Apparatus and method for treating cell culture solution, and method for producing product

Abstract

Provided is a cell culture solution treatment apparatus comprising: a bioreactor that contains and stores a cell culture solution; a pipeline that communicates with the bioreactor; and a pump unit that feeds the cell culture solution to the pipeline. The pump unit comprises two or more pump sections disposed on the pipeline, the pump sections expanding and contracting in the radial direction of the pipeline. Also provided are a treatment method and a method for producing a product.

Description

Cell culture medium treatment device, treatment method, and product production method

[0001] The present disclosure relates to a cell culture medium treatment device, a treatment method, and a product production method.

[0002] A method for recovering a culture product contained in a cell culture solution by filtration is known for producing biopharmaceuticals and the like. The culture product is recovered from a bioreactor in which cell culture is carried out via a filtration unit. A pump is used to transfer the cell culture solution from the bioreactor to the filtration unit. WO 2015 / 039115 discloses the use of a peristaltic pump as a pump capable of transferring the cell culture solution. WO 2012 / 026978 discloses a filtration system in which the transfer is performed using a diaphragm pump.

[0003] Conventionally known peristaltic pumps, such as the peristaltic pump described in WO 2015 / 039115, pump liquid in a tube by sequentially squeezing the tube with rollers. Crushing the tube with rollers causes significant damage to cells. On the other hand, using the diaphragm pump described in WO 2012 / 026978 can reduce damage to cells. However, diaphragm pumps have a small amount of liquid delivered per hour and are not suitable for large volumes of cell culture solution. While they can be used for bioreactors with a volume of approximately 500 L, they are insufficient when culturing using bioreactors with a volume greater than that, as a larger amount of liquid delivered per hour is required. The same applies to pumps used to deliver large amounts of cell culture solution from a bioreactor to another tank.

[0004] In view of the above circumstances, the technology disclosed herein aims to provide a cell culture medium processing device, processing method, and product manufacturing method that suppresses damage to cells when cell culture medium is transported and enables large-volume transport.

[0005] The cell culture medium treatment device of the present disclosure comprises: a bioreactor that contains cell culture medium; a pipeline that communicates with the bioreactor; and a pump unit that delivers the cell culture medium to the pipeline, wherein the pump unit is a pump section disposed on the pipeline and comprises two or more pump sections that expand and contract in the radial direction of the pipeline.

[0006] The pump section is a tubular member having a hollow section through which cell culture medium flows, and also has a space between its inner wall surface and outer wall surface, and includes a tubular member in which at least the inner wall surface has elasticity that allows it to expand and contract in the radial direction of the pipeline, and the pump unit may be equipped with a fluid supply and discharge mechanism that expands the pump section by supplying fluid to the space between the inner wall surface and outer wall surface of the tubular member, and contracts the pump section by discharging fluid from the space.

[0007] The pump section is a tubular member having a hollow section through which the cell culture medium flows, and also having a space between its inner wall surface and outer wall surface, and at least the inner wall surface has elasticity that allows it to expand and contract in the radial direction of the pipeline. The pump unit may be equipped with a pressing force application mechanism that mechanically presses the inner wall surface of the tubular member radially inward of the pipeline to expand the pump section, and then releases the pressure, causing the pump section to contract using the elastic force of the tubular member.

[0008] It is preferable that the cross-sectional area ratio of the flow passage in the pump portion when expanded to that when contracted is 0.01 or more.

[0009] It is preferable that a spacer be disposed in the flow path of the pump section to prevent the flow path of the pump section from being blocked when the pump section expands. The spacer may be a tubular member made of a mesh material and having an outer diameter smaller than the inner diameter of the flow path. The spacer may be provided on the wall surface of the flow path of the pump section.

[0010] The cell culture medium treatment device of the present disclosure may further include a filtration unit on the pipeline, which has an outlet through which the cell culture medium flows in and out and through which the filtrate is discharged, and may be configured so that the cell culture medium is sent from the bioreactor to the filtration unit by expanding and contracting the pump section.

[0011] In the pipeline, pump units may be disposed on both the downstream side and the upstream side of the filtration unit. In the pipeline, the filtration unit may be connected to the bioreactor by a single conduit.

[0012] The cell culture medium treatment device of the present disclosure may further include a collection tank on the pipeline for collecting the cell culture medium, and may be configured so that the cell culture medium is sent from the bioreactor to the collection tank by expanding and contracting the pump section.

[0013] The cell culture medium processing method of the present disclosure includes a liquid delivery step in which two or more pump units that expand and contract in the radial direction of a pipe line connected to a bioreactor containing the cell culture medium are arranged on the pipe line, and the cell culture medium is delivered by expanding and contracting the pump units.

[0014] The pipeline may further include a filtration unit through which the cell culture solution flows in and out, the filtration unit having an outlet for discharging the filtrate, and the liquid transfer step is a step of transferring the cell culture solution from the bioreactor to the filtration unit, and may include a step of collecting the filtrate from the filtration unit following the liquid transfer step.

[0015] The fluid supplying step may include: (a) a step of circulating the cell culture solution from the bioreactor through the filtration unit in a first flow direction for a first period by sequentially expanding and contracting two or more pump units; (b) a step of circulating the cell culture solution through the filtration unit in a second flow direction obtained by reversing the first flow direction for a second period by sequentially expanding and contracting two or more pump units in the reverse order of step (a); (c) a step of circulating the cell culture solution through the filtration unit in the first flow direction for a third period by sequentially expanding and contracting two or more pump units in the same order as step (a), with the second flow direction reversed; and (d) a step of repeating steps (b) and (c) at least twice. Preferably, the first period and the second period are each 30 seconds or less.

[0016] The method for producing a product disclosed herein is a method for producing a product by culturing cells to obtain a product, and includes: a culturing step of culturing cells in a bioreactor containing a cell culture medium; a liquid delivery step of arranging two or more pump sections that expand and contract in the radial direction of a pipe line communicating with the bioreactor and delivering the cell culture medium to a filtration unit arranged on the pipe line by contracting and expanding the pump sections; and a collection step of collecting the filtrate containing the product filtered from the cell culture medium by the filtration unit.

[0017] The cell culture solution treatment device, treatment method, and product production method of the techniques disclosed herein can suppress damage to cells during the delivery of cell culture solution and enable large-volume delivery.

[0018] 8A is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer when contracted, and FIG. 8B is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer when expanded. FIG. 8B is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer when expanded. FIG. 8A is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer when contracted, and FIG. 8B is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer when expanded. FIG. 10A is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer of a modified example when contracted, and FIG. 10B is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer of a modified example when expanded. FIG. 11A is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer of a modified example when contracted, and FIG. 11B is a perspective view and a radial cross-sectional view of a pump unit provided with a spacer of a modified example when expanded. Fig. 12A is a perspective view and a radial cross-sectional view of a pump section equipped with a spacer of a modified example when contracted, and Fig. 12B is a perspective view and a radial cross-sectional view of a pump section equipped with a spacer of a modified example when expanded. Fig. 13A is an axial cross-sectional view and a radial cross-sectional view of a pump section equipped with a spacer of a modified example when contracted, and Fig. 13B is an axial cross-sectional view and a radial cross-sectional view of a pump section equipped with a spacer of a modified example when expanded. Fig. 13B is a view showing the overall configuration of a cell culture medium treatment device of a modified example. Fig. 13C is a view showing the overall configuration of a cell culture medium treatment device of another embodiment. Fig. 13D is a view showing the state before (A) and after (B) connection of a pump unit, a filtration unit, and piping.

[0019] The cell culture medium treatment device, treatment method, and product production method according to the present disclosure are described below. However, the present disclosure is not limited to the following embodiments and can be implemented with appropriate modifications.

[0020] In this disclosure, the term "process" includes not only an independent process but also a process that cannot be clearly distinguished from another process as long as the intended purpose of the process is achieved. Components indicated by the same reference numerals in each drawing are the same components.

[0021] In the following description, Fig. 1 is a diagram showing the overall configuration of a cell culture solution treatment device 100 according to one embodiment. The treatment device 100 shown in Fig. 1 is a product manufacturing device that cultures cells in a cell culture solution to obtain a product. In the following description, the cell culture solution will be simply referred to as the "culture solution."

[0022] The culture solution contains a medium, cells, and products produced by the cells. The cells have a diameter of, for example, 5 μm or more, and the volume fraction of cells in the culture solution is, for example, 1% or more. The viscosity μ [Pa s] of the culture solution varies depending on the type of medium and the cell concentration in the culture solution. The viscosity of the culture solution is, for example, 0.5 to 5 mPa s. Here, the viscosity of the culture solution refers to the viscosity measured using a vibration viscometer after regulating the temperature of a sample of the culture solution at 38°C.

[0023] The cells are not particularly limited, but examples include animal cells, plant cells, eukaryotic cells such as yeast, prokaryotic cells such as Bacillus subtilis, and Escherichia coli. Animal cells such as CHO (Chinese Hamster Ovary cells), BHK (Baby Hamster Kidney)-21 cells, C127 cells, HEK (Human Embryonic Kidney cells) cells (e.g., HEK293), NS0 cells, and SP2 / 0-Ag14 cells are preferred. CHO cells are more preferred because numerous analyses have been conducted and genetic engineering techniques have been established. Even if a cell does not originally produce a desired product or produces only a small amount of the desired product, the desired product can be efficiently produced by introducing an expression vector such as a plasmid encoding the required protein into the cell.

[0024] The product is not particularly limited as long as it is a substance produced by the cells in the culture medium, and examples thereof include alcohol, enzymes, antibiotics, proteins, etc. Among these, preferred products are proteins and viruses, and more preferred are antibodies.

[0025] When the product is, for example, an antibody, the antibody may be produced in animal cells such as CHO cells. Examples of antibodies produced in animal cells include, but are not limited to, anti-IL-6 receptor antibodies, anti-IL-6 antibodies, anti-glypican-3 antibodies, anti-CD3 antibodies, anti-CD20 antibodies, anti-GPIIb / IIIa antibodies, anti-TNF antibodies, anti-CD25 antibodies, anti-EGFR antibodies, anti-Her2 / neu antibodies, anti-RSV antibodies, anti-CD33 antibodies, anti-CD52 antibodies, anti-IgE antibodies, anti-CD11a antibodies, anti-VEGF antibodies, and anti-VLA-4 antibodies. Examples of antibodies include monoclonal antibodies derived from animals such as humans, mice, rats, hamsters, rabbits, and monkeys, as well as artificially modified antibodies such as chimeric antibodies, humanized antibodies, and bispecific antibodies.

[0026] By culturing the cells, the desired product can be obtained.

[0027] 1 , the processing apparatus 100 includes a bioreactor 10, a filtration unit 20, a pump unit PU including a product recovery section 30 and a pump section P, conduits 61 and 62, and a processor 70. In this example, the conduits 61 and 62, the filtration unit 20, and the pump section P constitute a "pipe line communicating with the bioreactor" in the technology of the present disclosure. The pipe line is a general term for the portion outside the bioreactor 10 through which the culture medium flows.

[0028] The bioreactor 10 is a culture vessel that contains a culture medium and cultures cells in the culture medium. The culture process is carried out in the bioreactor 10. The bioreactor 10 preferably has a capacity of more than 500 L. The capacity of the bioreactor 10 is preferably 1000 L or more, and more preferably 2000 L or more. Furthermore, the capacity of the bioreactor 10 is preferably 200,000 L or less.

[0029] The filtration unit 20 includes, for example, a container 21 and a separation membrane 22 that divides the space within the container 21 into a supply side and a permeation side and performs membrane separation treatment on the culture solution delivered from the bioreactor 10. The filtration unit 20 has a first opening 20a and a second opening 20b through which the culture solution flows in and out. The filtration unit 20 has an outlet 20c on the permeation side that is connected to a conduit 62 that is connected to an external product recovery section 30. In this example, the culture solution delivered from the bioreactor 10 flows into the container 21 through the first opening 20a and flows along the membrane surface of the separation membrane 22 as it flows out of the container 21 through the second opening 20b. As a result, in this example, membrane separation is performed using the tangential flow method. In the membrane separation treatment using the tangential flow method, the culture solution sent from the bioreactor 10 may form a flow that circulates in one direction parallel to the membrane surface of the separation membrane 22, or the culture solution may form a flow that reciprocates along the membrane surface of the separation membrane. The treatment device 100 shown in Fig. 1 is a system that forms a flow that reciprocates along the membrane surface of the separation membrane 22 in the filtration unit 20, and the treatment device 101 shown in Fig. 14 described below is a system that can realize both a flow that circulates in one direction and a flow that reciprocates along the membrane surface of the separation membrane 22 in the filtration unit 20.

[0030] The separation membrane 22 does not allow cells in the culture solution to pass through, but allows products produced by the cells to pass through. A microfiltration membrane or an ultrafiltration membrane can be used as the separation membrane 22. A mesh filter or a hollow fiber membrane can be used as the separation membrane 22.

[0031] While the culture medium flows along the surface of the separation membrane, the permeate containing the product permeates from the supply side to the permeation side of the separation membrane 22. The permeate containing the product is discharged from the outlet 20c to the outside of the container 21 and recovered in the product recovery section 30. The product recovery section 30 functions as a recovery tank and a production treatment section for purifying the product.

[0032] One end of the conduit 61 is connected to the bioreactor 10, and the other end is connected to a first opening 20a that communicates with the supply side of the filtration unit 20 via a pump section P, which will be described later. In this example, the bioreactor 10 and the filtration unit 20 are connected only by this single conduit 61. One end of the conduit 62 is connected to the outlet 20c of the filtration unit 20, and the other end is connected to the product recovery section 30.

[0033] The pump unit PU delivers the culture solution to the pipeline. In this example, the pump unit PU includes four pump units P arranged on the pipeline and a fluid supply / discharge mechanism 50 as a drive unit for driving the pump units P. Of the four pump units P, two are arranged on the first opening 20a side of the filtration unit 20, and two are arranged on the second opening 20b side of the filtration unit 20. Assuming that the flow from the bioreactor 10 to the filtration unit 20 is forward, the first opening 20a is upstream and the second opening 20b is downstream. The pump units P expand and contract in the radial direction of the pipeline, thereby reducing and increasing the cross-sectional area of ​​the flow path through which the culture solution flows, thereby delivering the culture solution at least from the bioreactor 10 to the filtration unit 20. Hereinafter, the portion of the pump unit PU arranged on the first opening 20a side will be referred to as the first pump unit unit PUP1, and the portion arranged on the second opening 20b side will be referred to as the second pump unit unit PUP2.

[0034] Fig. 2 is a perspective view showing the appearance of the pump unit P. Fig. 2 shows two pump units P connected together. The pump unit P has a main body 40 made of a cylindrical member and flanges 41, 42 provided on both ends of the main body 40. The two pump units P are connected together by the flange 42 on one side and the flange 41 on the other side.

[0035] Figure 3 shows a cross-sectional view along the axial direction and a cross-sectional view along the radial direction of the pump portion P when the pump portion P is contracted. Figure 4 shows a cross-sectional view along the axial direction and a cross-sectional view along the radial direction of the pump portion P when the pump portion P is expanded. In Figures 3 and 4, the cross-sectional view along the radial direction (right figure) is a cross-sectional view taken along line A-A in the left figure.

[0036] As described above, the pump section P has a main body section 40 made of a cylindrical member having a hollow section 40a through which the culture medium flows, and flanges 41, 42 provided on both ends of the main body section 40. The hollow section 40a is a flow path through which the culture medium flows and constitutes part of a conduit. The main body section 40 has an inner wall member 44 that forms an inner wall surface 44a and an outer wall member 45 that forms an outer wall surface 45a. The main body section 40 has a space 46 between the inner wall surface 44a and the outer wall surface 45a, i.e., between the inner wall member 44 and the outer wall member 45.

[0037] The inner wall member 44 is a cylindrical body having elasticity that expands and contracts radially. The inner wall member 44 comes into contact with the culture medium when the culture medium is delivered. Therefore, the inner wall member 44 is subjected to sterilization treatment such as steam sterilization and gamma ray sterilization. While details of sterilization treatment will be described later, it is preferable to use a material that is resistant to sterilization treatment for the inner wall member 44. Therefore, the inner wall member 44 preferably has a high elongation rate (e.g., 150% or more) and low leakage, as well as heat resistance (e.g., 120°C or more) when steam sterilization is performed and radiation resistance when gamma ray sterilization is performed. The inner wall member 44 is made of an elastic material such as rubber or elastomer, such as natural latex rubber or silicone rubber. More specifically, materials that are suitable for both steam sterilization and gamma ray sterilization include silicone rubber, fluororubber, epichlorohydrin rubber, chloroprene rubber, chlorosulfone polyethylene (Hypalon), nitrile rubber, acrylic rubber, and thermoplastic elastomers (e.g., styrene-based thermoplastic elastomers). Materials suitable for gamma ray sterilization include natural rubber, synthetic natural rubber (e.g., isoprene rubber), styrene, butadiene rubber, urethane rubber, and multi-flow rubber. Materials suitable for steam sterilization include butyl rubber, ethylene propylene rubber, and the like. The outer wall member 45 is a cylindrical body that is concentric with the inner wall member 44 and has a larger diameter, and is made of metal, resin, or the like. The outer wall member 45 may be made of an elastic material, similar to the inner wall member 44. However, it is preferable that the elastic modulus of the outer wall member 45 is greater than that of the inner wall member 44. As an example, in this embodiment, the outer wall member 45 is made of a material that has a greater elastic modulus than that of the inner wall member 44.

[0038] The inner wall member 44 and the outer wall member 45 are fixed at both ends to the flanges 41 and 42, respectively. The flanges 41 and 42 are both flat, rectangular plates with circular center holes 41a and 42a in the center. One end of the inner wall member 44 is fixed to the flange 41 by wrapping around the surface of the flange 41, and the other end is fixed to the flange 42 by wrapping around the surface of the flange 42. Here, the surfaces of the flanges 41 and 42 refer to the surfaces facing outward in the axial direction of the main body 40, and the back surfaces of the flanges 41 and 42 refer to the surfaces facing inward in the axial direction of the main body 40. The back surfaces of the flanges 41 and 42 have grooves 41b and 42b concentric with the center holes 41a and 42a, respectively, outside the center holes 41a and 42a. One end of the outer wall member 45 is inserted into a groove 41b on the back surface of the flange 41, and the other end is inserted into a groove 42b on the back surface of the flange 42, and is fixed to the flanges 41, 42. The surfaces of the flanges 41 and 42 are configured to be connectable to each other.

[0039] Both ends of the inner wall member 44 and the outer wall member 45 are fixed to flanges 41 and 42, respectively, and a space 46 between the inner wall surface 44a and the outer wall surface 45a is a closed space. The pump section P is configured so that when a fluid is supplied to the space 46, the inner wall member 44 expands in the radial direction of the hollow section 40a. The flange 41 is provided with a supply / discharge hole 41c that communicates with the space 46 and supplies and discharges fluid from the space 46. The supply / discharge hole 41c is connected to a fluid supply / discharge mechanism 50. The outer wall member 45, flanges 41, 42, etc. are preferably made of a material that is resistant to sterilization treatment. Specific examples include stainless steel, polypropylene, and polycarbonate.

[0040] The fluid supply / discharge mechanism 50 is a drive unit that drives the pump unit P. The fluid supply / discharge mechanism 50 supplies fluid to the space 46 between the inner wall member 44 and the outer wall member 45 of the pump unit P to expand the space 46, and discharges fluid from the space 46 to contract the space 46. Note that "expanding the space 46" corresponds to "expanding the pump unit" in this disclosure, and "contracting the space 46" corresponds to "contracting the pump unit" in this disclosure. When the pump unit P expands, the cross-section of the flow path formed by the hollow portion 40a through which the culture medium flows becomes smaller, and when the pump unit P contracts, the cross-section of the flow path formed by the hollow portion 40a becomes larger. In other words, expansion and contraction of the pump unit P mean the contraction and shrinkage of the flow path cross-section.

[0041] The fluid may be a gas such as air, or a liquid such as water or oil. As an example, the fluid supply / discharge mechanism 50 includes a compressor, and supplies / discharges compressed air as the fluid to / from the space 46 of each pump portion P.

[0042] In the present treatment device 100, the pump unit PU includes four pump sections P, two of which are disposed upstream and two of which are disposed downstream of the filtration unit 20. However, two or more pump sections P may be included. When the pump unit PU includes only two pump sections P, the two connected pump sections P may be disposed either upstream or downstream of the filtration unit 20, or one pump section P may be disposed upstream and one pump section P may be disposed downstream. When the pump unit PU includes three or more pump sections P, three or more pump sections P may be connected only upstream or downstream of the filtration unit 20, or one pump section P may be disposed upstream and one pump section P may be disposed downstream. That is, the pump unit PU may include only one of the first pump section PUP1 and the second pump section PUP2, or each of the first pump section PUP1 and the second pump section PUP2 may include one or more pump sections P. Connecting multiple pump sections P can increase the liquid delivery capacity. It is more preferable to provide three pump sections P on each of the upstream side and downstream side of the filtration unit 20. It is preferable to install the pump sections P in consideration of the pressure loss in the pump sections P.

[0043] The processor 70 controls the fluid supply / discharge mechanism 50 and controls the timing of expansion and contraction of each pump unit P to send the culture solution from the bioreactor 10 to the filtration unit 20. The processor 70 can also control the timing of expansion and contraction of each pump unit P to switch between forward flow (sending the culture solution from the bioreactor 10 to the filtration unit 20) and reverse flow (sending the culture solution from the filtration unit 20 to the bioreactor 10). Staggering the timing of expansion and contraction of multiple pump units P can achieve the sending of the culture solution. For example, the pump units P are arranged from upstream to downstream based on the flow direction of the culture solution, and the pump units P are expanded in the order of arrangement so that the cross-sectional area of ​​the hollow portion 40a (i.e., the conduit) becomes gradually smaller, starting from the upstream pump unit P.

[0044] "Cell Culture Solution Treatment Method" Here, an example of a cell culture solution treatment method using the treatment device 100 configured as described above will be described. The cell culture solution treatment method using the treatment device 100 includes at least a liquid sending step of sending the culture solution by expanding and contracting the pump section P. In this example, the cell culture solution treatment method further includes a step of collecting filtrate from the filtration unit 20 (filtrate collection step). Note that this treatment method also includes a culture step of culturing cells in the bioreactor 10, and the filtrate separated from the culture solution by the filtration unit 20 contains a product of the cells, so this treatment method is also an example of a method for producing a product.

[0045] The liquid supply process includes a process in which the pump unit PU sequentially expands and contracts the four pump sections P at predetermined timings to supply the culture solution from the bioreactor 10 to the filtration unit 20, and a process in which the culture solution is supplied from the filtration unit 20 to the bioreactor 10. In the process of supplying the culture solution from the bioreactor 10 to the filtration unit 20, the culture solution supplied from the bioreactor 10 flows from the first opening 20a into the filtration unit 20 and toward the second opening 20b in a first flow direction. In addition, in the process of supplying the culture solution from the filtration unit 20 to the bioreactor 10, the culture solution flows in the filtration unit 20 in a second flow direction from the second opening 20b toward the first opening 20a. In other words, the culture solution flows back and forth within the filtration unit 20 along the membrane surface of the separation membrane 22 in the filtration unit 20. As the culture solution flows along the membrane surface of the separation membrane 22 within the filtration unit 20, the separation membrane 22 allows the filtrate containing the product to permeate to the permeate side. This separates the cells and the product in the culture solution. Then, in the filtrate collection step, the filtrate is discharged from the outlet 20c of the filtration unit 20 and collected in the product recovery section 30. Note that the conduit 62 connecting the filtration unit 20 and the product recovery section 30 may be equipped with a pump (not shown).

[0046] As described above, the liquid transfer process of the cell culture solution treatment method using the present treatment device 100 includes a process of transferring the culture solution from the bioreactor 10 to the filtration unit 20 in a first flow direction and transferring the culture solution from the filtration unit 20 to the bioreactor 10 in a second flow direction that is the opposite direction of the culture solution. More specifically, the liquid supplying step preferably includes: (a) a step of circulating the culture solution from the bioreactor 10 through the filtration unit 20 in a first flow direction for a first period by sequentially expanding and contracting the plurality of pump parts P; (b) a step of circulating the culture solution through the filtration unit 20 in a second flow direction obtained by reversing the first flow direction for a second period by sequentially expanding and contracting the plurality of pump parts P in the reverse order of step (a); (c) a step of circulating the culture solution through the filtration unit 20 in the first flow direction for a third period by sequentially expanding and contracting the plurality of pump parts P in the same order as step (a), thereby reversing the second flow direction; and (d) a step of repeating steps (b) to (c) at least twice.

[0047] In steps (a) and (c), when the culture medium is fed in the first flow direction (i.e., forward feed), the culture medium flows into the filtration unit 20 from the first opening 20a, then flows from the first opening 20a to the second opening 20b in the filtration unit 20, and then flows out from the second opening 20b to the pump section P. In step (b), when the culture medium is fed in the second flow direction (i.e., reverse feed), the culture medium flows from the pump section P located on the second opening 20b side of the filtration unit 20 into the filtration unit 20 from the second opening 20b, then flows from the second opening 20b to the first opening 20a in the filtration unit 20, and then flows out from the first opening 20a toward the bioreactor 10. As the culture medium flows through the filtration unit 20 in the first and second flow directions, the product is filtered by the separation membrane 22, and the filtrate containing the product moves to the permeate side. Then, in the filtrate collection step, the filtrate is collected in the product recovery section 30. In this example, the filtrate collection step is carried out in parallel with the liquid transfer step.

[0048] The first period in step (a), the second period in step (b), and the third period in step (c) are not particularly limited, but the first period and the second period are each preferably 30 seconds or less, more preferably less than 30 seconds, and the third period is also preferably 30 seconds or less, even more preferably less than 30 seconds.

[0049] In this way, by circulating the culture solution within the filtration unit 20 by reversing the flow between the first flow direction and the second flow direction multiple times, a flushing effect can be achieved against adhesions such as clogging substances that have adhered to the wall surface of the separation membrane 22, and clogging of the separation membrane 22 can be suppressed.

[0050] As described above, the cell culture medium treatment device 100 of this embodiment includes a bioreactor 10, a conduit communicating with the bioreactor 10, and a pump unit PU. The pump unit PU includes two or more pump units P arranged on the conduit. The pump unit P delivers the culture medium by expanding and contracting radially along the conduit. Conventional tube pumps deliver the culture medium by compressing the tube (conduit) with a rotor, sequentially blocking the flow path, resulting in high shear stress and susceptibility to cell damage. However, the pump unit P of the present treatment device 100, which expands and contracts radially, reduces the shear stress applied to the culture medium during delivery, thereby minimizing cell damage. Furthermore, while it is difficult to increase the flow rate with a diaphragm pump, the pump unit P of the present treatment device 100 also enables increased flow rate.

[0051] The pump section P of this embodiment is a cylindrical member having a hollow section 40a through which the culture medium flows. The pump section P has a space 46 between an inner wall surface 44a and an outer wall surface 45a. The inner wall surface 44a has elasticity that allows expansion and contraction in the radial direction of the conduit. The pump unit PU includes a fluid supply / discharge mechanism 50 that supplies fluid to the space 46 to expand the pump section P and discharges fluid from the space 46 to contract the pump section P. With this configuration, the expansion and contraction of the space 46 causes peristaltic movement that increases or decreases the cross-sectional area of ​​the hollow section 40a through which the culture medium flows, thereby pumping the culture medium. The fluid supply / discharge mechanism 50 adjusts the amount of fluid supplied to the space 46 so as not to completely block the hollow section 40a, which serves as the flow path, thereby suppressing shear stress.

[0052] The method for treating a cell culture solution according to this embodiment includes a liquid delivery step in which two or more pump units P that expand and contract in the radial direction of a conduit connected to a bioreactor 10 containing the culture solution are arranged in the conduit, and the culture solution is delivered by expanding and contracting the pump units P. By adjusting the expansion and contraction of the pump units P, the culture solution can be delivered without blocking the flow path, as occurs when the tube is crushed by rollers in conventional tube pumps, thereby minimizing damage to the cells.

[0053] In addition, as a method for producing a product, it is preferable to use perfusion culture, which further includes a supply step of supplying fresh medium to a bioreactor. Perfusion culture is a culture method in which fresh medium is added and used medium is simultaneously removed. In perfusion culture, 100 × 10 ６It is possible to achieve high cell densities exceeding 10 ...

[0054] In the method for producing the product, the cell density of the culture medium is preferably 30 x 10 ６ The cell density of the culture medium is 50 x 10 cells / mL or more. ６ More preferably, 80 x 10 cells / mL or more ６ More preferably, 120 x 10 cells / mL or more ６ More preferably, 150 x 10 cells / mL or more ６ The cell density of the culture medium is preferably 400 x 10 cells / mL or more. ６ cells / mL or less, more preferably 250 x 10 ６ The cell density can be determined by measuring the number of cells by a standard method and dividing the number of cells by the volume of the culture medium.

[0055] The cell density of the culture medium was 30 × 10 ６ When the concentration is high, such as 100 cells / mL or more, the effect of suppressing cell damage by the technology of the present disclosure becomes more effective.

[0056] It should be noted that the mechanism for expanding and contracting the inner wall surface 44a of the pump unit PU is not limited to the fluid supply / discharge mechanism 50 that supplies and discharges fluid to and from the space 46 as described above. Figures 5 to 7 are explanatory diagrams of a modified pump unit PU2. Figure 5 shows one pump section P and its drive mechanism as a schematic configuration of the pump unit PU2. Figures 6 and 7 show the pump section P of the pump unit PU2 in a contracted state and an expanded state. In Figures 6 and 7, the left figures are cross-sectional views along the axial direction of the pump section P, and the right figures are cross-sectional views taken along line A-A of the left figures.

[0057] As shown in FIG. 5 , the pump unit PU2 of the modified example includes a pressing force application mechanism 52 that mechanically presses the inner wall surface 44a radially inward of the hollow portion 40a, instead of the fluid supply / discharge mechanism 50 that supplies / discharges fluid to / from the space 46. The pressing force application mechanism 52 includes a pressing member 54 and a drive unit 55 that drives the pressing member 54. The pressing member 54 has a pressing portion 54a that is disposed in the space 46 between the inner wall member 44 and the outer wall member 45 and presses against the inner wall member 44, and is movable in the radial direction within the space 46. The drive unit 55 is a moving mechanism that reciprocates the pressing member 54 in the radial direction, and is, for example, a linear actuator equipped with a stepping motor 55a as shown in FIG. 5 .

[0058] In the drive unit 55, rotation of the stepping motor 55a rotates a gear 55b provided at the tip of the motor, which in turn rotates a ball screw 55c via a gear 55d provided at one end of the ball screw 55c. The pressing member 54 is fixed to an attachment portion 55e that moves along the ball screw 55c as the ball screw 55c rotates, and moves in the axial direction of the ball screw 55c as the attachment portion 55e moves. The axial direction of the ball screw 55c is aligned with the radial direction of the hollow portion 40a, and the pressing member 54 is movable in the radial direction of the hollow portion 40a.

[0059] As shown in Figures 6 and 7, the pressing portion 54a of the pressing member 54 has a shape that extends along the axial direction of the main body portion 40. In this example, four pressing members 54 are arranged at 90° intervals on the outer peripheral surface of the inner wall member 44. Each of the four pressing members 54 is configured to be movable in the radial direction by a drive unit 55. As shown in Figure 7, the four pressing members 54 press the inner wall member 44 inward, causing the inner wall member 44 to expand, and as a result, causing the pump portion P to expand. By returning the pressing member 54 to the position shown in Figure 6, the pressure on the inner wall member 44 is released, causing the inner wall member 44 to contract, and as a result, causing the pump portion P to contract. The drive unit 55 is controlled by a processor 70.

[0060] Like the pump unit PU2 of the modified example, by providing a pressing force application mechanism 52 that mechanically presses the inner wall surface 44a radially inward of the hollow portion 40a, the culture solution can be pumped by peristaltic movement that increases or decreases the cross-sectional area of ​​the hollow portion 40a through which the culture solution flows by expanding or contracting the space 46. By controlling the amount of radial movement of the pressing member 54 by the pressing force application mechanism 52, it is possible to adjust the amount of movement so that the hollow portion 40a, which serves as the flow path, is not completely blocked, and shear stress can be suppressed.

[0061] When the culture medium is being delivered by the pump unit PU of the treatment device 100 of the above embodiment or the pump unit PU2 of the modified example, it is preferable that the ratio S2 / S1 of the cross-sectional area S2 of the hollow portion 40a when the pump portion P is expanded as shown in Figure 4 or 6 to the cross-sectional area S1 of the hollow portion 40a when the pump portion P is contracted as shown in Figure 3 or 5 be 0.01 or more. Note that the cross-sectional areas S1 and S2 are the cross-sectional areas at approximately the center position in the axial direction of the main body portion 40. By ensuring that the hollow portion 40a is not completely blocked when expanded, damage to the cells can be suppressed.

[0062] As mentioned above, damage to the culture medium and therefore to the cells can be suppressed by controlling the expansion of the pump section P using the fluid supply / discharge mechanism 50 or the pressing force application mechanism 52. However, to more reliably prevent blockage of the flow path consisting of the hollow section 40a of the pump section P, it is preferable to provide a spacer 80 in the hollow section 40a.

[0063] Fig. 8A shows the pump section P equipped with the spacer 80 in a contracted state, and Fig. 8B shows the pump section P in an expanded state. Fig. 9 is a perspective view of the spacer 80. In Figs. 8A and 8B, the left figure is a perspective view of the pump section P, and the right figure is a cross-sectional view taken along line A-A in the left figure. Note that Figs. 8A and 8B omit the thicknesses of the inner wall member 44 and the outer wall member 45, and the flanges 41, 42 at both ends of the main body 40. The same applies to Figs. 10A to 12A and 10B to 12B, which will be described later.

[0064] As shown in FIG. 9 , the spacer 80 is a cylindrical member made of a mesh material. The spacer 80 has an outer diameter smaller than the inner diameter of the hollow portion 40a. In this example, the spacer 80 has a length approximately equal to that of the main body portion 40. As shown in FIG. 8A , the spacer 80 is disposed approximately at the center of the hollow portion 40a of the main body portion 40. As shown in FIG. 8A , the spacer 80 is fixed at the end of the main body portion 40 by a fixing portion 81 indicated by a dashed line. As shown in FIG. 8B , when the pump portion P expands, i.e., when the space 46 expands, the spacer 80 restricts the expansion of the inner wall member 44 as it expands toward the radial center of the hollow portion 40a. The spacer 80 reliably prevents the hollow portion 40a from being blocked.

[0065] The spacer 80 is a cylindrical member, but the spacer in the technology of the present disclosure is not limited to a cylindrical member. As shown in Figures 10A and 10B, the spacer 80 may be a spacer 82 made of a tubular member having a square prism-like outer shape. Furthermore, although not shown, the spacer 80 may be a tubular member having a triangular prism-like outer shape or a polygonal prism-like outer shape having pentagonal or more polygonal prism-like outer shape.

[0066] 8A shows a configuration in which the spacer 80 is fixed to the center of the hollow portion 40a by the fixing portion 81, but as shown in Fig. 11A, the spacer 80 may be fixed to the inner wall surface 44a of the main body portion 40. When the spacer 80 is fixed to the inner wall surface 44a as shown in Fig. 11A, when the pump portion P expands, the inner wall surface 44a expands substantially evenly, and the spacer 80 is positioned approximately at the center of the main body portion 40.

[0067] 8A, 10A, and 11A, spacers 80, 82 having a length substantially equal to that of the main body 40 are provided. However, as shown in FIGS. 12A and 12B, multiple short spacers 83 may be arranged in the axial direction of the main body 40. As shown in FIGS. 8A, 10A, and 11A, when only one spacer 80, 82 is provided, the length of the spacer 80, 82 is preferably equal to or equal to half the axial length of the main body 40. When the spacer 80, 82 is shorter than the length of the main body 40, it is preferable that the spacer 80, 82 be arranged in the axial center of the main body 40. When multiple short spacers 83 are arranged at intervals in the axial direction of the main body 40 as shown in FIGS. 12A and 12B, it is preferable that the total axial length of the short spacers 83 in the axial direction of the main body 40 be at least half the axial length of the main body 40.

[0068] Furthermore, the spacer that prevents the hollow portion 40a from being blocked is not limited to the above-described embodiment. As shown in FIGS. 13A and 13B , a spacer 85 may be provided on the inner wall surface 44a of the inner wall member 44. The spacer 85 is provided as a protrusion that protrudes inward from the inner wall surface 44a as part of the inner wall member 44. In this example, a plurality of spacers 85 are provided on the inner wall surface 44a. As shown in FIG. 13B , the spacers 85 that are positioned opposite each other are in contact with each other. Even when the pump portion P is expanded, space remains in the hollow portion 40a in areas other than where the spacers 85 are in contact with each other, preventing the hollow portion 40a from being completely blocked.

[0069] In the treatment device 100 of the embodiment described above, the filtration unit 20 and the bioreactor 10 are connected by a single conduit 61. The treatment device of the present disclosure is not limited to this configuration, and may include a conduit 63 arranged on the second opening 20b side of the filtration unit 20 to connect the pump section P and the bioreactor 10, as in a treatment device 101 of a modified example shown in FIG. 14 . In the case of the treatment device 101, during forward flow from the bioreactor 10 to the filtration unit 20 via the conduit 61, the culture solution flowing out from the second opening 20b of the filtration unit 20 does not remain at the pump section P but is sent to the bioreactor 10 via the conduit 63. During reverse flow, the culture solution is sent from the bioreactor 10 to the pump section P on the second opening 20b side of the filtration unit 20 via the conduit 63, and the culture solution flows into the filtration unit 20 from the second opening 20b. In the treatment device 101 shown in FIG. 14, the culture solution may be filtered by flowing it in only the first flow direction or in only the second flow direction in the filtration unit 20 without switching the liquid supply direction.

[0070] Furthermore, a configuration not including the filtration unit 20 is also contemplated for the cell culture medium treatment device of the present disclosure. Figure 15 shows a schematic configuration of a treatment device 102 of another embodiment. The treatment device 102 shown in Figure 15 includes a bioreactor 10, a conduit 64, a pump unit PU3, a recovery tank 110, and a processor 70. In this example, the conduit 64, the pump unit P, and the recovery tank 110 constitute the "pipe line communicating with the bioreactor" of the technology disclosed herein. The pump unit PU3 includes three pump units P arranged on the pipe line and a fluid supply / discharge mechanism 50 that serves as a drive unit for the pump units P. Although the pump unit PU3 of this example includes three connected pump units P, the number of pump units P may be two or more.

[0071] One end of the conduit 64 is connected to the bioreactor 10 and the other end is connected to the recovery tank 110 via the pump section P.

[0072] The three pump units P expand and contract sequentially, thereby sending the culture medium from the bioreactor 10 to the collection tank 110. In this example, the processor 70 also controls the fluid supply and discharge mechanism 50, and controls the timing of expansion and contraction of each pump unit P in order to send the culture medium from the bioreactor 10 to the collection tank 110.

[0073] In this way, the treatment device 102 equipped with the pump unit PU3, which has two or more pump sections that expand and contract in the radial direction of the pipeline, for transferring the culture solution from the bioreactor 10 to the recovery tank 110, can reduce damage to cells when transferring the culture solution compared to when a conventional tube pump is used. Also, the flow rate can be increased compared to when a diaphragm pump is used.

[0074] In the above embodiment, the hardware structure of the processor 70 may be any of the various processors listed below. The various processors include a CPU, which is a general-purpose processor that executes software (programs) and functions as various processing units, as well as dedicated electrical circuits, such as a PLD (Programmable Logic Device) whose circuit configuration can be changed after manufacture, such as an FPGA (Field-Programmable Gate Array), and an ASIC (Application Specific Integrated Circuit), which is a processor having a circuit configuration specifically designed to execute specific processing.

[0075] The above-described processing may be performed by one of these various processors, or by a combination of two or more processors of the same or different types (e.g., a plurality of FPGAs, or a combination of a CPU and an FPGA). Furthermore, a plurality of processing units may be configured by a single processor. An example of configuring a plurality of processing units by a single processor is a system-on-chip (SOC), in which a processor is used to realize the functions of an entire system including a plurality of processing units on a single IC (Integrated Circuit) chip.

[0076] Furthermore, more specifically, the hardware structure of these processors can be an electric circuit that combines circuit elements such as semiconductor elements.

[0077] In addition to the operating program of the analytical device, the technology disclosed herein also extends to a computer-readable storage medium (such as a USB memory or a DVD (Digital Versatile Disc)-ROM (Read Only Memory)) that non-temporarily stores the operating program of the analytical device.

[0078] Here, the connection structure between the piping and the filtration unit after sterilization of the pump unit PU will be described. Fig. 16(A) shows the state before assembly of the main components of the treatment device 101 shown in Fig. 14, and Fig. 16(B) shows the state after assembly of the main components.

[0079] As shown in FIG. 16(A), an air filter AF is provided at the end of the tube constituting the conduit 61 connected to the bioreactor 10. The first pump unit section PUP1 and the second pump unit section PUP2 each have tubes 91 and 92 with air filters AF at both ends. The pump unit sections PUP1 and PUP2 are connected to the tubes 91 and 92, and the filtration unit 20 is connected to a tube 97 using appropriate joints. For example, the first pump unit section PUP1 and the second pump unit section PUP2 are each provided with a ferrule 94 on the flange connecting to the filtration unit 20, and the tube 92 is connected to the ferrule 94. Similarly, the filtration unit 20 is provided with a ferrule 96 at both ends, and each ferrule 96 is connected to a tube 97 with an air filter AF. The air filter AF allows steam to pass through during steam sterilization but also functions to prevent the intrusion of foreign matter from the outside. Note that in FIGS. 1 and 14, some of the tubing and ferrules connecting the units are omitted.

[0080] The conduit 61 connected to the bioreactor 10, the first pump unit section PUP1, the filtration unit 20, and the second pump unit section PUP2 are each subjected to a sterilization process such as steam sterilization or gamma ray sterilization in the pre-assembled state shown in FIG. 16(A). After the sterilization process, the tubes constituting the ends of each unit are aseptically connected to each other. Specifically, the tubes are aseptically connected to each other by welding using, for example, Biowelder (registered trademark). As shown in FIG. 16(B), the ends of the tubes equipped with the air filter AF are cut off and the tubes are connected to each other.

[0081] If the first pump unit part PUP1, the second pump unit part PUP2, the filtration unit 20, and other units are not to be used immediately after sterilization, they are stored in a sterilized bag or the like, and are removed from the sterilized bag when they are to be used.

[0082] After being used in the processing device 101, the first pump unit part PUP1 and the second pump unit part PUP2 can be washed and sterilized, so that they can be reused.

[0083] 16(A), the conduit 61 connected to the bioreactor 10, the first pump unit section PUP1, the filtration unit 20, and the second pump unit section PUP2 may be connected by aseptically connecting the tubes together, or by providing aseptic connectors at the ends of the tubes and connecting the connectors together. An example of an aseptic connector is a CPC coupling for aseptic connection from CPC (Colder Products Company).

[0084] The above-described description and illustrations are a detailed explanation of the parts related to the technology of the present disclosure and are merely an example of the technology of the present disclosure. For example, the above description of the configuration, functions, actions, and effects is an explanation of an example of the configuration, functions, actions, and effects of the parts related to the technology of the present disclosure. Therefore, it goes without saying that unnecessary parts may be deleted, new elements may be added, or replacements may be made to the above-described description and illustrations within the scope of the gist of the technology of the present disclosure. Furthermore, to avoid confusion and facilitate understanding of the parts related to the technology of the present disclosure, the above-described description and illustrations omit explanations of common technical knowledge that do not require particular explanation to enable the implementation of the technology of the present disclosure.

[0085] The disclosures of Japanese Patent Application No. 2023-166525 filed on September 27, 2023, and Japanese Patent Application No. 2024-023031 filed on February 19, 2024 are incorporated herein by reference in their entirety. All documents, patent applications, and technical standards described herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard were specifically and individually indicated to be incorporated by reference.

[0086] The following additional notes are further disclosed regarding the above embodiment.

[0087] <Supplementary Note 1> A cell culture solution treatment device comprising: a bioreactor that stores a cell culture solution; a pipeline that communicates with the bioreactor; and a pump unit that delivers the cell culture solution to the pipeline, wherein the pump unit is a pump section disposed on the pipeline and comprises two or more pump sections that expand and contract in a radial direction of the pipeline. <Supplementary Note 2> The cell culture solution treatment device according to Supplementary Note 1, wherein the pump section is a tubular member having a hollow section through which the cell culture solution flows, the tubular member having a space between its inner wall surface and its outer wall surface, and at least the inner wall surface having elasticity that allows it to expand and contract in the radial direction of the pipeline, and the pump unit comprises a fluid supply and discharge mechanism that supplies fluid to the space between the inner wall surface and the outer wall surface of the tubular member to expand the pump section and discharges fluid from the space to contract the pump section. <Supplementary Note 3> The cell culture medium treatment device according to Supplementary Note 1, wherein the pump section is a tubular member having a hollow section through which the cell culture medium flows, a space between the inner wall surface and the outer wall surface, and at least the inner wall surface has elasticity that allows it to expand and contract in the radial direction of the pipeline, and the pump unit includes a pressing force application mechanism that mechanically presses the inner wall surface of the tubular member radially inward of the pipeline to expand the pump section and releases the pressure to contract the pump section using the elastic force of the tubular member. <Supplementary Note 4> The cell culture medium treatment device according to any one of Supplements 1 to 3, wherein a cross-sectional area ratio of the flow path of the pump section when expanded to that when contracted is 0.01 or more. <Supplementary Note 5> The cell culture medium treatment device according to any one of Supplements 1 to 4, wherein a spacer is disposed in the flow path of the pump section to prevent blockage of the flow path of the pump section when the pump section is expanded. <Supplementary Note 6> The cell culture medium treatment device according to Supplementary Note 5, wherein the spacer is a tubular member made of a mesh material and having an outer diameter smaller than the inner diameter of the flow path. <Supplementary Note 7> The cell culture solution treatment device according to Supplementary Note 5, wherein a spacer is provided on a wall surface of the flow path of the pump section.<Appendix 8> The cell culture solution treatment device according to any one of Appendices 1 to 7, further comprising a filtration unit on the pipeline, the filtration unit having an outlet through which the cell culture solution flows in and out and through which a filtrate is discharged, wherein the cell culture solution is sent from the bioreactor to the filtration unit by expansion and contraction of the pump unit. <Appendix 9> The cell culture solution treatment device according to Appendices 8 and 9, wherein the pump units are arranged on the pipeline respectively downstream and upstream of the filtration unit. <Appendix 10> The cell culture solution treatment device according to Appendices 8 or 9, wherein the filtration unit is connected to the bioreactor by a single conduit on the pipeline. <Appendix 11> The cell culture solution treatment device according to any one of Appendices 1 to 10, further comprising a recovery tank on the pipeline for recovering the cell culture solution, wherein the cell culture solution is sent from the bioreactor to the recovery tank by expansion and contraction of the pump unit. <Supplementary Note 12> A method for treating a cell culture solution, comprising a liquid feeding step of disposing two or more pump units that expand and contract in a radial direction of a pipe line connected to a bioreactor that contains the cell culture solution, and feeding the cell culture solution by expanding and contracting the pump units. <Supplementary Note 13> The method for treating a cell culture solution according to Supplementary Note 12, further comprising a filtration unit, into which the cell culture solution flows and which has an outlet for discharging the filtrate, disposed in the pipe line, wherein the liquid feeding step is a step of feeding the cell culture solution from the bioreactor to the filtration unit, and comprising a step of collecting the filtrate from the filtration unit following the liquid feeding step. <Supplementary Note 14> The method for treating a cell culture solution according to Supplementary Note 13, wherein the solution sending step includes: (a) a step of circulating the cell culture solution from the bioreactor through the filtration unit in a first flow direction for a first period by sequentially expanding and contracting two or more pump units; (b) a step of circulating the cell culture solution through the filtration unit in a second flow direction obtained by reversing the first flow direction for a second period by sequentially expanding and contracting two or more pump units in the reverse order of step (a); (c) a step of circulating the cell culture solution through the filtration unit in the first flow direction by reversing the second flow direction for a third period by sequentially expanding and contracting two or more pump units in the same order as step (a); and (d) a step of repeating steps (b) to (c) at least twice.<Supplementary Note 15> The method for treating a cell culture solution according to Supplementary Note 14, wherein the first period and the second period are each 30 seconds or less. <Supplementary Note 16> A method for producing a product by culturing cells to obtain a product, comprising: a culturing step of culturing cells in a bioreactor that contains a cell culture solution, a liquid sending step of arranging two or more pump units that expand and contract in a radial direction of a pipe line that communicates with the bioreactor and sending the cell culture solution to a filtration unit arranged on the pipe line by contracting and expanding the pump units, and a collection step of collecting a filtrate containing the product filtered from the cell culture solution by the filtration unit. <Supplementary Note 17> A product manufacturing device comprising: a bioreactor that contains a cell culture solution; a pipeline that communicates with the bioreactor; a filtration unit that is arranged on the pipeline and filters the cell culture solution to obtain a filtrate containing a product; and a pump unit that sends the cell culture solution from the bioreactor to the filtration unit, wherein the pump unit is a pump section that is arranged on the pipeline and has two or more pump sections that expand and contract in the radial direction of the pipeline.

Claims

1. A device for processing cell culture media, A bioreactor containing the cell culture medium, A pipeline communicating with the bioreactor, The system includes a pump unit for supplying the cell culture medium to the pipeline, The pump unit comprises a pump section arranged on the pipeline, and includes two or more pump sections that expand and contract in the radial direction of the pipeline. A cell culture medium processing apparatus comprising a spacer placed in the flow path of the pump section to prevent blockage of the flow path of the pump section when the pump section expands.

2. The pump section includes a cylindrical member having a hollow portion through which the cell culture medium flows, having a space between the inner wall surface and the outer wall surface, and at least the inner wall surface being elastic, which expands and contracts in the radial direction of the conduit. The cell culture medium processing apparatus according to claim 1, wherein the pump unit comprises a fluid supply and discharge mechanism that expands the pump section by supplying fluid to the space between the inner wall surface and the outer wall surface of the cylindrical member, and contracts the pump section by discharging the fluid from the space.

3. The pump section includes a cylindrical member having a hollow portion through which the cell culture medium flows, having a space between the inner wall surface and the outer wall surface, and at least the inner wall surface being elastic, which expands and contracts in the radial direction of the conduit. The cell culture medium processing apparatus according to claim 1, wherein the pump unit includes a pressing force application mechanism that mechanically presses the inner wall surface of the cylindrical member toward the radially inward direction of the pipeline to expand the pump section, and releases the pressing force to contract the pump section due to the elastic force of the cylindrical member.

4. The cell culture medium processing apparatus according to claim 1, wherein the ratio of the cross-sectional area of ​​the flow path of the pump section during expansion and contraction of the pump section is 0.01 or more.

5. The cell culture medium processing apparatus according to claim 1, wherein the spacer is a cylindrical member made of mesh material with an outer diameter smaller than the inner diameter of the flow path.

6. The cell culture medium processing apparatus according to claim 1, wherein the spacer is provided on the wall surface of the flow path of the pump section.

7. The aforementioned conduit further includes a filtration unit equipped with an outlet for discharging the cell culture medium and for discharging the filtered liquid, The cell culture medium processing apparatus according to any one of claims 1 to 6, wherein the cell culture medium is delivered from the bioreactor to the filtration unit by the expansion and contraction of the pump section.

8. The cell culture medium processing apparatus according to claim 7, wherein the pump unit is located on the downstream and upstream sides of the filtration unit in the aforementioned pipeline.

9. The cell culture medium processing apparatus according to claim 7, wherein the filtration unit is connected to the bioreactor by a single conduit in the aforementioned pipeline.

10. The aforementioned pipeline is further equipped with a recovery tank for recovering the cell culture medium, The cell culture medium processing apparatus according to any one of claims 1 to 6, wherein the cell culture medium is delivered from the bioreactor to the recovery tank by the expansion and contraction of the pump section.

11. A method for processing cell culture medium, The process includes a liquid delivery step in which two or more pump units that expand and contract radially along a pipeline communicating with a bioreactor containing the cell culture medium are arranged, and the cell culture medium is delivered by expanding and contracting the pump units. A method for processing cell culture medium, wherein in the liquid delivery step, a spacer is placed in the flow path of the pump unit to prevent blockage of the flow path of the pump unit when the pump unit expands, and the cell culture medium is delivered.

12. The aforementioned conduit further comprises a filtration unit through which the cell culture medium flows in and out, and which is equipped with an outlet for discharging the filtered liquid, The liquid delivery step is a step of delivering the cell culture medium from the bioreactor to the filtration unit, A method for processing a cell culture medium according to claim 11, further comprising the step of collecting the filtrate from the filtration unit, following the liquid delivery step.

13. The aforementioned liquid delivery process, (a) A step of sequentially expanding and contracting the two or more pump units to circulate the cell culture medium from the bioreactor through the filtration unit in a first flow direction for a first period of time, (b) A step of sequentially expanding and contracting the two or more pump units in the reverse order of step (a) so that the cell culture medium flows through the filtration unit for a second period of time in a second flow direction, with the first flow direction reversed. (c) A step of circulating the cell culture medium through the filtration unit for a third period of time in the direction of the first flow, by sequentially expanding and contracting the two or more pump units in the same order as in step (a), thereby reversing the direction of the second flow. (d) A step of repeating steps (b) to (c) at least twice, A method for processing a cell culture medium according to claim 12, including the method described in claim 12.

14. The method for processing a cell culture medium according to claim 13, wherein the first period and the second period are each 30 seconds or less.

15. A method for producing a product by culturing cells and obtaining a product, A cell culture process in which cells are cultured in a bioreactor containing a cell culture medium, A liquid delivery step is to arrange two or more pump units that expand and contract radially along a pipeline communicating with the bioreactor, and deliver the cell culture medium to a filtration unit located along the pipeline by contracting and expanding the pump units, A collection step of collecting the filtrate containing the product filtered from the cell culture medium by the filtration unit, Includes, In the liquid delivery step, a spacer is placed in the flow path of the pump unit to prevent blockage of the flow path of the pump unit when the pump unit expands, and the cell culture medium is delivered. Methods for producing biological products.