56 in the annular base structure defining the centrifugal filter pump chamber 32. The upward movement of the centrifugal filter through the centrifugal filter orifices 56 forms a pool of liquid centrifugal filter within the centrifugal filter chamber. The centrifugal filter moves from the centrifugal filter chamber by the operation of the centrifugal filter centrifugal pump 24 and is delivered from the core through the centrifugal filter tube 30.

[0111] exist Figure 16 In an exemplary arrangement, the concentrate pump and the centrifugal filter pump may have generally similar... Figure 17 The structure shown. In Figure 17 The centrifugal filter centrifugal pump 24 is shown in an isometric exploded view. (See image below.) Figure 17 As shown, the exemplary centripetal pump has a disc-shaped body composed of a first plate 58 and a second plate 60. During operation, the first plate and the second plate are held in a releasably engaged relationship via fasteners represented by screws 62. It should be understood, of course, that other constructions and fastening methods may be used in other arrangements.

[0112] In this exemplary arrangement, the second plate 60 includes walls defining three sides of the curved volute channel 64. It should be understood that, although in this exemplary arrangement, the centripetal pump includes a pair of generally opposing volute channels 64, other numbers and configurations of volute channels may be used in other arrangements.

[0113] In this exemplary arrangement, the first and second plates constitute the disc-shaped body of the centrifugal pump, having an annular, vertically extending wall 67 defining an annular periphery 66. An inlet 68 leading to a volute passage 64 extends within the annular periphery. An annular collection chamber 70 extends radially outward from axis 12 within the disc-shaped body and is fluidly connected to the volute passage. The annular collection chamber 70 receives material entering the inlet 68. The annular collection chamber 70 is fluidly connected to an annular outlet coaxial with axis 12. In the exemplary arrangement of the centrifugal filter centrifugal pump, the annular outlet is an annular space extending between the outer wall of the feed pipe 18 and the inner wall of the second plate 60, which is fluidly connected to the centrifugal filter outlet pipe 30.

[0114] In this exemplary arrangement, each volute channel 64 is configured such that the volute channel bends toward the rotational direction of the drum and the separation chamber, the rotational direction being... Figure 17 The arrow R represents this. In this exemplary structure, the vertically extending walls 74 that define the volute channels and face the direction of rotation are all curved in the direction of rotation. The curved construction of the walls 74 that horizontally define the volute channels provides enhanced pumping characteristics for this exemplary arrangement. Furthermore, the opposing defining walls 76 of each volute channel in this exemplary arrangement have similar curved constructions. The curved construction of the vertically extending walls that horizontally define the volute channels provides a constant cross-sectional area for each volute channel from the respective inlet to the collection chamber. This consistent cross-sectional area is further achieved by using a generally flat wall 78 that extends between walls 74 and 76 and vertically defines the volute channel on one side. Furthermore, in this exemplary arrangement, the first plate 58 includes a generally flat circular surface 80 on its side, which faces inward when the plates are assembled to form the disc-shaped body of the centripetal pump. In this exemplary arrangement, surface 80 is used to vertically define the sides of the two volute channels 64 of the centripetal pump.

[0115] Of course, it should be understood that this exemplary arrangement comprising a pair of plates is exemplary, wherein one plate includes a recess having a wall having three of the four sides defining the curved volute channel, and the other plate includes a surface defining the remaining sides of the volute channel. It should be understood that other constructions and structures may be used in other arrangements.

[0116] exist Figure 16 The exemplary centripetal pump structure shown uses a centripetal pump structure and has the ability to move more liquid than a scraper-type centripetal pump of the same size. Furthermore, this exemplary configuration generates less liquid heating than a comparable scraper-type centripetal pump.

[0117] Furthermore, in the exemplary arrangement described above, the annular periphery of the centrifugal filter pump 24 has a smaller outer diameter than the periphery of the concentrate centrifugal pump 34. In this exemplary arrangement, this configuration is used to prevent the centrifugal filter pump from removing excessive liquid from the pool of liquid centrifugal filter formed in the centrifugal filter pump chamber 32. Ensuring sufficient liquid centrifugal filter in the centrifugal filter pump chamber helps ensure that no waves are formed in the centrifugal filter near the inlet of the centrifugal filter pump. Waves formed due to insufficient liquid centrifugal filter can cause vibration of the centrifuge and core, and other undesirable properties.

[0118] The larger annular periphery of the concentrate pump in this exemplary arrangement causes material to preferentially flow out of the core via the concentrate centrifugal pump. In this exemplary arrangement, the concentrate stream downstream of the concentrate output pipe 40 can be controlled to control the ratio of the centrifugal filter stream to the concentrate stream from the core.

[0119] Furthermore, in the exemplary arrangement, the properties and flow characteristics of the centrifuge, utilizing a centrifugal pump with the aforementioned configuration, can be tailored to the requirements of a specific material and the separation process being performed. Specifically, the diameter of the annular periphery of the centrifugal pump can be determined to achieve optimal properties for a particular processing activity. For example, a larger diameter of the centrifugal pump's periphery results in greater flow rate and pressure at the outlet. Additionally, a larger diameter tends to produce greater mixing than a relatively smaller diameter. However, a larger diameter also results in greater heating than a smaller periphery diameter of the centrifugal pump. Therefore, a smaller diameter periphery can be used to achieve less heating. Furthermore, it should be understood that, for the purposes of a specific separation process, flow and pressure properties can be altered as needed by utilizing inlets of different sizes, areas, and numbers, as well as different volute channel configurations.

[0120] Figure 19 An exemplary system is schematically illustrated for helping to maintain positive pressure within a separation chamber, alternatively referred to herein as a cavity, during cell suspension treatment. As discussed in conjunction with the preceding exemplary arrangement, it is generally desirable to maintain a positive pressure above atmospheric pressure within the separation chamber at all times. This reduces the risk of contaminants being introduced into the separation chamber by permeation through one or more fluid seals operatively extending between a fixed component and a rotatable component of the core. Further, as previously stated, it is also generally desirable to maintain air under positive pressure within the separation chamber in contact with the inner surface of the fluid seals. The presence of cavitation adjacent to the seals prevents the seals from contacting the material being treated and further helps to reduce the risk of contaminants being introduced into the treated material and any material escaping from the separation chamber.

[0121] Combination Figure 19 The exemplary system described is used to maintain a consistent positive pressure in the separation chamber and to reduce the risk of contaminant introduction and escape of the processed material.

[0122] like Figure 19 As schematically shown, the centrifuge includes a rotatable drum 82. The centrifuge drum can be rotated about axis 84 by a motor 86 or other suitable rotating device.

[0123] The exemplary centrifuge structure shown includes a rotatable, single-use core 88 that defines a cavity 90, which is referred to herein alternatively as a separation chamber.

[0124] Similar to other arrangements described above, the exemplary core includes a fixing assembly comprising a suspension inlet feed pipe 92 having an inlet 94 located near the bottom region of the cavity. The fixing assembly also includes at least one centrifugal pump 96. The centrifugal pump of this exemplary arrangement comprises a disc-shaped body having at least one pump inlet 98 adjacent to its periphery and a pump outlet 100 adjacent to the center of the centrifugal pump. The pump outlet is fluidly connected to a centrifugal filter outlet pipe 102. The centrifugal filter outlet pipe extends in a coaxial relationship with the suspension inlet pipe, similar to the previously discussed manner. A rotatable top 104 containing the fluid separation chamber is operatively connected to at least one seal 106, which operates to fluidly seal the cavity of the core relative to the inlet and outlet pipes. The at least one seal 106 extends in a sealing relationship between the outer annular surface of the fixed centrifugal filter outlet pipe 102 and the rotatable top 104 of the core, the rotatable top having an upper inner wall that, as shown, internally defines the cavity 90.

[0125] In this exemplary arrangement, inlet pipe 92 is fluidly connected to pump 108. In one exemplary arrangement, pump 108 is a peristaltic pump that effectively pumps the cell suspension without damaging it. It should be understood, of course, that this type of pump is exemplary and other types of pumps can be used in other arrangements. Furthermore, in this exemplary arrangement, pump 108 is reversible. This allows pump 108 to function as a feed pump, enabling the cell suspension to be pumped from inlet line 110 into the inlet pipe at a controlled rate. Additionally, in this exemplary arrangement, pump 108 can be operated as a concentrate removal or discharge pump after the cell concentrate has been separated by centrifugation. In performing this function, pump 108 operates to pump the cell concentrate out of the separation chamber by reversing the flow of material in inlet pipe 92 from the flow that supplied the cell suspension into the separation chamber. The cell concentrate is then pumped to concentrate line 112. Figure 19 As shown, inlet line 110 and concentrate line 112 can be selectively opened and closed via valves 114 and 116, respectively. In this exemplary arrangement, valves 114 and 116 include pinch valves that open and close via flow through flexible lines or pipes. It should be understood, of course, that this method is exemplary and other methods may be used in other arrangements.

[0126] In this exemplary system, the centrifugal filter outlet pipe 102 is fluidly connected to the centrifugal filter discharge line 118. The centrifugal filter discharge line is fluidly connected to the centrifugal filter discharge pump 120. In this exemplary arrangement, the centrifugal filter discharge pump 120 is a variable flow pump, which can selectively adjust its flow rate. For example, in some exemplary arrangements, pump 120 may include a peristaltic pump, which includes a motor whose speed can be controlled to selectively increase or decrease the flow rate through the pump. The outlet of the centrifugal filter discharge pump delivers the processed centrifugal filter to a suitable collection chamber or other processing device.

[0127] exist Figure 19 In the exemplary arrangement schematically shown, a pressure damping reservoir 122 is fluidly connected to a centrifugal filter discharge line 118, which is fluidly located between the centrifugal filter outlet line 102 and the pump 120. In this exemplary arrangement, the pressure damping reservoir includes a generally vertically extending container having an internal region configured to contain liquid centrifugal filter material in a fluid-tight relationship. The pressure damping reservoir includes a bottom port 124 fluidly connected to the centrifugal filter discharge line 118.

[0128] On the opposite side of reservoir 122 is a top port 126. The top port is exposed to air pressure. In this exemplary arrangement, the top port is exposed to air pressure from a high-pressure source, schematically indicated as 128. In this exemplary arrangement, the high-pressure source may include a compressor, an air reservoir, or other suitable means for providing a high-pressure source above atmospheric pressure within the range required for system operation. Air from high-pressure source 128 passes through a sterile filter 130 to remove impurities. Regulator 132 is operable to maintain a substantially constant air pressure level above atmospheric pressure at the top port of the pressure-damped reservoir. In this exemplary arrangement, the pressure regulator includes an electronically fast-acting regulator to help ensure that the air pressure is maintained at a substantially constant level. The exemplary fast-acting regulator 132 operates to rapidly increase the pressure acting on top port 126 when the pressure drops below the desired level and to rapidly decrease the pressure by means of the regulator when the pressure acting on the top port exceeds a regulator setpoint.

[0129] In some arrangements, the regulator outlet may also be operatively fluidly connected to the interior of the top 104 of the separation chamber via an air line 143, schematically shown in dashed lines. In this exemplary arrangement, the regulator outlet pressure acting on the top port 126 of the reservoir also acts via the air line 143 on a cavitation inside the separation chamber, which extends downward to the level of the cavity above the centrifugal pump inlet and inside at least one seal 106, and radially from a region adjacent to axis 84 to the upper inner wall on the inner side of the top 104. In this exemplary arrangement, the line 143 applies positive pressure to a region within the separation chamber located below the at least one seal via at least one isolation channel extending through a fixed structure comprising an assembly including the centrifugal filter outlet pipe 102 and the inlet feed pipe 92. This at least one exemplary isolation channel of the air line 143 applies air pressure to the interior of the top 104 via at least one air opening 145 leading to the separation chamber. An exemplary at least one opening 145 is located on the outer side of the outer surface of the outlet pipe 102, above the inlet 98 of the centrifugal pump and below at least one seal 106. It should be understood, of course, that this described structure for the exemplary air line providing positive air pressure to the separation chamber and the cavitation on the inner side of the at least one seal, and that other structures and methods may be used in other arrangements.

[0130] In an exemplary arrangement of the pressure-damped reservoir 122, an upper level sensor 134 is configured to sense the liquid centrifuge filter material inside the pressure-damped reservoir. The upper level sensor is operable to sense the liquid at an upper level. A lower level sensor 136 is positioned to sense the liquid at a lower level in the reservoir. A high level sensor 138 is positioned to detect a high level in the reservoir above the upper level. The high level sensor is positioned to sense an unacceptably high level to indicate an abnormal condition that may require system shutdown or other appropriate safety measures. In this exemplary arrangement, level sensors 134, 136, and 138 include capacitive proximity sensors adapted to sense the level of the liquid centrifuge filter material adjacent to them within the pressure-damped reservoir. It should be understood, of course, that these types of sensors are exemplary, and other sensors and methods may be used in other arrangements.

[0131] This exemplary arrangement also includes other components, provided they are suitable for the operation of the system. This may include additional valves, lines, pressure connections, or other suitable components to perform the processing and handling of suspensions, centrifuged filters, and concentrates as required by the specific system. Additional valves, such as valve 140 schematically shown, may be included to control the opening and closing of the centrifuged filter discharge line 118. The included additional lines, valves, connections, or other items may vary depending on the nature of the system.

[0132] Figure 19 The exemplary system also includes at least one control circuit 142, which may alternatively be referred to as a controller. The exemplary at least one control circuit 142 includes one or more processors 144. The processors are operatively connected to one or more data memories, schematically represented as 146. As used herein, a processor means any electronic device configured to operate via processor-executable instructions to process data stored in or received from the one or more data memories or from an external source, parse information, and provide outputs that can be used to control other devices or perform other actions. The one or more control circuits may be implemented as hardware circuitry, software, firmware, or an application program operable to enable the control circuitry to receive, store, or process data and perform other actions. For example, the control circuitry may include one or more of a microprocessor, CPU, FPGA, ASIC, or other integrated circuit or other type of circuitry capable of performing functions in a manner consistent with an electronic computing device. Furthermore, it should be understood that data memory may correspond to one or more volatile or non-volatile memory devices such as RAM, flash memory, hard disk drives, solid-state devices, CDs, DVDs, optical storage, magnetic storage, or other circuit-readable media or media on which computer-executable instructions and / or data may be stored.

[0133] The executable instructions of the circuit can include instructions in any of a variety of programming languages ​​and formats, including but not limited to routines, subroutines, programs, threads of execution, objects, scripts, methods, and functions that perform actions such as those described herein. The structure of the control circuit can include, correspond to, and utilize the principles described in Ramesh S. Gaonker's textbook entitled "Microprocessor Architecture, Programming, and Applications of the 8085 Model" (Prentice Hall, 2002), which is incorporated herein by reference in its entirety. It should be understood, of course, that these control circuit structures are exemplary, and other circuit structures for storing, processing, parsing, and outputting information can be used in other arrangements.

[0134] In this exemplary arrangement, the at least one control circuit 142 is operatively connected to at least one sensor (e.g., sensors 134, 136, and 138) via a suitable interface. The at least one control circuit is also operatively connected to a variable flow rate discharge pump 120. Furthermore, in some exemplary arrangements, the at least one control circuit may also be operatively connected to other devices, such as a motor 86, a pump 108, a regulator 132, a pneumatic pressure source 128, a fluid control valve, and other devices.

[0135] At least one exemplary control circuit is operable to receive data and control these devices according to circuit-executable instructions stored in data memory 146. In this exemplary arrangement, the fluid level 147 in the fluid damping reservoir is a property corresponding to the pressure in the centrifugal filter discharge pipe 102. In an exemplary implementation that does not utilize the air line 143, the fact that the pressure in the centrifugal filter discharge pipe indicates the pressure in the top 104 of the core and the pressure in the separation chamber adjacent to the seal 106 is used to control the operation of the discharge pump and other components. As previously stated, it is desirable to maintain a positive pressure above atmospheric pressure in the separation chamber and cavitation adjacent to the at least one seal to avoid the introduction of contaminants into the separation chamber that could be caused by negative pressure. However, if the fluid level in the separation chamber becomes too high, the pressure and the suspended material being processed may overflow the seal, which could lead to potential contamination and undesirable exposure, as well as loss of processed material. This could be due to excessive back pressure on the centrifugal filter line connected to the outlet of the centrifugal pump.

[0136] In this exemplary arrangement, the drum speed generates a corresponding pumping force and a centrifugal pump output pressure level. This centrifugal pump output pressure level varies with the rotational speed of the drum and the core. An exemplary arrangement without air line 143 provides controlled back pressure at the centrifugal filter outlet. Back pressure is provided by controlling the speed of the motor operating pump 120 and the liquid level 147 in the pressure damping reservoir. The back pressure is maintained below the pump output pressure level (allowing the centrifugal pump to deliver the centrifugal filter out of the separation chamber), but maintained at a positive pressure above atmospheric pressure to ensure that contaminants do not seep into the separation chamber through the seal, and to maintain elevated air pressure inside the separation chamber adjacent to the seal to isolate the seal from the components of the suspension being processed.

[0137] In this exemplary arrangement, the increased pressure applied to the top port 126 of the pressure-damped reservoir is maintained by a regulator 132. Furthermore, the speed of the pump 120 is controlled by at least one control circuit 142 to maintain the liquid level 147 between the upper and lower liquid levels 136 sensed by the sensor 134, controlling the flow of centrifugal filter material leaving the separation chamber so that the pressure in the top region of the separation chamber remains at a desired constant value, and the centrifugal filter material does not contact or overflow the seals.

[0138] In the alternative arrangement using air line 143, the positive pressure level of the regulator acts on the fluid in reservoir 122 and on the area of ​​the separation chamber above the centrifugal pump inlet. Because the positive pressure level of the air applied at both locations is the same, the back pressure on the centrifugal filter discharge line (which is the pressure applied above the fluid in the reservoir) is virtually always the same as the pressure in the cavitation at the top of the separation chamber. This allows the centrifugal pump to operate without any net effect from either pressure.

[0139] In this exemplary arrangement, the pump 120 and other system components are controlled in response to the at least one control circuit 142 to ensure that a sufficient volume of air is always present inside the reservoir 122 during centrifugal filter production. This ensures that the reservoir provides the desired damping effect against changes in the centrifugal filter discharge line pressure that might otherwise be caused by the pumping action of the pump 120. This is achieved by maintaining the liquid in the reservoir 122 at no higher than the upper liquid level detected by the sensor 134. Furthermore, the liquid level in the reservoir is controlled to remain above the lower liquid level sensed by the sensor 136. This ensures that the centrifugal pump does not pump air and permeate the centrifugal filter.

[0140] In this exemplary arrangement, the flow of centrifuged filter material leaving the separation chamber is controlled by the operation of the at least one control circuit. This exemplary control circuit can operate during processing conditions to maintain the flow of cell suspension entering the separation chamber 90 at a substantially constant rate via pump 108, while the separation process occurs with motor 86 operating to maintain a constant drum speed to achieve the separation of the centrifuged filter material and cell concentrate. The exemplary arrangement also operates to maintain an ideal constant back pressure from the centrifugal pump on the centrifuged filter material discharge line, while keeping the air in the separation chamber above the level of the lower side of the cavitation, so that the at least one seal 106 is isolated from the centrifuged filter material and concentrate material being processed.

[0141] In one exemplary arrangement, the pressure maintained in the pressure-damped reservoir by the operation of the regulator is set to approximately 2 kPa (0.29 psi) above atmospheric pressure. In this exemplary system, this pressure has been found suitable for ensuring the integrity of the seal and isolation throughout all stages of cell suspension processing. Of course, it should be understood that this value is exemplary, and other pressure values ​​and pressure-damped reservoir constructions, sensors, and other features may be utilized in other arrangements.

[0142] Figure 20 An exemplary logic executed by the operation of the at least one control circuit 142 is schematically illustrated, relating to maintaining a desired pressure level in the centrifuge filter discharge tube and at the top of the separation chamber. It should be understood that in some exemplary arrangements, the control circuit may perform many additional or different functions besides those shown. In addition to the pressure control function, these functions may include overall control of different processes and steps for centrifuge operation. Figure 20As shown, in the initial subroutine step 148, the at least one control circuit 142 is operable to determine whether the centrifuge operation is currently in a mode where centrifuged filter media is being discharged from the separation chamber. If so, the at least one control circuit is operable to cause the centrifuged filter media discharge pump 120 to operate to discharge the delivered centrifuged filter media through the centrifuged filter media discharge line 118. This can be accomplished by operating the pump motor. In this exemplary arrangement, the flow rate of pump 120 may initially be a set value, or alternatively, it may vary depending on specific operating conditions determined by the operation of the control circuit during this process. The operation of the centrifuged filter media discharge pump is represented by step 150.

[0143] Then, in step 152, the at least one control circuitry is operable to determine whether liquid is sensed at a high level on the high level sensor 138. If so, this represents an undesirable condition. If liquid is sensed at the level on sensor 138, the control circuitry operates to take measures to address the condition. This may include operating pump 120 to increase its flow rate, and making a further determination if the level drops during a period of continued centrifuge operation. Alternatively or additionally, the at least one control circuitry may reduce the speed of pump 108 to reduce the flow of material into it. If this action does not cause the level to drop within a set time period, additional steps are taken. These steps may also include slowing down or stopping the rotation of drum 182. These actions may also include stopping the operation of pump 108 to avoid introducing more suspension material into the separation chamber. These steps, generally referred to as shutting down normal system operation, are represented by step 154.

[0144] If no liquid is sensed at the high level sensor 138, the at least one control circuit can then operate to determine whether liquid is sensed at the upper level sensor 134. This is indicated by step 156. If liquid is sensed at the upper level sensor, the at least one circuit operates in response to its stored instructions to increase the speed of the discharge pump 120 and thus increase its flow rate. In an exemplary arrangement, this is achieved by increasing the speed of a motor that is part of the pump. This is indicated by step 158. Increasing the pump's flow rate causes the liquid level 147 in the pressure-damped reservoir to begin to drop as the pump 120 moves more liquid.

[0145] If no liquid is sensed at the upper level of sensor 134 in step 156, the at least one control circuit then operates to determine whether no liquid is sensed at the lower level of sensor 136. This is indicated by step 160. If the liquid level is not at the level of sensor 136, the control circuit operates according to its programmed instructions to control pump 120 to reduce its flow rate. In one exemplary arrangement, this is achieved by slowing down the speed of the motor. This is indicated by step 162. In this exemplary arrangement, slowing down the flow rate of pump 120 causes the liquid level 147 to begin to rise in the pressure-damped reservoir. In some exemplary arrangements, if the liquid level in the reservoir does not rise within a given time, the control circuit can operate according to its programmed instructions to cause additional actions, such as actions associated with the previously discussed shutdown step 154. The control circuitry of the exemplary arrangement can operate to change the pumping rate of pump 120, thereby maintaining the liquid level 147 in the pressure-damped reservoir at a substantially constant level between the liquid levels of sensors 134 and 136 during centrifugal filter production.

[0146] In this exemplary arrangement, maintaining a substantially constant elevated pressure of sterile air above the liquid in the pressure-damped reservoir helps ensure a similar elevated pressure is consistently maintained in the centrifugal filter outlet line and at the seal within the separation chamber. Furthermore, this exemplary arrangement allows for pressure control at a desired level during different operating conditions of the centrifuge, in which the drum rotates at different speeds. This includes, for example, conditions during which the separation chamber is initially filled at a relatively high rate by introducing a cell suspension, and during which the centrifuge rotates at a relatively low speed. Pressure can also be maintained during subsequent final filling conditions, where the flow rate of the cell suspension into the separation chamber occurs at a slower rate, and during this period the drum rotation speed increases to a higher rotation speed. Additionally, positive pressure is maintained as previously discussed during the supply of suspension to the drum and during the discharge of centrifugal filter from the separation chamber. Furthermore, in this exemplary arrangement, the at least one control circuitry can be operated to also maintain positive pressure during the period when the concentrate is removed by pumping it out of the separation chamber. Maintaining positive pressure in the separation chamber during all these conditions reduces the risk of contamination and other undesirable conditions that might otherwise arise due to negative pressure (below atmospheric pressure) conditions.

[0147] Of course, it should be understood that the features, components, structures, and control methods are exemplary, and other methods may be used in other arrangements. Furthermore, although this exemplary arrangement includes a system operating in a batch mode rather than a mode in which both centrifuged filter media and concentrate are processed continuously, its principles can also be applied to other types of such systems.

[0148] While pressure-damped reservoirs are used in the exemplary arrangement to help ensure desired pressure levels are maintained in the outlet pipe and separation chamber, other methods may be employed in other exemplary arrangements. For example, in some arrangements, pressure may be sensed and / or applied directly in the outlet pipe, in the separation chamber, or at other locations corresponding to the pressure in the separation chamber. In some arrangements, the flow rate of the discharge pump may be controlled to maintain an appropriate pressure level. In other arrangements, exemplary control circuitry may operate to control the discharge pump and pumps supplying the suspension to the core, and / or suitable valves or other flow control devices, to maintain an appropriate pressure level. Such alternative methods may be necessary depending on the specific centrifuge apparatus used and the type of material being processed.

[0149] Figure 21 An alternative centrifuge system 170 is schematically shown, specifically configured to continuously or semi-continuously separate cells from a batch of cell cultures into cell centrifuge filtrate and cell concentrate. This exemplary system illustrates a rigid centrifuge drum 172 rotatable about axis 174. The drum includes a cavity 176 configured to releasably receive a single-use structure 178 therein. The rigid drum includes an upper opening 180. An annular retaining ring or other securing structure, schematically shown as 182, enables the single-use structure 178 to be releasably secured within the drum cavity.

[0150] This exemplary single-use structure 178 includes a feed tube 184 extending axially from a center. As discussed later, the feed tube is used to deliver batches of cell culture material into an internal region 186 of the single-use structure 178. The feed tube 184 extends from an upper portion at a first axial end 188 of the single-use device to an opening 190 in the internal region at a lower portion at a second axial end 192. The single-use structure 178 includes a generally disc-shaped portion 194 adjacent to the first axial end. The exemplary disc-shaped portion 194 is generally rigid, meaning it is rigid or semi-rigid, and includes an annular outer periphery 196. This annular outer periphery is configured to engage an upper annular defining wall 198 of a centrifuge drum cavity 176. The annular outer periphery of the disc-shaped portion 194 is configured to engage a rigid drum 172 such that the single-use structure rotates with it.

[0151] The exemplary single-use structure 178 also includes a hollow, rigid or at least semi-rigid cylindrical core 200. The core 200 is operatively engaged with and rotatable with the disc-shaped portion 194. The core 200 is axially aligned with the disc-shaped portion and extends axially between the upper and lower portions of the single-use structure. The core 200 includes an upper opening 202 and a lower opening 204 through which a feed tube 184 extends.

[0152] The disc-shaped portion 194 includes a substantially circular centrifugal filter centrifugal pump chamber 206. A centrifugal filter centrifugal pump 208 is positioned within the pump chamber 206. A substantially annular centrifugal filter opening 210 is fluidly connected to the centrifugal filter pump chamber 206. "Substantially annular" means that the opening can consist of discrete openings and / or continuous openings arranged in annular order. The centrifugal filter centrifugal pump 208 is fluidly connected to a centrifugal filter discharge pipe 212. The centrifugal filter discharge pipe 212 extends coaxially around the feed pipe 184. The discharged centrifugal filter passes through the substantially annular opening around the periphery of the centrifugal filter centrifugal pump and through an annular space in the centrifugal filter discharge pipe 212 located outside the feed pipe.

[0153] The disc-shaped portion 194 also includes a concentrate centrifugal pump chamber 214. The concentrate centrifugal pump chamber 214 is a generally circular chamber positioned above the centrifugal filter centrifugal pump chamber 206. The concentrate centrifugal pump chamber 214 has a concentrate centrifugal pump 216 positioned therein. The concentrate centrifugal pump is in fluid connection with a concentrate discharge pipe 220. The concentrate discharge pipe 220 extends annularly around the centrifugal filter discharge pipe 212. The concentrate passes through a generally annular opening at the periphery of the concentrate centrifugal pump and through an annular space in the concentrate discharge pipe 220 located outside the centrifugal filter discharge pipe.

[0154] The substantially annular concentrate opening 218 is fluidly connected to the concentrate pump chamber 214. In this exemplary arrangement, the substantially annular concentrate opening and the substantially annular centrifugal filter opening are concentric coaxial openings, with the concentrate opening radially positioned outside the centrifugal filter opening. Of course, this arrangement is exemplary, and other methods and constructions may be used in other arrangements.

[0155] The exemplary single-use structure 178 also includes a flexible outer wall 222. The flexible outer wall 222 is a fluid-tight wall that, in the operating position of the exemplary single-use structure 178, extends in a manner that engages with a wall operatively supporting a rigid drum cavity 176. In this exemplary arrangement, the flexible outer wall 222 is operatively engaged with the disc-shaped portion 194 in a fluid-tight connection. The flexible outer wall has an inner frustoconical shape having a smaller inner radius adjacent to the lower portion of the single-use structure, which is adjacent to the second axial end portion 192.

[0156] An exemplary flexible outer wall 222 extends around at least a portion of the core 200. The wall 222 also defines an annular separation chamber 224. The separation chamber 224 extends radially between the outer wall of the core 200 and the flexible outer wall 222. A substantially annular concentrate opening 218 and a substantially annular centrifugal filter opening 210 are each in fluid communication with the separation chamber 224.

[0157] In this exemplary arrangement, the flexible outer wall 222 has a textured outer surface 226. This textured outer surface is configured to allow air to escape from the space between the surface defining the cavity of the rigid drum 172 and the flexible outer wall 222. In one exemplary arrangement, the textured outer surface may comprise substantially the entire area of ​​the flexible outer wall in contact with the rigid drum. In another exemplary arrangement, the textured outer surface may include a pattern of one or more outwardly extending protrusions or recesses 228, spaced or recessed between these protrusions or recesses to allow air passage. When the single-use structure 178 is positioned in the drum cavity 176, air can escape from therethrough through the upper opening 180 or through the lower opening 230. In this exemplary arrangement, the protrusion may be made of an elastically deformable material that can decrease in height in response to the force of the liner abutting against the rigid wall of the drum. The textured outer surface 226 of the flexible outer wall 222 reduces the risk of air cavitation being trapped between the rigid drum of the centrifuge and the single-use structure. Such cavitation can lead to irregularities in the wall profile, which may result in imbalance and / or alter the profile of the separation chamber in a way that adversely affects the separation process. It should be understood, of course, that the described air release structure is exemplary and that other arrangements of other air release structures may be used.

[0158] Figure 21 The exemplary single-use structure shown also includes a rigid or semi-rigid lower disc-shaped portion 232. The rigid or semi-rigid material operates during operation to maintain its shape. In this exemplary arrangement, the lower disc-shaped portion 232 has a tapered shape and is operatively attached to the lower end of the core 200 via a vertically extending wall or other structure. A plurality of angledly spaced fluid channels 234 extend between the upper surface of the disc-shaped portion 232 and the radially outward lower portion of the core. The fluid channels 232 extend radially outward and upward relative to the bottom of the second axial end 192, allowing cells in a batch of cell culture material entering the inner region 186 through an opening 190 in the feed tube 184 to enter the separation chamber 224 radially outward and upward.

[0159] In this exemplary arrangement, the flexible outer wall 222 extends below the lower disc-shaped portion 232 at the second axial end 192 of the single-use structure. The flexible outer wall 222 extends between the lower disc-shaped portion 232 and the wall surface of the rigid drum 172, which defines the cavity in which the single-use structure is located.

[0160] In this exemplary arrangement, the feed pipe 184, centrifuge filter discharge pipe 212, and concentrate discharge pipe 220, as well as the centrifuge filter centrifugal pump 208 and the concentrate centrifugal pump 216, remain fixed, while the centrifuge drum 172 and the upper disc portion 194, the lower disc portion 232, and the flexible outer wall 222 rotate relative to the drum. At least one annular resilient seal 236 extends operatively between the outer surface of the concentrate discharge pipe 220 and the upper disc portion 194 in a sealing engagement. This at least one seal 236 maintains an airtight seal in a manner similar to that discussed above, such that cavitation can be retained in the internal region 186 during cell processing to isolate the seal from the batch of cell culture material being processed. The cavitation retained in the internal region of the single-use structure is configured such that the centrifuge filter centrifugal pump 208 and the concentrate centrifugal pump 216 remain in fluid communication with the batch of cell culture material. In a manner similar to those previously discussed, positive pressure can be maintained within the internal region to ensure cavitation, thereby adequately isolating the at least one seal 236 from the cell culture batch material being processed. Alternatively, other methods can be used to maintain isolation between the seal and the material being processed.

[0161] The exemplary system 170 operates in a manner similar to that previously discussed. Cells from a batch of cell culture material are introduced into the inner region 186 of the single-use structure 178 via a feed tube 184. Cells enter the inner region 186 through a feed tube opening 190 at the lower axial end of the single-use structure. Centrifugal force causes the cells to move outward through opening 234 and into the separation chamber 224. The outward and upward tapered outer wall 222 causes cells, or cell material containing cell concentrates, to be collected near the radially outward and upper region of the separation chamber 224. Typically cell-free centrifuged filtrate is collected in the separation chamber, radially inward adjacent to the outer wall of the core 200.

[0162] In this exemplary arrangement, the cell centrifuged filter material enters upward through a substantially annular centrifuged filter material opening into the centrifuged filter material pump chamber. The centrifuged filter material then flows inward through a substantially annular opening of the centrifuged filter material centrifugal pump and upward through the centrifuged filter material discharge pipe 212. Simultaneously, the cell concentrate flows inward through a substantially annular concentrate opening 218 and into the concentrate centrifugal pump chamber 214. The cell concentrate flows inward through a substantially annular opening of the concentrate centrifugal pump 216 and upward through the concentrate discharge pipe 220. This exemplary configuration allows the exemplary system 170 to operate on a continuous or semi-continuous basis. The operation of the system 170 can be controlled in a manner similar to that discussed later to facilitate reliable extended operation of the system and delivery of desired cell concentrate and typically cell-free centrifuged filter material in separate output fluid flows.

[0163] Figure 22An alternative centrifuge system, generally designated 238, is shown. System 238 has a single-use configuration 240. The single-use configuration 240 is similar in most respects to the aforementioned single-use configuration 178. Some structures and features of the single-use configuration 240 that are substantially the same as those described in conjunction with the single-use configuration 178 are labeled with the same reference numerals as those used to describe the single-use configuration 178.

[0164] The single-use structure 240 differs from the single-use structure 178 in that it includes a rigid or semi-rigid lower disc-shaped portion 242. The lower disc-shaped portion 242 is a generally tapered structure operatively connected to the lower end of the core 200. A plurality of radially outward and upward-extending fluid channels 244 extend between the lower end of the core 200 and the lower disc-shaped portion 242. The exemplary lower disc-shaped portion 242 also includes a plurality of radially extending blades 246 spaced at an angle. The fluid channels extend radially outward between pairs of blades 246 adjacent at each angle. In this exemplary arrangement, the blades 246 extend upward from the bottom of the disc-shaped portion 242, and at least some of the blades are operatively engaged with the core at their radially outer portion. In this exemplary arrangement, the blades 246 accelerate cell culture batches to facilitate movement and separation within the internal region of the single-use structure.

[0165] Figure 23 An alternative exemplary arrangement of centrifuge system 248 is shown. This exemplary arrangement includes a single-use structure 250. The single-use structure 250 is similar in many respects to the previously described single-use structure 178. Some structures and features similar to those in the aforementioned single-use structure 178 are labeled with the same reference numerals on the single-use structure 250.

[0166] The exemplary single-use structure 250 differs from single-use structure 178 in that it includes a lower disc-shaped portion 252. The lower disc-shaped portion 252 is a rigid or semi-rigid conical structure operatively attached to the core 200 via a wall portion or other suitable structure. The lower disc-shaped portion 252 includes a plurality of radially outwardly extending accelerator blades 254 spaced at an angle. The accelerator blades 254 extend downward from the lower conical side of the disc-shaped portion 252. Pairs of blades 254 adjacent at each angle have a fluid channel extending therebetween. In this exemplary arrangement, a flexible outer wall 222 extends in an intermediate relationship between the lower ends of the blades 254 and the wall of the rigid drum 172 defining the cavity 176. This exemplary configuration provides an immersion accelerator operable to accelerate batches of cell culture material, thereby facilitating their separation within the internal region of the single-use structure. Of course, it should be understood that the single-use structural features described herein can be arranged and combined in different ways to facilitate the separation of different types of materials and substances with different properties and to achieve the desired output fluid flow.

[0167] Figure 26 An alternative single-use structure 304 is shown. Single-use structure 304 is similar to the previously described single-use structure 178, except as otherwise mentioned herein. The same elements as those in single-use structure 178 are present in… Figure 26 The same reference numerals are already used in the figures.

[0168] The single-use structure 304 includes a continuous annular concentrate dam 306. The concentrate dam 306 extends downward in the separation chamber 224 and is radially disposed inside the substantially annular concentrate opening 218. An exemplary annular concentrate dam shown in cross-section extends downward below the concentrate opening, and an exemplary annular concentrate dam shown in axial section includes a tapered outer surface 308 extending outward and toward the opening 218.

[0169] The single-use structure 304 also includes a continuous annular centrifugal filter dam 310. The centrifugal filter dam 310 extends downward within the separation chamber 224 below the substantially annular centrifugal filter opening 210. The centrifugal filter dam 310 is disposed radially outward from the centrifugal filter opening 210. In this exemplary arrangement, the downward distances of the concentrate dam 306 and the centrifugal filter dam 310 extending within the separation chamber 224 are substantially the same. However, in other exemplary arrangements, other configurations may be used. Similarly, in other exemplary arrangements, the centrifuge structure may include either a concentrate dam or a centrifugal filter dam, but not both.

[0170] An annular recess 312 extends radially within the separation chamber between the centrifugal filter dam and the concentrate dam. This exemplary annular recess extends upward between the centrifugal filter dam and the concentrate dam to form an annular cavitation therebetween.

[0171] In the exemplary arrangement, the concentrate dam 306 helps ensure that the primary cellular material or other solid material to be separated can pass outward along the upper part of the defining separation chamber 224 to reach the concentrate opening 218 and the concentrate centrifugal pump chamber 214. The centrifugal filter dam 310 also helps ensure that the primary cell-free centrifugal filter material can pass along the upper surface of the defining separation chamber 224 and enter the substantially annular centrifugal filter opening 210 to reach the centrifugal filter pump chamber 206. It should be understood that various different configurations of the concentrate dam and centrifugal filter dam may be used in different example arrangements, depending on the nature of the material being processed and the requirements for processing such material.

[0172] Figure 24This is a schematic diagram of an exemplary control system for providing a generally continuous process of cell culture material to produce a typically cell-free centrifugal filter stream and a concentrated cell stream. In this exemplary arrangement, the centrifuge system 170 previously discussed is shown. However, it should be understood that these exemplary system features can be used with many different types of materials and centrifuge systems and structures, such as those discussed herein.

[0173] In the illustrated exemplary arrangement, the centrifuge drum 172 is rotated at a selected speed about axis 174 by a motor 256. A feed line 184 is operatively connected to a cell culture feed line 258 through which batches of cell culture material are received. The feed line is operatively connected to a feed pump 260. In the exemplary arrangement, the feed pump 260 may be a peristaltic pump or other suitable pump for delivering cell cultures at a selected flow rate into a single-use configuration.

[0174] Centrifugal filter discharge tube 212 is fluidly connected to centrifugal filter discharge line 262. A centrifugal filter optical density sensor 264 is operatively connected to an internal region of the centrifugal filter discharge line 262. In this exemplary arrangement, the centrifugal filter optical density sensor is an optical sensor operable to determine the density of cells currently passing through the centrifugal filter from a single-use structure. In this exemplary arrangement, this is achieved by measuring a decrease in the intensity of light emitted by an emitter, which is received by a receiver positioned from the emitter and has at least a portion of the centrifugal filter stream passing between them. The amount of light received by the receiver from the emitter decreases as the density of cells in the centrifugal filter increases. Of course, this is only one example of a sensor that can be used to determine the density or amount of cells present in the centrifugal filter, and other types of sensors can be used in other arrangements. For example, the light can be near-infrared light or other visible or invisible light. In other sensing arrangements, other forms of electromagnetic, acoustic, or other types of signals can be used for sensing. The centrifugal filter discharge line is also operatively connected to a centrifugal filter pump 266. In this exemplary arrangement, the centrifugal filter pump may include a peristaltic pump or other variable-rate pump suitable for pumping centrifugal filter material.

[0175] In this exemplary arrangement, the concentrate discharge line 220 is operatively connected to the concentrate discharge line 268. The concentrate optical density sensor 270 is operatively connected to at least a portion of the internal region of the concentrate discharge line 268. The exemplary concentrate optical density sensor can operate in a manner similar to the centrifugal filter optical density sensor discussed previously. It should be understood, of course, that the concentrate optical density sensor may include different structures or properties, and different types of cell density sensors may be used in other exemplary arrangements. The concentrate discharge line 268 is operatively connected to the concentrate pump 272. In this exemplary arrangement, the concentrate pump 272 may include a peristaltic pump or other variable-rate pump adapted to pump the concentrate without causing damage to it. It should be understood, of course, that these structures and components are exemplary, and alternative systems may include different or additional components.

[0176] This exemplary control system includes control circuitry 274, which is alternatively referred to herein as a controller. In an exemplary arrangement, the control circuitry may include one or more processors, schematically designated 276. The control circuitry may also include one or more data memories, schematically designated 278. The one or more data memories may include one or more types of tangible media that hold circuit-executable instructions and data, which, when executed by the controller, cause the controller to perform operations such as those discussed later herein. Such media may include, for example, solid-state memory, magnetic memory, optical memory, or other suitable non-transitory media for storing circuit-executable instructions and / or data. The control circuitry may include a structure similar to those previously discussed.

[0177] Now we will combine Figure 25 The schematic representation of the logical flow shown illustrates the operations performed by the exemplary controller 274. In this exemplary arrangement, the controller 274 is operable to control the operation of components in the system to maintain the simultaneous delivery of the output streams of normally cell-free centrifuged filter material and cell concentrate. This is achieved by using optical density sensors in the respective centrifuged filter material and concentrate outlet lines to detect the cell density (or turbidity) of the output feed and adjusting the operation of the system components to keep the output within a desired range.

[0178] When using this exemplary control system, the cell concentration in the cell culture material to be processed is measured before the system begins operation. The desired axial rotational speed of the centrifuge is determined as the speed for operating the feed pump 260. In this exemplary arrangement, the centrifuge rotational speed and the feed rate of the cell material through the feed pump are typically maintained at constant setpoints by the controller. Of course, alternative methods can be used in other arrangements and systems, where the speed and feed rate can be adjusted by the controller during cell treatment.

[0179] In this exemplary arrangement, the discharge rate (flow rate) of the external concentrate pump 272 is set to an initial value, referred to herein as the "primary value," based on the determined cell concentration. A "perfusion duration" is also preset in this exemplary arrangement, corresponding to the period of time during which the external concentrate pump 272 will initially operate at the perfusion value. This duration allows for partial filling of structure 178 in a single use. Also in this exemplary system, a "base speed" is set for the concentrate pump based on the cell density and the feed rate from the feed pump 260. The base speed of the concentrate pump is the speed at which the concentrate pump will operate after the perfusion duration (which corresponds to the flow rate). In this exemplary arrangement, the set base speed is generally expected to correspond to a concentrate pump speed that will produce centrifuged filter media with a cell density below a desired set limit and cell concentrate with a cell density generally above another desired set limit. These set values ​​and limits are received by the controller in response to input via a suitable input device and stored in the at least one data memory.

[0180] exist Figure 25 In the exemplary logic flow shown, step 280 represents the operation of the concentrate pump 272 at the initial infusion rate. In step 282, the controller determines whether the concentrate pump has operated at the infusion rate for a period of time corresponding to the infusion duration, which is operable to at least partially fill the single-use structure 178.

[0181] Once the concentrate pump has operated at the perfusion rate for the perfusion duration, the controller causes the concentrate pump speed to increase to the base speed, as indicated by step 284. Controller 274 operates to monitor the cell density in the centrifuged filter as detected by sensor 264. The controller operates to determine whether the optical density is above a desired setpoint, as indicated by step 286. If the optical density of the centrifuged filter is not above the setpoint, the centrifuged filter is sufficiently free of cells or cellular material, such that this measurement does not cause the controller to change the operating speed of the concentrate pump, and the logic returns to step 284.

[0182] If it is determined in step 286 that the optical density of the centrifuged filter is higher than a set point, the logic proceeds to step 288. In step 288, the controller operates to increase the speed of the concentrate pump by a set increment step amount. This increase in speed step is typically intended to reduce the optical density of the centrifuged filter by decreasing the number of cells present.

[0183] After increasing the speed of the concentrate pump 272 in step 288, the controller then operates in response to sensor 264 to determine in step 290 whether the optical density of the centrifuged filter remains above a set point after a set time following the incremental increase in the concentrate pump speed (flow rate). If so, the controller continues to monitor the optical density of the centrifuged filter until it is no higher than the set point. In this exemplary arrangement, the instructions include a set time period during which the optical density of the centrifuged filter must not be higher than the set point before the concentrate pump speed controller determines that the adjustment of the base speed is sufficient to maintain the optical density of the centrifuged filter at or below the desired set point. Step 292 indicates that the controller determines that the increased concentrate pump speed has maintained the optical density of the centrifuged filter at or below the set point of a stored set time period value, which corresponds to the consistent production of completely cell-free centrifuged filter outflow or the achievement of a programmed waiting time. In response to the production of completely cell-free centrifuged filter for the desired duration or the achievement of the programmed waiting time, the controller then operates in step 294 to cause the base speed value of the concentrate pump to be adjusted to correspond to the increased base speed. The controller sets a new base speed, and the logic returns to step 284. Note that if the optical density of the centrifuged filter remains higher than the setpoint determined in step 286, the concentrate pump speed will be adjusted again.

[0184] The exemplary controller also simultaneously monitors the optical density of the cells in the output concentrate stream. This is done by monitoring the optical density as detected by sensor 270. As shown in step 296, the controller operates to determine whether the optical density in the concentrate is below a desired setpoint. If the concentrate optical density is detected at or above the desired setpoint value stored in the data memory, the concentration of cells in the concentrate output stream is at or above the desired level, and the logic returns to step 284. However, if the optical density of the concentrate is below the desired setpoint, meaning that the level of cells in the concentrate is below the desired level, the controller moves to step 298. In step 298, the speed of the concentrate pump is reduced by a predetermined increment step. Reducing the speed of the concentrate pump will decrease the output flow rate, typically increasing the amount of cells in the concentrate output stream, and thus increasing the optical density of the concentrate output stream.

[0185] Then, the controller operates the concentrate pump 272 at a new reduced speed, as shown in step 300. As shown in step 302, the controller operates the concentrate pump at this reduced speed for a set time period, which corresponds to a set value stored in the data memory, such that the concentration of cells in the output concentrate stream can increase before determining whether the speed reduction is sufficient. Once it is determined in step 302 that the time period has elapsed, the controller returns to step 284 and then repeats the logic flow from that step to determine whether further speed adjustment is needed.

[0186] Of course, it should be understood that this illustrative simplified logic flow is exemplary, and in other arrangements, different logic flows and / or additional operating parameters of system components can be monitored and adjusted to achieve the desired output flow of centrifuged filter media and concentrate. For example, in other exemplary arrangements, the speed of the centrifuged filter media discharge pump, and therefore the centrifuged filter media discharge flow rate, can be changed by the controller, at least in part, in response to the optical density detected by the centrifuged filter media optical density sensor corresponding to the cell level in the centrifuged filter media. For example, if the cell level in the centrifuged filter media is detected to be higher than a set limit, the controller can operate to reduce the flow rate of the centrifuged filter media pump. This can be done by the controller, either as an alternative to or in combination with controlling the concentrate discharge flow rate. The controller can appropriately change the centrifuged filter media flow rate to ensure that the cell level in the centrifuged filter media remains below or within a set limit.

[0187] Alternatively or additionally, the controller can also control the flow rate of the cell suspension entering the single-use structure. This can be accomplished by altering the flow rates of the centrifuged filter and concentrate from the single-use structure to maintain the cell levels in the centrifuged filter and concentrate within programmed limits stored in memory associated with the controller. Additionally, the controller can also, according to its programmed operation, modify other process parameters, such as variations in drum rotation speed, diluent introduction and diluent introduction rate, and other process parameters, to maintain the properties of the centrifuged filter and concentrate within programmed limits and desired process rates. Furthermore, in other exemplary arrangements, other properties or parameters can be monitored and regulated by the control system to achieve the desired product.

[0188] Figure 27 A cross-sectional view of another alternative single-use centrifuge structure 314 is shown. Single-use structure 314 is generally similar to the previously discussed single-use structure 178, except as specifically mentioned. Single-use structure 314 includes elements operable to help ensure that the air / liquid interface of the cavitation extending in the single-use structure and isolating the seal 236 from the material being processed is more stably maintained in the desired radial position.

[0189] In the single-use configuration 314, the centrifugal filter pump 208 is positioned within the centrifugal filter pump chamber 316. The centrifugal filter pump chamber 316 is vertically defined at the bottom by a circular lower centrifugal filter inward pump chamber surface 318. The centrifugal filter pump chamber 316 is vertically defined at the top by a circular upper centrifugal filter inward pump chamber surface 320.

[0190] The lower centrifugal filter pump chamber surface 318 extends radially outward from the lower centrifugal filter inward pump chamber opening 322. In this exemplary arrangement, the lower centrifugal filter inward pump chamber opening 322 extends through the circular top of the core 200 and corresponds to the previously discussed upper opening 202. The feed pipe 184 extends through the lower centrifugal filter inward pump chamber opening.

[0191] The surface 320 of the upper centrifugal filter centrifugal pump chamber extends radially outward from the circular upper centrifugal filter centrifugal pump chamber opening 324. The feed pipe 184 and the centrifugal filter discharge pipe 212 extend axially through the upper centrifugal filter centrifugal pump chamber opening.

[0192] Multiple angled, upwardly extending lower centrifugal filter chamber blades 326 extend on the surface 318 of the lower centrifugal filter centrifugal pump chamber. Each lower centrifugal filter chamber blade 326 extends radially outward from the lower centrifugal filter centrifugal pump chamber opening 322. Figure 28 The lower centrifugal filter chamber blade 326, shown in more detail, extends radially outward from the rotation axis 174 by a distance V. In this exemplary arrangement, the lower centrifugal filter chamber blade 326 extends upward within a circular recess on the lower centrifugal filter centrifugal pump chamber surface 318. However, it should be understood that this arrangement is exemplary and other arrangements can be used; for example, the radial length of the blades, the blade height, and the depth and diameter of the recess can be varied to achieve desired fluid pressure properties.

[0193] Multiple downwardly extending upper centrifugal filter chamber blades 328, spaced at an angle, extend from the upper centrifugal filter towards the pump chamber surface 320. Each of the upper centrifugal filter chamber blades 328 extends radially outward from the upper centrifugal filter towards the pump chamber opening 324. The upper centrifugal filter chamber blades extend radially outward from the rotation axis 174 by an upper centrifugal filter blade distance. In this exemplary arrangement, the upper centrifugal filter blade distance substantially corresponds to the lower centrifugal filter blade distance V. In this exemplary arrangement, the upper centrifugal filter chamber blades extend downward in a circular recess on the upper centrifugal filter towards the pump chamber surface, the circular recess having a... Figure 28 The structure shown in the middle is similar to that of the blades in the lower centrifugal filter chamber, but in the opposite orientation.

[0194] In the exemplary arrangement shown, the centrifugal filter centrifugal pump 208 includes a substantially annular centrifugal filter centrifugal pump opening 330. The substantially annular centrifugal filter centrifugal pump opening 330 is radially outward from the axis of rotation 174. For reasons discussed later, the centrifugal filter pump opening distance at which the centrifugal filter centrifugal pump opening 330 is located is a radial distance greater than the distance between the lower centrifugal filter blades and the distance between the upper centrifugal filter blades.

[0195] In an exemplary arrangement of the single-use structure 314, the concentrate centripetal pump 216 is positioned within the concentrate pump chamber 332. The concentrate pump chamber 332 is vertically defined on its lower side by a circular lower concentrate centripetal pump chamber surface 334. The concentrate pump chamber 332 is vertically defined on its upper side by a circular upper concentrate centripetal pump chamber surface 336.

[0196] The lower concentrate centrifugal pump chamber surface 334 extends radially outward from the lower concentrate centrifugal pump chamber opening 338. In this exemplary arrangement, the lower concentrate centrifugal pump chamber opening corresponds in size to and is continuous with the upper concentrate centrifugal pump chamber opening 324. The feed pipe 184 and the centrifugal filter discharge pipe 212 extend through the lower concentrate centrifugal pump chamber opening 338.

[0197] Multiple angled, upwardly extending lower concentrate chamber blades 340 extend on the lower concentrate centripetal pump chamber surface 334. The lower concentrate chamber blades 334 extend radially outward from the lower concentrate centripetal pump chamber opening 338. The lower concentrate chamber blades 334 extend radially outward from the axis of rotation by a distance equal to the lower concentrate blade distance. In this exemplary arrangement, the lower concentrate chamber blades 334 extend over a circular recess on the lower concentrate centripetal pump chamber surface, similar to the upper and lower concentrate chamber blades discussed previously. It should be understood, of course, that this configuration is exemplary.

[0198] The upper concentrate centrifugal pump chamber surface 336 extends radially outward from the upper concentrate centrifugal pump chamber opening 342. The feed pipe 184, centrifugal filter discharge pipe 212, and concentrate discharge pipe 220 extend coaxially through the upper concentrate centrifugal pump chamber opening 342. A plurality of angledly spaced upper concentrate chamber blades 344 extend downward from the surface 336. The upper concentrate chamber blades extend radially outward from the upper concentrate centrifugal pump chamber opening 342. The upper concentrate chamber blades extend within upwardly extending circular recesses in the upper concentrate centrifugal pump chamber surface. In this exemplary arrangement, the upper concentrate chamber blades are constructed in a manner similar to the lower concentrate chamber blades, as well as the upper and lower centrifugal filter chamber blades, discussed previously. It should be understood, of course, that this method is exemplary, and other methods may be used in other arrangements.

[0199] The concentrate centripetal pump 216 includes a substantially annular concentrate pump opening 346. The concentrate pump opening is radially positioned from the axis of rotation 174. In this exemplary arrangement, the distance between the upper and lower concentrate blades is less than the distance between the concentrate pump openings. It should be understood, of course, that this configuration is exemplary and other methods may be used in other arrangements.

[0200] In the exemplary single-use configuration 314, the upper concentrate chamber blade 344 and the lower concentrate chamber blade 340, as well as the upper centrifugal filter chamber blade 326 and the lower centrifugal filter chamber blade 328, operate to stably and radially position the annular air / liquid interface 348 in the centrifugal filter pump chamber 330 and the air / liquid interface 350 in the concentrate pump chamber 332. Figure 28 As shown, the air / liquid interface 348 is radially positioned at the center along the radial length of the centrifugal filter chamber blades. This is radially inward from the centrifugal filter pump opening 330. The radially extending centrifugal filter chamber blades operate to provide centrifugal pumping force, which holds the annular air / liquid interface 348 at a radial position above and below the centrifugal filter centrifugal pump, the radial position being located radially inward of the centrifugal filter pump opening 330. In this exemplary arrangement, the blades further help stabilize the air / liquid interface, ensuring it maintains a coaxial circular configuration both above and below the centrifugal filter pump. Furthermore, in this exemplary arrangement, the radial position of the interface relative to the axis of rotation can be controlled, as discussed later, so that the centrifugal filter pump opening 330 is always kept within the liquid centrifugal filter and not exposed to air.

[0201] The upper concentrate chamber blades 344 and lower concentrate chamber blades 340 operate in a manner similar to those of the centrifugal filter chamber blades. The concentrate chamber blades hold the circular air / liquid interface 350 in the concentrate pump chamber 332 at a radial distance inside the substantially annular concentrate pump opening 346. This configuration ensures that the concentrate pump opening is always exposed to the concentrate, not air. It should also be understood that although the centrifugal filter centrifugal pump and the concentrate centrifugal pump have substantially the same dimensions in the illustrated arrangement, other arrangements of the centrifugal pumps can have different dimensions. In such cases, the radial distances from the axes of rotation extending from the centrifugal filter chamber blades and the concentrate chamber blades can differ. Furthermore, the radial positions of the air / liquid interfaces in the centrifugal filter pump chamber and the concentrate pump chamber relative to the axes of rotation can differ. Various blade configurations and arrangements can be used depending on the specific relationship between the components constituting the single-use device and the specific materials processed via the single-use structure.

[0202] Figure 30The upper portion of another alternative single-use structure 352 is shown. Single-use structure 352 is similar to single-use structure 304, except as otherwise discussed. Single-use structure 352 includes an air tube 354 extending coaxially around a concentrate discharge tube 220. The air tube 354 communicates with an opening 356 within the single-use structure. The opening 356 extends from the interior of the air tube above a centrifugal pump 216 in a concentrate pump chamber 332. In this exemplary arrangement, a seal 236, as schematically shown, operatively engages the air tube 354 to maintain an airtight connection with the air tube, as well as the concentrate discharge tube, centrifuge filter discharge tube, and feed tube. As can be understood, the air tube can be used to selectively maintain the air pressure level in the cavitation within the single-use structure. This arrangement can be used in conjunction with systems as described above, or in other systems where externally supplied pressurized air is used to isolate the seals of the centrifuge structure from the material being processed and to maintain the air / liquid interface in a desired position. Of course, it should be understood that this structure is exemplary and other methods can be used in other arrangements.

[0203] Figure 31 A system 358 is schematically illustrated for the continuous separation of cell suspensions into substantially cell-free centrifugal filtrate and concentrate. System 358 is similar to System 170 previously discussed, except as otherwise mentioned herein. In this exemplary arrangement, System 358 operates using a single-use structure similar to Single-Use Structure 352. A controller 274 of System 358 operates to control the position of the air / liquid interface within the single-use structure to ensure that the interface remains radially inward relative to the axis of rotation from each of the centrifugal filtrate pump openings and the concentrate pump opening.

[0204] In this exemplary arrangement, the flow back pressure regulator 360 is fluidly connected to the centrifugal filter discharge line 262. In this exemplary arrangement, the flow back pressure regulator 360 is fluidly positioned between the centrifugal filter discharge line 212 and the centrifugal filter pump 266. The exemplary system 358 includes a pressurized air source, schematically represented as 362. The pressurized air source 362 is connected to a pilot pressure control valve 364. The control valve is operatively connected to a controller 274. Signals from the controller 274 induce selectively variable pressure in the pilot line 366. The pilot line 366 is fluidly connected to the back pressure regulator 360. The pressure applied to the pilot line 366 by the pilot pressure control valve 264 is operable to control the flow of centrifugal filter material, and thus control the flow back pressure of the centrifugal filter material applied by the flow back pressure regulator 360.

[0205] In this exemplary arrangement, pressure control valve 368 is in fluid communication with pressurized air source 362. Control valve 368 is also operatively connected to controller 274. In this exemplary arrangement, control valve 368 is controlled to selectively apply precise pressure to cavitation within air pipe 354 and the upper part of single-use structure 352.

[0206] In this exemplary arrangement, controller 274 operates according to stored executable instructions, controlling the operation of system 358 in a manner similar to that discussed previously in conjunction with system 170. Furthermore, in this exemplary arrangement, controller 274 operates to control pilot pressure valve 364, thereby changing the back pressure applied to centrifugal filter discharge line 212 by back pressure regulator 360. Controller 274 also operates to control valve 368. The controller operates to maintain and selectively change the pressure applied to the cavitation at the top of the interior of the single-use structure. The controller operates according to its programming to change the back pressure and / or cavitation pressure of the centrifugal filter stream to maintain the air / liquid interface of the cavitation at a radial distance from the axis of rotation, this radial distance extending inward from the centrifugal filter pump opening 330 and the concentrate pump opening 346. This pressure variation, encompassing both the back pressure and cavitation pressure of the centrifuged filter flow, combined with the action of the centrifuged filter chamber blades and concentrate chamber blades in this exemplary arrangement, maintains the stability and radially outward extent of the air / liquid interface to ensure minimal air introduction into the centrifuged filter and concentrate output from the single-use structure. Furthermore, the ability to selectively alter the back pressure and flow rate of the centrifuged filter can affect the cell level and the corresponding detected optical density of the discharged concentrate. Therefore, the controller can, according to its programmed operation, selectively alter the concentrate flow rate, the centrifuged filter back pressure and flow rate, the internal cavitation pressure, the rate at which the cell suspension enters the single-use structure, and other possible operating variables of the centrifugation process to maintain the properties of the centrifuged filter and concentrate within set limits and / or ranges stored in at least one data memory associated with the controller. Moreover, this exemplary arrangement allows for the separation of different types of materials and operation at different flow rates while maintaining reliable control of the separation process. Of course, while the control of the position of the air / liquid interface is described in conjunction with the features of system 170, such control can also be used in other types of systems that include other or different types of processing elements.

[0207] Figures 32 to 34 Another alternative single-use structure 370 is shown. The exemplary single-use structure 370 includes many features similar to those discussed in conjunction with the previously described single-use structures 178, 240, and 250. It should be understood that the additional features discussed herein for use in conjunction with other single-use structures can also be used in arrangements having the features and relationships shown in single-use structure 370.

[0208] The single-use structure 370 includes an upper disc-shaped portion 372. An exemplary upper disc-shaped portion 372 includes a centrifugal filter centrifugal pump chamber 374. A centrifugal filter centrifugal pump 208 is housed within the centrifugal filter centrifugal pump chamber 374. The centrifugal filter centrifugal pump chamber has a centrifugal filter chamber volume within the upper disc-shaped portion.

[0209] The centrifugal filter centrifugal pump chamber is in fluid communication with the separation chamber via at least one centrifugal filter channel 410. The centrifugal filter channel 410 is fluidly connected to at least one centrifugal filter channel inlet 412. Exemplarily, at least one centrifugal filter channel inlet 412 is in fluid communication with the separation chamber at a radially outer location adjacent to the cylindrical wall of the cylindrical core. In the illustrated exemplary arrangement, the at least one centrifugal filter channel inlet 412 is a single substantially annular inlet, and the centrifugal filter channel is a single substantially annular channel.

[0210] The upper disc-shaped portion also includes a concentrate centrifugal pump chamber 376. The exemplary concentrate centrifugal pump chamber 376 is a cylindrical chamber horizontally defined by a vertically extending circular defining wall 378. The concentrate centrifugal pump chamber 376 has a concentrate chamber volume within the upper disc-shaped portion. In the exemplary arrangement, the centrifugal filter chamber volume within the upper disc-shaped portion is larger than the concentrate chamber volume for reasons discussed later.

[0211] An exemplary upper disc-shaped portion includes an upper component 394 and a lower component 396. In the exemplary arrangement, the upper and lower components are held together in a releasably engaged manner. Of course, this method is exemplary, and other methods may be used in other arrangements. The exemplary lower component 396, in its operating position, is defined on its upper side by an upper annular defining surface 398. The exemplary lower component 396 is defined on its lower side by a lower annular defining surface 400. The upper annular defining surface 398 includes a radially outwardly tapered annular upper surface portion 402 and a radially inwardly radially plane-extending upper surface portion 404. The lower annular defining surface 398 includes a radially outwardly tapered annular lower surface portion 406 and a radially inwardly radially plane-extending lower surface portion 408. In the operating position of the upper component 394 and the lower component 396, the radially inwardly radially plane-extending lower surface 408 and the radially inwardly radially plane-extending upper surface 404 extend parallel to each other. However, the upper conical annular surface portion 402 and the lower conical annular surface portion in the operating position are not in a parallel relationship for reasons discussed later.

[0212] In an exemplary arrangement, a substantially annular cell concentrate channel 380 extends between the upper portion 394 and the lower portion 396 of the upper disc-shaped portion 372. The annular cell concentrate channel 380 extends radially inward from a substantially annular cell concentrate channel inlet 382. The concentrate channel inlet is located further radially outward from the centrifugal filter inlet 412. The concentrate channel inlet 382 is positioned in fluid communication with the upper region of the separation chamber 224 at its radially outer periphery, adjacent to the inner surface of the outer wall, where, during rotation of the apparatus with the centrifuge drum, cell concentrate 384 is collected in the annular radially outward region 384 of the separation chamber, as... Figure 34 As shown.

[0213] In an exemplary arrangement, a substantially annular funnel channel 381 extends upward and radially inward to an annular cell concentrate channel inlet 382. The lower portion 396 of the exemplary upper disc-shaped portion 372, in the operating position, is defined in the separation chamber by a substantially planar radially extending surface 379 on its lower radially inward side. The exemplary radially extending surface 379 terminates radially outward at an annular edge 377. In the operating position of the single-use configuration, the annular funnel channel 381 extends upward from the annular edge 377. The exemplary upper portion 394 of the exemplary annular disc-shaped portion 372 also includes a substantially annular cell concentrate guiding surface 383. The annular cell concentrate guiding surface 383 extends below the annular funnel channel 381 and radially outward at the axial level of the radially extending planar surface 379, defining the separation chamber 224. In this exemplary arrangement, the annular cell concentrate guiding surface 383 further extends radially outward and upward to approach the funnel channel.

[0214] In this exemplary arrangement, the annular cell concentrate channel 380 terminates radially inward at a substantially annular cell concentrate outlet 386 within a concentrate centripetal pump chamber 376. In this exemplary arrangement, the annular cell concentrate outlet 386 is positioned to extend at the midpoint of a vertically extending defining wall 378. In this exemplary arrangement, the concentrate centripetal pump includes a substantially annular concentrate centripetal pump inlet 388. The annular cell concentrate outlet of channel 380 is radially and axially aligned with the concentrate centripetal pump inlet 388.

[0215] In an exemplary arrangement, the annular cell concentrate channel includes a tapered portion 390 and a radially extending portion 392 in axial section. The radially extending portion 392 extends directly radially outward between an upper surface portion 404 extending radially in the lower plane of the lower component 396 and a lower surface portion 408 extending radially in the upper plane of the upper component 394. The exemplary radially extending portion 392 further extends directly radially outward from the annular cell concentrate outlet 386. In the operating position of the single-use structure, the horizontal and radially extending portion 392 of the annular cell concentrate channel has a constant channel height, wherein the channel height refers to the dimension of the channel transverse to the concentrate flow direction in the corresponding region of the channel. As a result, the horizontal and radially extending portion has a constant cross-sectional area over its entire length. In this exemplary arrangement, the horizontal and radially extending portion 392 is axially and radially aligned and has the same height in axial section as the inlet of the concentrate centripetal pump.

[0216] The tapered portion 390 of the annular cell concentrate channel 380 extends between the tapered annular upper surface portion 402 of the lower component and the tapered annular lower surface portion 406 of the upper component. The annular cell concentrate channel 380 is configured to have a channel portion having a gradually increasing channel height (and cross-sectional channel area) from the cell concentrate passage inlet 382 to the location where the tapered portion fluidly connects with the radially extending portion 392. This configuration causes the cross-sectional area of ​​the channel portion 390 perpendicular to the concentrate flow direction within the channel portion to increase with increasing proximity to the axis of rotation. The gradually increasing cross-sectional area of ​​the concentrate channel means that the cross-sectional area of ​​the channel perpendicular to the concentrate flow direction within the channel portion increases steadily, whereas there is no location in the channel portion where the channel cross-sectional area experiences an abrupt change of more than 10% to form any discrete steps.

[0217] In an exemplary arrangement, the continuously increasing height of the channel within the tapering portion 390, with increasing proximity to the axis of rotation of the single-use system, helps maintain an appropriately high fluid velocity of the cell concentrate. In an exemplary arrangement, the annular cell concentrate channel has a configuration that avoids pressure drop regions to maintain an appropriately high radially inward velocity of the cell concentrate components from the channel inlet 382 to the passage outlet 386.

[0218] In the exemplary arrangement, the annular inlet 382 leading to the annular channel 380 is the narrowest and smallest cross-sectional area of ​​the channel along its height direction. At the annular inlet 382, ​​cells and the liquid in which they are suspended begin to flow radially inward. In this region of the single-use structure, cells, which are denser than the liquid, experience radially outward centrifugal acceleration due to centrifugal rotation. During operation of the exemplary arrangement, an external concentrate pump (e.g., the previously discussed concentrate pump 272) is operated to maintain a flow rate such that the average velocity of the radially inward liquid flow at the annular channel inlet 382 is higher than the settling velocity, and maintains the force acting on the radially outward-oriented cells, which is caused by the centrifugal force acting on the concentrate at the channel inlet. Furthermore, in some exemplary arrangements, the upwardly tapering construction of the tapered portion 390 makes the component of the settling force against cell flow at the channel inlet and in the channel portion less than the component against cell movement in the directly radially inward channel at the same radial location.

[0219] In the exemplary arrangement, the height of the annular tapering portion of the annular concentrate channel increases as the radial distance from the rotation axis of the single-use structure decreases. In the axial section of the exemplary channel configuration, the channel height of the tapering portion 390, and therefore the cross-sectional area perpendicular to the concentrate flow direction, gradually and continuously increases as it approaches the rotation axis of the single-use structure (from which the radial distance decreases). This exemplary configuration, where the channel height gradually and continuously increases with decreasing radial distance from the axis, allows cells in the cell concentrate to move radially inward continuously through the concentrate channel at a suitably high speed along with the liquid in which the cells are suspended. Since the radially outward centrifugal acceleration force acting on the cells decreases as the radial distance from the rotation axis decreases accordingly, the cell concentrate can maintain a suitable radially inward velocity throughout its radially inward journey from the channel inlet 382, ​​despite the increase in channel height. Therefore, in the exemplary arrangement, as the cell concentrate moves radially inward from the annular inlet 382 toward the cell concentrate outlet 386 and enters and passes through the concentrate centripetal pump chamber 376, the cell concentrate maintains an appropriately high radially inward velocity in the channel portion 390 throughout the channel 380.

[0220] It should be understood that, although in Figures 32 to 34In the exemplary arrangement shown, a channel section with a gradually increasing cross-sectional area begins at the channel inlet, but other methods and constructions may be used in other arrangements. For example, in some alternative arrangements, the channel section with this construction may be located at other locations. This location may depend on the specific construction of the concentrate channel and the requirements in a particular section of the channel to achieve a sufficiently high flow rate of the concentrate to help move the concentrate and the cells therein in a desired manner to overcome sedimentation or other forces opposite to the desired flow. Furthermore, it should be understood that while only a single annular concentrate channel section with a gradually increasing cross-sectional area exists in this exemplary arrangement, other arrangements may include other channels, such as multiple concentrate channels. It should be understood that... Figures 32 to 34 The arrangement shown is exemplary, and other arrangements may be used.

[0221] In the exemplary arrangement, the concentrate discharge line 220 is operatively fluidly connected to an external concentrate pump as previously discussed. In this exemplary arrangement, the concentrate pump may operate in a system similar to the previously described system 170, or in another system responsive to control circuitry, to provide an outlet flow of cell concentrate while maintaining a suitable back pressure in the concentrate discharge line. It should be understood, of course, that many other types of components may be included in a system operating the single-use structure 370 to achieve the operational capabilities described herein.

[0222] In operation of the exemplary system, the single-use structure 370 is rotated in a manner operatively connected to a centrifuge drum to separate a cell suspension in an internal region of the structure. The cell suspension is separated into a substantially cell-free cell isolate and a cell-rich cell concentrate in a manner similar to those previously discussed. In the exemplary arrangement, centrifugation creates an annular cell concentrate region 384 at the upper radially outer periphery of the separation chamber. This exemplary annular cell concentrate region remains in fluid contact with an annular channel inlet 382 and maintains contact with a substantially annular cell concentrate guide surface and an annular funnel channel along which the cell concentrate moves toward the channel inlet 382.

[0223] In some exemplary arrangements, the annular cell concentrate guiding surface 383 is configured to propel the cell concentrate upward into an annular funnel channel 381, the guiding surface defining the radially outer periphery of a radially extending surface 379 adjacent to the upper disc-shaped portion of the separation chamber. This is likely due to the configuration of the guiding surface extending further radially outward and upward toward the final passage. The cell concentrate, propelled radially outward against the annular cell concentrate guiding surface 383 by the centrifugal force generated by the rotation of the centrifuge, can move into the annular funnel channel in engagement with the guiding surface, the annular funnel channel guiding the cell concentrate upward and radially inward toward the annular cell concentrate inlet. As the cell concentrate is radially guided upward toward the channel inlet 382 by the annular converging surface that defines the axial cross-section of the annular funnel channel, the radially inward velocity of the liquid component of the cell concentrate increases as the area of ​​the funnel channel decreases. As previously discussed, the exemplary configuration has a minimum height dimension (and minimum cross-sectional area) configured to produce the highest fluid velocity of the liquid phase of the cell concentrate at the annular channel inlet 382.

[0224] In the exemplary arrangement and its operation, an external concentrate pump is operable to generate flow such that cell concentrate in the annular cell concentrate channel 380 continuously moves from the annular inlet 382 to the annular outlet 386 of the cell concentrate at an average velocity of the liquid phase producing radially inward cell concentrate, which is higher than the sedimentation velocity of the cells. In the exemplary arrangement, achieving this consistently high average velocity of the liquid phase in the cell concentrate across the height of the channel and its entire radial length helps ensure proper movement of the cell concentrate and the cells therein through the annular cell concentrate channel. Furthermore, in the exemplary arrangement, the gradually increasing cross-section of the tapered portion 390 of the channel, the constant height of the radially extending portion 392, and the relatively small cross-sectional area that is substantially constant over the entire length of the annular cell concentrate channel avoid regions of significant pressure drop along the channel length, thus maintaining a sufficiently high continuity of liquid phase and cell velocity throughout the channel.

[0225] Furthermore, in the operation of the exemplary arrangement, the cell concentrate entering the centripetal pump chamber 376 is able to move at a sufficiently high speed and flow rate to ensure that the liquid phase and cellular phase of the cell concentrate pass radially inward through the inlet of the centripetal pump. This result is facilitated in the exemplary arrangement by the volume and construction of the centripetal pump chamber and the construction of the channel outlet 386 relative to the centripetal pump inlet 388 of the centripetal pump 216.

[0226] These features of the exemplary arrangement facilitate radial inward flow of cell concentrate in the exemplary single-use structure and enable beneficial operation of the single-use structure and associated systems. It should be understood, of course, that these features and configurations are exemplary, and the principles described herein can be utilized in combination with other configurations and other single-use or multiple-use structures to achieve desired performance characteristics and cell separation in other centrifugation processes.

[0227] Figures 35 to 38 Another alternative arrangement of the single-use structure 414 is shown. This exemplary alternative single-use structure includes many features of the aforementioned arrangement. The exemplary single-use structure includes an upper disc-shaped portion 416. An outer wall 418 is configured for operative connection to a centrifuge drum, and the single-use structure 414 is configured to be positioned within the centrifuge drum. The structure includes a lower portion 420 of the wall 418. Figure 36 The exemplary single-use structure shown has a truncated cone-shaped inner region and a smaller inner radius adjacent to the lower part 420.

[0228] Similar to the previously described arrangement, the single-use structure 414 includes a cylindrical core 422. The cylindrical core 422 extends axially between the upper and lower portions of the structure's interior region. The core includes a cylindrical outer retaining wall 424. It should be understood that, although in Figure 36 The core 422 is shown as a solid structure, but a hollow core structure can be used in other arrangements. In an exemplary arrangement, the cylindrical core 422 extends in an internal region between the bottom of the upper disc-shaped portion and a plurality of upwardly oriented, angledly spaced blades 426. The blades 426 include fluid channels therebetween that extend upward from the inside of the wall defining the lower portion of the internal region of the single-use structure.

[0229] In an exemplary arrangement, the single-use structure 414 is configured to rotate about axis 428 within a centrifuge drum. When in the operating position, the single-use structure also includes a vertically extending feed tube 430 configured to receive cell culture material into an internal region of the structure. The exemplary feed tube 430 extends downwards to a tube opening 432 in the lower portion of the single-use structure and into a region where the inlet material to be separated into cell centrifuge filtrate and cell concentrate is introduced. In the illustrated exemplary arrangement, the feed tube 430 extends axially through a cylindrical opening 434 in the core.

[0230] The exemplary single-use structure, when in the operating position, also includes a vertically extending centrifugal filter discharge tube 436. The vertically extending centrifugal filter discharge tube 436 is fluidly connected to a centrifugal centrifugal pump 438. The centrifugal centrifugal pump is positioned within a centrifugal centrifugal pump chamber 440 located in the upper disc-shaped portion 416. The centrifugal centrifugal pump chamber 440 is fluidly connected to a separation chamber 442, which extends radially between the outer wall of the core 422 and the wall defining the internal region of the single-use structure. The centrifugal centrifugal pump chamber is fluidly connected to the separation chamber 442 via at least one centrifugal filter channel inlet 444 and at least one centrifugal filter channel 446. In the exemplary arrangement, at least one centrifugal filter channel inlet 444 is positioned in the separation chamber and is radially outside but radially close to the cylindrical wall defining the core 422. In the exemplary arrangement, the centrifugal filter channel inlet has an arcuate shape. Furthermore, in the operating position of the exemplary arrangement, the centrifugal filter centrifugal pump chamber 440 includes a horizontally extending upper centrifugal filter pump chamber surface and a lower centrifugal filter pump chamber surface, which may include upper centrifugal filter chamber blades and lower centrifugal filter pump chamber blades, such as the blades 326 and 328 previously discussed.

[0231] The exemplary single-use structure 414 also includes a vertically extending concentrate discharge pipe 448 in the operating position. As in other described arrangements, the concentrate discharge pipe 448, the centrifugal filter discharge pipe 436, and the feed pipe 430 are coaxially arranged on the single-use structure. The concentrate discharge pipe 448 is in fluid connection to a concentrate centrifugal pump 450. The concentrate centrifugal pump 450 is positioned within a concentrate centrifugal pump chamber 452 within the upper disc-shaped portion 416. In the exemplary arrangement, the concentrate centrifugal pump chamber is defined by a respective upper and lower concentrate centrifugal pump chamber surface, each of which may include radially extending chamber blades similar to those previously discussed.

[0232] In this exemplary arrangement, the concentrate centripetal pump chamber is fluidly connected to the separation chamber via a plurality of radially extending concentrate channels 454. In this exemplary arrangement, each concentrate channel extends within an upper disc-shaped portion and is angularly spaced from each of the other channels. The exemplary upper disc-shaped portion 416 includes an upper component 456 and a lower component 458. The exemplary upper disc-shaped portion also includes a bottom component 460. In the exemplary arrangement in the operating state, each of the upper component 456, the lower component 458, and the bottom component 460 is in a sandwich-joint relationship. Each of the plurality of concentrate channels in the operating position is defined by at least one downward-facing surface of the upper component 456 and at least one upward-facing surface of the lower component 458.

[0233] like Figure 36As shown, each of the plurality of concentrate channels 454 includes a concentrate channel inlet 462. In an exemplary arrangement, the concentrate channel inlet has the minimum cross-sectional area of ​​the entire respective concentrate channel in a direction perpendicular to the concentrate flow direction. Each concentrate channel inlet 462 is fluidly connected to the outer periphery of the separation chamber via a vertical opening 464 extending in the upper disc-shaped portion. In an exemplary arrangement, each concentrate channel 454 is fluidly connected to the separation chamber via a corresponding vertical opening 464 extending through the bottom member 460 and the concentrate channel being between and defined by the upper member 456 and the lower member 458. In an exemplary arrangement, each corresponding vertical opening 464 includes an arcuate elongated slot located in the bottom member 460. Of course, it should be understood that this configuration is exemplary and other methods may be used in other arrangements.

[0234] In the exemplary arrangement, each concentrate channel has a generally constant cross-sectional width from the channel inlet 462 to the corresponding opening from the channel into the concentrate centripetal pump chamber. Each concentrate channel includes a channel portion whose cross-sectional area perpendicular to the concentrate flow direction within the corresponding concentrate channel portion gradually and continuously increases. The cross-sectional area increases with increasing proximity of the position in the corresponding channel portion to the axis of the single-use structure. In the exemplary arrangement, each of the plurality of concentrate channels is configured such that the cross-sectional area perpendicular to the concentrate flow direction in the tapered portion 468 gradually and continuously increases due to the varying height of the channel in the tapered portion. The height of each channel increases with increasing proximity to the axis of rotation. Of course, it should be understood that this arrangement is exemplary, and other methods may be used in other arrangements.

[0235] In the exemplary arrangement, each channel portion, constructed with a gradually increasing cross-sectional area, begins at a corresponding concentrate channel inlet 462 and continues through a tapered portion 468 extending upward and radially inward from the concentrate channel inlet. Each tapered portion 468 is fluidly connected to a horizontal and radially extending portion 470 of a corresponding concentrate channel 454. In the exemplary arrangement, each horizontal and radially extending portion of the corresponding concentrate channel extends from the tapered portion 468 to the concentrate centripetal pump chamber 450. In the exemplary arrangement, the horizontal and radially extending portions of the concentrate channel have a constant cross-sectional area radially inward from the tapered portion to the concentrate centripetal pump chamber perpendicular to the concentrate flow direction. However, it should be understood that this arrangement is exemplary, and other methods may be used in other arrangements.

[0236] In the operation of the exemplary single-use structure 414, the upper disc-shaped portion 416, wall 418, and core rotate operatively connected to the centrifuge drum. The feed pipe 430, centrifuge filter discharge pipe 436, and concentrate discharge pipe 448 remain stationary together with the concentrate centrifugal pump 450 and the centrifuge filter centrifugal pump 438. In this exemplary arrangement, cell culture material is separated into cell centrifuge filter and cell concentrate in the separation chamber 442 by the centrifugal force generated by rotation. The cell concentrate accumulates in the upper radially outer region of the separation chamber 442, while the substantially cell-free centrifuge filter accumulates in the region of the cylindrical outer wall of the separation chamber near the core.

[0237] Centrifuged material enters the centrifugal filter chamber through multiple centrifugal filter channel inlets 444 and exits the centrifugal filter chamber through the centrifugal filter centrifugal pump 438 and the centrifugal filter discharge pipe. An external concentrate pump, as previously discussed, is operatively connected to the concentrate discharge pipe and causes a concentrated stream from the separation chamber of the single-use structure. This concentrated stream causes the cell concentrate to flow upward through each vertical opening 464 and to each corresponding concentrate channel inlet 462, where the relatively small cross-sectional area of ​​the concentrate channel inlet allows for a high flow rate of the cell concentrate. The high flow rate of the liquid and the cells of the cell concentrate applies forces to the cells contained within the cell concentrate, propelling the cells in the upwardly and radially inwardly tapering portion 468 by overcoming radially outwardly oriented forces acting on the cells in a manner similar to those discussed in conjunction with the existing arrangement.

[0238] The cross-sectional area of ​​the upwardly and radially inwardly extending tapering section, perpendicular to the flow direction of the concentrate, gradually and continuously increases. This gradually increasing cross-sectional area maintains a sufficiently high flow velocity of the concentrate at each radial location throughout the channel section to ensure that the cell concentrate continues to move toward the concentration chamber at an appropriately high velocity, regardless of the radially outward forces at each location in the channel section. In the exemplary arrangement, the cell concentrate exits the tapering section of the concentrate channel and passes through the horizontal and radially extending portion of each corresponding channel to reach the concentrate centripetal pump chamber 452, through which the cell concentrate maintains an appropriately high velocity. As a result, this exemplary arrangement provides flow characteristics for the cell concentrate that facilitate flow within the single-use structure and aid in the cell separation process. Of course, as will be understood, the construction of the single-use structure 414 is exemplary, and other constructions may be used in other arrangements.

[0239] In some exemplary arrangements, the upper, lower, and bottom components of the upper disc-shaped portion 416 can be releasably engaged. This facilitates manufacturing and enables inspection, cleaning, or other purposes. In other exemplary arrangements, these components can be permanently engaged. In other exemplary arrangements, structures similar to those described can be formed from other components that provide the useful characteristics and capabilities discussed herein. Furthermore, it should be understood that the construction of the single-use structure 414 is exemplary, and the useful principles and structures described herein can be used in other separator structural arrangements.

[0240] Therefore, the novel centrifuge system and method of this exemplary arrangement achieves at least some of the above-mentioned objectives, eliminates the difficulties encountered when using existing devices and systems, solves problems, and obtains the desired results described herein.

[0241] In the above description, certain terms have been used for the sake of brevity, clarity, and understanding; however, since these terms are for descriptive purposes and are intended to be broadly interpreted, they are not intended to imply unnecessary limitations. Furthermore, the descriptions and illustrations herein are by way of example, and the features of the invention are not limited to the exact details shown and described.

[0242] It should be understood that features and / or relationships associated with one exemplary arrangement may be combined with features and / or relationships from another exemplary arrangement. That is, various features and / or relationships from various arrangements may be combined in further arrangements. The scope of this disclosure is not limited to the exemplary arrangements already shown and described herein.

[0243] In the claims, any feature described as a means for performing a function should be interpreted to include any means known to those skilled in the art capable of performing said function, and should not be limited to the structure shown herein or its purely equivalent alternatives.

[0244] The features, discoveries and principles of the new and useful features have been described, as well as the ways of constructing, utilizing and operating them, and the advantages and useful results obtained. The appended claims set forth new and useful structures, devices, elements, arrangements, components, combinations, systems, equipment, operations, methods and relationships.

Claims

1. An apparatus comprising: A structure configured to be releasably housed within a rotatable centrifuge drum, wherein the structure is positionable within the drum and operable to separate cells from cell culture material into concentrates and centrifugal filtrates within the internal region of the structure. Wherein, the structure in the operating position includes: The upper disc-shaped part, lower part, A cylindrical core is vertically positioned between the upper disc-shaped portion and the lower portion; a separation chamber is arranged radially outward from the core and surrounds the core. An outer wall, configured to operatively engage with the drum, wherein the outer wall extends and defines the separation chamber in a fluid-tight operative relationship with the upper disc-shaped portion. It extends in a surrounding relationship with the core and the separation chamber, and has an inner truncated cone shape, the inner truncated cone shape having a smaller inner radius near the lower portion than near the upper disc-shaped portion. Vertically extending feed pipe, Vertically extending centrifugal filter discharge tube, Vertically extending concentrate discharge pipe, The upper disc-shaped portion and the outer wall are operably engaged with the drum around a vertical axis. A centrifugal filter centrifugal pump, wherein the centrifugal filter centrifugal pump is axially aligned with the core, the centrifugal filter centrifugal pump is coaxially arranged around the feed pipe and is in fluid communication with the centrifugal filter discharge pipe. The centrifugal filter centrifugal pump is located in the centrifugal filter centrifugal pump chamber within the upper disc-shaped portion. The centrifugal filter centrifugal pump chamber is in fluid communication with the separation chamber through at least one centrifugal filter channel extending in the upper disc-shaped portion. Each centrifugal filter channel extends fluidly between its corresponding centrifugal filter channel inlet, located radially outward of the core, and the centrifugal filter centripetal pump chamber. A concentrate centrifugal pump, wherein the concentrate centrifugal pump is axially aligned with the core, the concentrate centrifugal pump is coaxially arranged around the feed pipe, the concentrate centrifugal pump is vertically positioned above the centrifugal filter centrifugal pump and is in fluid communication with the concentrate discharge pipe. The concentrate centripetal pump is located in the concentrate centripetal pump chamber within the upper disc-shaped portion. The concentrate centripetal pump chamber is in fluid communication with the separation chamber via at least one radially extending concentrate channel extending in the upper disc-shaped portion. Each of the at least one radially extending concentrate channel extends radially between corresponding concentrate channel inlets that are radially positioned outside each centrifugal filter inlet. During the rotation of the drum, the upper disc-shaped portion and the outer wall rotate relative to each of the feed pipe, the centrifugal filter discharge pipe, the concentrate discharge pipe, the centrifugal filter centrifugal pump, and the concentrate centrifugal pump. Each of the concentrate channels includes a channel portion located between the corresponding concentrate channel inlet and the concentrate centripetal pump chamber. The cross-sectional area of ​​the channel portion perpendicular to the concentrate flow direction within the corresponding concentrate channel portion region gradually and continuously increases with the increase of the corresponding radial proximity to the axis.

2. The device according to claim 1, in, The channel portion of each of the concentrate channels begins at the corresponding concentrate channel inlet and extends radially inward.

3. The device according to claim 1, in, The channel portion of each of the concentrate channels begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet.

4. The device according to claim 1, in, Each of the concentrate channels begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, wherein each concentrate channel also includes a horizontal and radially extending portion that fluidly extends between the channel portion and the concentrate centripetal pump chamber.

5. The device according to claim 1, in, Each of the concentrate channels begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, wherein each concentrate channel also includes a horizontally extending portion that fluidly extends between the channel portion and the concentrate centripetal pump chamber. The horizontal and radially extending portion of each concentrate channel terminates radially inward at the corresponding cell concentrate channel outlet in the concentrate centripetal pump chamber. The horizontal and radially extending portion of each of the concentrate channels has a constant cross-sectional area over its entire length.

6. The device according to claim 1, in, Each of the concentrate channels begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, wherein each of the concentrate channels also includes a corresponding horizontal and radially extending portion, wherein the horizontal and radially extending portion extends radially outward from the concentrate centripetal pump chamber.

7. The device according to claim 1, in, Each of the concentrate channels begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, wherein each concentrate channel also includes a corresponding horizontal and radially extending portion, wherein the horizontal and radially extending portion extends outward from the concentrate centripetal pump chamber. The channel portion terminates radially inward at the horizontal and radially extending portion. Each of the corresponding concentrate channels has a horizontal and radially extending portion with a constant cross-sectional area over its entire length.

8. The device according to claim 1, in, Each of the concentrate channels begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, wherein each concentrate channel also includes a corresponding horizontal and radially extending portion, wherein the horizontal and radially extending portion extends outward from the corresponding cell concentrate channel outlet to the concentrate centripetal pump chamber. The concentrate centripetal pump includes a concentrate centripetal pump inlet, wherein each of the cell concentrate channel outlets is axially and radially aligned with the concentrate centripetal pump inlet, and wherein each channel portion terminates radially inward at a corresponding horizontal and radially extending portion. Each of the corresponding concentrate channels has a horizontal and radially extending portion with a constant cross-sectional area over its entire length.

9. The device according to claim 1, in, The upper disc-shaped portion includes an upper component and a lower component that are in a mating relationship. Each of the concentrate channels is defined by at least one lower surface of the upper component and at least one upper surface of the lower component.

10. The device according to claim 1, in, The at least one radially extending concentrate channel comprises a single substantially annular concentrate channel.

11. The device according to claim 1, in, The at least one radially extending concentrate channel includes a plurality of separate, angledly spaced concentrate channels.

12. The device according to claim 1, in, The at least one radially extending concentrate channel includes a single substantially annular concentrate channel. The channel portion of the concentrate channel begins at the substantially annular inlet of the concentrate channel and extends upward and radially inward from the inlet of the concentrate channel.

13. The device according to claim 1, in, The at least one radially extending concentrate channel includes a single substantially annular concentrate channel. The channel portion of the concentrate channel begins at the substantially annular inlet of the concentrate channel and extends upward and radially inward from the inlet of the concentrate channel. The concentrate channel further includes a substantially annular horizontal and radially extending portion, wherein the horizontal and radially extending portion extends outward from the substantially annular cell concentrate channel outlet to the concentrate centripetal pump chamber. The channel portion terminates radially inward at the horizontal and radially extending portion.

14. The device according to claim 1, in, The at least one radially extending concentrate channel includes a single substantially annular concentrate channel. The channel portion of the concentrate channel begins at the substantially annular inlet of the concentrate channel and extends upward and radially inward from the inlet of the concentrate channel. The upper disc-shaped portion includes a substantially annular funnel channel, wherein the annular funnel channel extends upward and radially inward to the inlet of the annular concentrate channel.

15. The device according to claim 1, in, The at least one radially extending concentrate channel includes a single substantially annular concentrate channel. The channel portion of the concentrate channel begins at the substantially annular inlet of the concentrate channel and extends upward and radially inward from the inlet of the concentrate channel. The upper disc-shaped portion includes a substantially annular funnel channel extending upward and radially inward to the annular concentrate channel inlet. The upper disc-shaped portion also includes a substantially annular cell concentrate guiding surface extending below the annular funnel channel and radially outward to define the separation chamber. The annular cell concentrate guiding surface extends further radially outward and upward to approach the annular funnel channel.

16. The device according to claim 1, in, The at least one radially extending concentrate channel includes a single substantially annular concentrate channel. The channel portion of the concentrate channel begins at a substantially annular concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet. The upper disc-shaped portion includes a substantially annular funnel channel extending upward and radially inward to the annular concentrate channel inlet. The upper disc-shaped portion also includes a substantially annular cell concentrate guiding surface extending below the annular funnel channel and radially outward to define the separation chamber. The annular cell concentrate guiding surface extends further radially outward and upward to approach the annular funnel channel. The upper disc-shaped portion is defined on the lower side of the separation chamber by a radially extending surface, wherein the radially extending surface terminates radially outward at a substantially annular edge, wherein the annular edge is axially located above the radially outwardly extending annular cell concentrate guiding surface, and wherein the annular funnel channel extends upward from the annular edge.

17. The device according to claim 1, in, The at least one radially extending concentrate channel comprises a plurality of separate, angledly spaced concentrate channels. Wherein, the channel portion of each corresponding concentrate channel It begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, and It has a constant cross-sectional width perpendicular to the direction of concentrate flow and a vertical height that varies with the radial distance from the axis.

18. The device according to claim 1, in, The at least one radially extending concentrate channel comprises a plurality of separate, angledly spaced concentrate channels. Wherein, the channel portion of each corresponding concentrate channel It begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, and It has a constant cross-sectional width perpendicular to the direction of concentrate flow and a vertical height that varies with the radial distance from the axis. The upper disc-shaped portion includes a plurality of vertically spaced openings at an angle, wherein the corresponding vertical openings extend between the radial outer periphery of the separation chamber and the corresponding channel inlet.

19. The device according to claim 1, in, The at least one radially extending concentrate channel comprises a plurality of separate, angledly spaced concentrate channels. Wherein, the channel portion of each corresponding concentrate channel It begins at the corresponding concentrate channel inlet and extends upward and radially inward from the concentrate channel inlet, and It has a constant cross-sectional width perpendicular to the direction of concentrate flow and a vertical height that varies with the radial distance from the axis. The upper disc-shaped portion includes a joined upper part and a lower part, wherein each of the concentrate channels is defined by a corresponding surface of each of the upper part and the lower part.

20. The device according to claim 1, in, The structure includes a single-use structure.

21. An apparatus comprising: A structure configured to be releasably positioned within a rotating centrifuge drum, wherein, when positioned within the drum, the structure operates to separate cells from cell culture material into concentrates and centrifugal filtrates within an internal region of the structure. The structure in the operating position includes: The upper disc-shaped part, The cylindrical core extends vertically below the upper disc-shaped portion. The outer wall is configured to operatively engage with the drum, wherein the outer wall It extends in a fluid-sealed operative engagement with the upper disc-shaped portion and extends in a surrounding relationship with the core. It has a truncated cone shape, wherein the truncated cone shape has a smaller inner radius at the vertically positioned end of the structure away from the upper disc-shaped portion. A separation chamber is defined within the structure, extending radially between the core and the outer wall, surrounding the core. A vertically extending cell culture material feed tube is also included. Vertically extending centrifugal filter discharge tube, Vertically extending concentrate discharge pipe, The upper disc-shaped portion and the outer wall are rotatable around a vertical axis in an operable manner with the drum, and the feed pipe, the centrifugal filter discharge pipe, and the concentrate discharge pipe are coaxial with the vertical axis. The upper disk-shaped portion includes: A centrifugal filter centrifugal pump chamber, wherein the centrifugal filter centrifugal pump chamber is in fluid communication with the separation chamber through at least one centrifugal filter opening. A concentrate centripetal pump chamber, wherein the concentrate centripetal pump chamber is in fluid communication with the separation chamber through at least one concentrate channel, wherein the at least one concentrate channel The mixture includes a concentrate channel inlet, wherein the concentrate channel inlet is arranged radially outward from the at least one centrifugal filter opening within the separation chamber. Extending radially and fluidly between the at least one concentrate inlet and the concentrate centripetal pump chamber, A centrifugal filter centrifugal pump, wherein the centrifugal filter centrifugal pump is coaxially arranged around the feed pipe in the centrifugal filter centrifugal pump chamber, and the centrifugal filter centrifugal pump is in fluid communication with the centrifugal filter discharge pipe. A concentrate centrifugal pump, wherein the concentrate centrifugal pump is coaxially arranged around the feed pipe in the concentrate centrifugal pump chamber, the concentrate centrifugal pump is vertically positioned above the concentrate centrifugal pump and is in fluid communication with the concentrate discharge pipe. The rotation of the drum is operated such that the upper disc-shaped portion and the outer wall rotate relative to each of the feed pipe, the centrifugal filter discharge pipe, the concentrate discharge pipe, the centrifugal filter centrifugal pump, and the concentrate centrifugal pump. Each of the concentrate channels includes a channel portion extending between the corresponding concentrate channel inlet and the centripetal pump chamber, wherein the cross-sectional area of ​​the channel portion perpendicular to the concentrate flow direction within the corresponding concentrate channel portion gradually and continuously increases with the radial proximity to the corresponding axis.

22. The device according to claim 21, in, Each of the respective concentrate channel portions begins at the respective concentrate channel inlet of the respective concentrate channel and extends upward and radially inward from the respective channel inlet.

23. The device according to claim 22, in, At least one of the channels comprises a single, substantially annular concentrate channel.

24. The device according to claim 22, in, At least one of the channels comprises a plurality of separate, angled-spaced concentrate channels.

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