阅读说明：本技术 灌注生物处理系统和其操作方法 (Perfusion bioprocessing system and method of operating the same ) 是由 P·鲍尔 P·H·莫翰 A·高雷 S·阿拉古尔 于 2019-09-20 设计创作，主要内容包括：一种灌注生物处理系统(10)包含生物反应器(12)和再循环流径(14),该再循环流径(14)设有至少一个第一供给流控制装置(46)和至少一个第二供给控制装置(48)。灌注生物处理系统(10)还包含经由再循环流径(14)联接到生物反应器(12)的第一切向流过滤器(16)和经由再循环流径(14)联接到生物反应器(12)的第二切向流过滤器(18)。第一切向流过滤器和第二切向流过滤器联接到渗透物流径和渗余物流径。另外,灌注生物处理系统(10)包含控制单元(90),该控制单元(90)联接到至少一个第一供给流控制装置(38)和至少一个第二供给控制装置(40)。(A perfusion bioprocessing system (10) includes a bioreactor (12) and a recirculation flow path (14), the recirculation flow path (14) being provided with at least one first feed flow control device (46) and at least one second feed control device (48). The perfusion bioprocessing system (10) further includes a first tangential flow filter (16) coupled to the bioreactor (12) via the recirculation flow path (14) and a second tangential flow filter (18) coupled to the bioreactor (12) via the recirculation flow path (14). The first tangential flow filter and the second tangential flow filter are coupled to the permeate flow path and the retentate flow path. In addition, the perfusion bioprocessing system (10) comprises a control unit (90), the control unit (90) being coupled to the at least one first supply flow control device (38) and the at least one second supply control device (40).)

1. A method for operating a perfusion bioprocessing system (10), the method comprising the steps of:

causing a first amount (39) of process fluid (42) to flow from the bioreactor (12) to the first tangential flow filter (16) via the recirculation flow path (14);

operating a control unit (90) to control at least one first supply flow control device (38) in the recirculation flow path (14) for controlling the flow of the first quantity (39) of process fluid (42);

allowing the first tangential flow filter (16) to separate the first quantity (39) of process fluid (42) into a first quantity (58) of permeate fluid (60) and a first quantity (71) of retentate fluid (73);

upon determining, by the control unit (90), a blocked or substantially blocked condition of the first tangential flow filter (16), causing a second amount (41) of the process fluid (42) to flow from the bioreactor (12) to a second tangential flow filter (18) bypassing the first tangential flow filter (16) via the recirculation flow path (14);

operating the control unit (90) to control at least one of the at least one first supply flow control device (38) and at least one second supply control device (40) in the recirculation flow path (14) for controlling the flow of the second quantity (41) of process fluid (42); and

allowing the second tangential flow filter (18) to separate the second quantity (41) of process fluid (42) into a second quantity (59) of the permeate fluid (60) and a second quantity (74) of the retentate fluid (73).

2. The method of claim 1, comprising determining the flow rate of the first quantity (58) of permeate fluid (60) in a permeate flow path (48) from a permeate flow sensor (82).

3. The method according to claim 2, characterized in that operating the control unit (90) comprises the steps of:

determining a permeate flux rate of the first tangential flow filter (16) based on the determined flow rate of the first amount (58) of permeate fluid (60); and

determining a condition of clogging or substantial clogging of the first tangential flow filter (16) based on the determined permeate flux rate of the first tangential flow filter (16).

4. A method according to claim 3, characterized in that operating the control unit (90) comprises the steps of: determining a blocked or substantially blocked condition of the first tangential flow filter (16) if the determined permeate flux rate is less than a threshold permeate flux rate.

5. A method according to claim 3, characterized in that operating the control unit (90) comprises the steps of:

determining a change in rpm of a permeate pump (52) in the permeate flow path (48) based on at least one of the flow rate of the first quantity (58) of permeate fluid (60) and the determined revolutions per minute of the permeate pump (52); and

determining a condition of clogging or substantial clogging of the first tangential flow filter (16) based on the determined permeate flux rate of the first tangential flow filter (16) and a change in rpm of the permeate pump (52).

6. The method according to claim 5, characterized in that operating the control unit (90) comprises the steps of: determining a blocked or substantially blocked condition of the first tangential flow filter (16) if the determined permeate flux rate is less than a threshold permeate flux rate.

7. The method of claim 1, comprising determining, by a permeate pressure sensor (84), a pressure of the first quantity (58) of permeate fluid (60) in a permeate flow path (48); wherein operating the control unit (90) further comprises determining a clogged or substantially clogged condition of the first tangential flow filter (16) based on the determined pressure of the first amount (58) of osmotic fluid (60).

8. The method according to claim 7, characterized in that operating the control unit (90) comprises the steps of: determining a clogged or substantially clogged condition of the first tangential flow filter (16) if the determined pressure of the first amount (58) of osmotic fluid (60) is less than a threshold pressure.

9. The method according to claim 1, comprising determining, by the control unit (90), an rpm of a recirculation pump (36) in the recirculation flow path (14); wherein operating the control unit (90) further comprises determining a condition of clogging or substantial clogging of the first tangential flow filter (16) based on the determined rpm of the recirculation pump (36).

10. The method according to claim 9, characterized in that operating the control unit (90) comprises the steps of: determining a clogged or substantially clogged condition of the first tangential flow filter (16) if the determined rpm of the recirculation pump (36) is greater than a threshold rpm.

11. The method according to claim 1, characterized in that it comprises:

determining a pressure of the first quantity (39) of process fluid (42); and

determining a pressure of the first amount (71) of retentate fluid (73);

wherein operating the control unit (90) further comprises determining a clogged or substantially clogged condition of the first tangential flow filter (16) based on the determined pressure of the first amount (39) of process fluid (42) and the determined pressure of the first amount (71) of surplus fluid (73).

12. The method according to claim 11, characterized in that operating the control unit (90) comprises the steps of: determining a blocked or substantially blocked condition of the first tangential flow filter (16) if a pressure differential across the first tangential flow filter (16) is greater than a threshold pressure.

13. The method according to claim 1, characterized in that it comprises:

determining a pressure of the first quantity (39) of process fluid (42);

determining a pressure of the first amount (71) of retentate fluid (73); and

determining a pressure of the first amount (58) of osmotic fluid (60);

wherein operating the control unit (90) comprises the steps of:

determining a transmembrane pressure based on the pressure of the first quantity (39) of process fluid (42), the pressure of the first quantity (58) of osmotic fluid (60), and the pressure of the first quantity (71) of retentate fluid (73); and

determining a condition of clogging or substantial clogging of the first tangential flow filter (16) based on the determined transmembrane pressure.

14. The method according to claim 13, characterized in that operating the control unit (90) comprises the steps of: determining a clogged or substantially clogged condition of the first tangential flow filter (16) if the determined transmembrane pressure is greater than a threshold pressure.

15. The method according to claim 14, characterized in that operating the control unit (90) comprises the steps of: determining the threshold pressure based on a plurality of parameters including the determined flow rate of the first amount (58) of permeate fluid (60) in the permeate flow path (48), cell viability, cell density, and the determined permeate flux rate of the first tangential flow filter (16).

16. The method of any one of the preceding claims, further comprising: providing one or more additional tangential flow filters, and

causing another flow of process fluid from the bioreactor (12) to the one or more additional filters;

operating a control unit (90) to control at least one first supply flow control device (38) in the recirculation flow path (14) for controlling another flow of the process fluid (42);

allowing the additional filter to separate the first amount (39) of process fluid (42) into an additional amount of permeate fluid (60) and an additional amount of retentate fluid (73);

upon determining a condition in which the first tangential flow filter, the second tangential flow filter, or any additional tangential flow filter (16) is blocked or substantially blocked, causing a further amount of the process fluid (42) to flow from the bioreactor (12) to the additional filter bypassing the first tangential flow filter, the second tangential flow filter, and any additional tangential flow filter via the recirculation flow path (14).

17. A perfusion bioprocessing system (10), comprising:

a bioreactor (12);

a recirculation flow path (14), the recirculation flow path (14) being provided with at least one first feed flow control device (38) and at least one second feed control device (40);

a first tangential flow filter (16), the first tangential flow filter (16) coupled to the bioreactor (12) via the recirculation flow path (14);

a second tangential flow filter (18), the second tangential flow filter (18) being coupled to the bioreactor (12) via the recirculation flow path (14);

a permeate flow path (46, 48), wherein the first tangential flow filter (16) and the second tangential flow filter (18) are coupled to the permeate flow path (46, 48);

a retentate flow path (62), wherein the first tangential flow filter (16) and the second tangential flow filter (18) are coupled to the retentate flow path (62); and

a control unit (90), said control unit (90) being coupled to said at least one first supply flow control device (38) and to said at least one second supply control device (40);

wherein the control unit (90) is configured to control the at least one first feed flow control device (38) for controlling a flow of a first amount (39) of process fluid (42) from the bioreactor (12) to the first tangential flow filter (16) via the recirculation flow path (14); and wherein the control unit (90) is further configured to control at least one of the at least one first feed flow control device (38) and the at least one second feed control device (40) for controlling a flow of a second quantity (41) of the process fluid (42) from the bioreactor (12) to the second tangential flow filter (18) via the recirculation flow path (14) bypassing the first tangential flow filter (16) upon determination of a clogged or substantially clogged condition of the first tangential flow filter (16).

18. The perfusion bioprocessing system (10) according to claim 17, wherein the perfusion bioprocessing system (10) includes a permeate flow sensor (82) coupled to the permeate flow path (48), wherein the control unit (90) is communicatively coupled to the permeate flow sensor (82).

19. The perfusion bioprocessing system (10) according to claim 17, wherein the perfusion bioprocessing system (10) includes:

a supply pressure sensor (78), the supply pressure sensor (78) coupled to the recirculation flow path (14);

a retentate pressure sensor (80), the retentate pressure sensor (80) coupled to the retentate flow path (62); and

a permeate pressure sensor (84), the permeate pressure sensor (84) coupled to the permeate flow path (46, 48);

wherein the control unit (90) is communicatively coupled to the supply pressure sensor (78), the retentate pressure sensor (80), and the permeate pressure sensor (84).

20. The perfusion bioprocessing system (10) of claim 17, wherein the recirculation flow path (14) includes a main portion (19), a first branch portion (20), and a second branch portion (22), wherein the bioreactor (12) is coupled to the first tangential flow filter (16) via the main portion (19) and the first branch portion (20), and wherein the bioreactor (12) is coupled to the second tangential flow filter (18) via the main portion (19) and the second branch portion (22).

21. The perfusion bioprocessing system (10) according to claim 17, wherein the permeate flow path includes a first permeate flow path (46) and a second permeate flow path (48), and wherein the first tangential flow filter (16) is coupled to a permeate collection unit (44) via the first permeate flow path (46) and the second permeate flow path (48).

22. The perfusion bioprocessing system (10) according to claim 21, wherein the second tangential flow filter (18) is coupled to the permeate collection unit (44) via the second permeate flow path (48).

23. The perfusion bioprocessing system (10) of claim 17, wherein the retentate flow path (62) includes a main portion (64), a first branch portion (66), and a second branch portion (68), wherein the bioreactor (12) is coupled to the first tangential flow filter (16) via the main portion (64) and the first branch portion (66), and wherein the bioreactor (12) is coupled to the second tangential flow filter (18) via the main portion (64) and the second branch portion (66).

24. The perfusion bioprocessing system (10) according to claim 17, wherein the perfusion bioprocessing system (10) further comprises one or more additional tangential flow filters, the control unit further arranged to cause sequential filtration of the fluid after a determination of a clogged or substantially clogged condition of the first and second filters.

Technical Field

Embodiments of the present description relate generally to filtration systems, and more particularly to a perfusion bioprocessing system having a plurality of tangential flow filters and a method for operating a perfusion bioprocessing system.

Background

The presence of many substances as solutions or mixtures creates a need for the development of processes for separating solutions or mixtures. The need for separation techniques has been driven by the need to purify, recover, separate, and remove materials in process streams in chemical, pharmaceutical, food, petroleum, healthcare, and wastewater applications.

The most common filtration processes are Microfiltration (MF), Ultrafiltration (UF) and Reverse Osmosis (RO). Such filtration processes are pressure driven and are used to separate macromolecules from fluids using filters. The filter acts as a selective barrier by allowing certain components of the mixture to pass while retaining other components of the mixture. The filtration process results in two phases, a permeate phase and a retentate phase.

For bioprocessing applications, continuous processing is a growing trend because smaller bioreactors can be used to produce the desired amount of product as compared to the use of larger bioreactors operating in batch and fed-batch modes. Perfusion allows for continuous processing by allowing for continuous nutrient supply and removal of spent media and metabolic waste. Continuous processes result in better product yield, product quality, process intensification, reduced capital expenditure (capex), and reduced operating costs.

A drawback associated with the use of filter separation processes is a phenomenon known as filter fouling. Fouling is the deposition of materials, known as fouling, on the surface of the membranes or pores of the filter, resulting in changes in the filter performance or even complete clogging of the filter, and an increase in product retention, resulting in loss of process and product quality. Filter clogging can be caused by various reasons, such as cells, cell debris, the presence of extracellular components in the process fluid, and the addition of certain materials, such as antifoam agents, as needed for the process. As a result, filter efficiency is reduced due to filter clogging, which in turn affects filtration quality, loses control over the continuous process, and increases overall processing time. In scenarios where tangential flow filters are used for continuous processing, filter clogging limits the duration during which the process can run uninterrupted. In particular, filter clogging limits the duration of perfusion and limits the cell density achievable at the end of the process. Furthermore, the tangential flow filter would need to be changed manually, resulting in stopping the process for filter replacement.

There is a need for an enhanced perfusion bioprocessing system and a method for operating a perfusion bioprocessing system.

Disclosure of Invention

According to one aspect of the present description, a method for operating a perfusion bioprocessing system is disclosed. The method comprises the following steps: a first amount of process fluid is caused to flow from the bioreactor to the first tangential flow filter via the recirculation flow path. The method further comprises the following steps: the control unit is operated to control at least one first supply flow control device in the recirculation flow path for controlling the flow of a first quantity of process fluid. Furthermore, the method comprises the steps of: the first tangential flow filter is allowed to separate a first amount of the process fluid into a first amount of the permeate fluid and a first amount of the retentate fluid. The method further comprises the following steps: upon determining, by the control unit, a condition in which the first tangential flow filter is clogged or substantially clogged, a second amount of process fluid is caused to flow from the bioreactor to the second tangential flow filter bypassing the first tangential flow filter via the recirculation flow path. In addition, the method comprises the following steps: the control unit is operated to control at least one of the at least one first and at least one second supply control device in the recirculation flow path for controlling the flow of the second quantity of process fluid. Furthermore, the method comprises the steps of: a second tangential flow filter is allowed to separate a second quantity of the process fluid into a second quantity of the permeate fluid and a second quantity of the retentate fluid.

In accordance with another aspect of the present description, a perfusion bioprocessing system is disclosed. The perfusion bioprocessing system comprises a bioreactor and a recirculation flow path provided with at least one first feed control device and at least one second feed control device. The perfusion bioprocessing system further includes a first tangential flow filter coupled to the bioreactor via the recirculation flow path and a second tangential flow filter coupled to the bioreactor via the recirculation flow path. In addition, the perfusion bioprocessing system includes a permeate flow path coupled to the first tangential flow filter and the second tangential flow filter, and a retentate flow path coupled to the first tangential flow filter and the second tangential flow filter. In addition, the perfusion bioprocessing system comprises a control unit coupled to the at least one first supply control device and the at least one second supply control device. The control unit is configured to control the at least one first feed flow control device for controlling a flow of a first amount of process fluid from the bioreactor via the recirculation flow to the first tangential flow filter. The control unit is further configured to control at least one of the at least one first feed flow control device and the at least one second feed control device for controlling the flow of a second amount of process fluid from the bioreactor to the second tangential flow filter bypassing the first tangential flow filter via the recirculation flow path upon determination of a blocked condition or a substantially blocked condition of the first tangential flow filter.

Drawings

These and other features, aspects, and advantages of the present disclosure will become better understood when the following detailed description is read with reference to the accompanying drawings in which like characters represent like parts throughout the drawings, wherein:

FIG. 1 is a schematic diagram of a perfusion bioprocessing system having a plurality of tangential flow filters according to embodiments herein; and

fig. 2 is a flow diagram illustrating a number of steps involved in a method for operating a perfusion bioprocessing system having a plurality of tangential flow filters according to another embodiment of the present description.

Detailed Description

Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the terms "first," "second," and the like, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another. Furthermore, the terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

In accordance with an embodiment of the present description, a method for operating a perfusion bioprocessing system is disclosed. The method includes causing a first amount of process fluid to flow from the bioreactor to the first tangential flow filter via the recirculation flow path. The method also includes operating the control unit to control at least one first supply flow control device in the recirculation flow path for controlling the flow of a first quantity of process fluid. In addition, the method includes allowing the first tangential flow filter to separate the first amount of the process fluid into a first amount of the permeate fluid and a first amount of the retentate fluid. The method further comprises causing a second amount of process fluid to flow from the bioreactor to the second tangential flow filter bypassing the first tangential flow filter via the recirculation flow path upon determining a plugged or substantially plugged condition of the first tangential flow filter by the control unit. In addition, the method includes operating the control unit to control at least one of at least one first supply flow control device and at least one second supply control device in the recirculation flow path for controlling the flow of a second quantity of process fluid. In addition, the method comprises allowing a second tangential flow filter to separate a second quantity of the process fluid into a second quantity of the permeate fluid and a second quantity of the retentate fluid.

According to another embodiment, an associated system is disclosed. In accordance with embodiments of the present description, the exemplary systems and methods allow for switching flow of process fluid between a plurality of tangential flow filters when a blocked or substantially blocked condition of a first tangential flow filter is determined by a control unit. The switching of the flow of process fluid between tangential flow filters is completely sterile and automatic since no user intervention is required. Furthermore, there is no need to manually replace the tangential flow filter depending on the needs of the process. Thus, there is no need to stop the process in order to change the tangential flow filter, which is undesirable for e.g. a perfusion process.

Referring to fig. 1, a schematic diagram of a perfusion bioprocessing system 10 is shown according to embodiments herein. In the illustrated embodiment, perfusion bioprocessing system 10 includes a bioreactor 12, the bioreactor 12 coupled to a first tangential flow filter 16 and a second tangential flow filter 18 via a recirculation flow path 14. In one embodiment, the first tangential flow filter 16 and the second tangential flow filter 18 can be hollow fiber filters. The recirculation flow path 14 has a main portion 19 and first and second branch portions 20 and 22 extending from the main portion 19. In the illustrated embodiment, the first and second branch portions 20, 22 extend parallel to each other. The first tangential flow filter 16 has an inlet 24, a first outlet 26, and a second outlet 28. The second tangential flow filter 18 has an inlet 30, a first outlet 32 and a second outlet 34. In particular, the first branch portion 20 is coupled to an inlet 24 of the first tangential flow filter 16. The second branch portion 22 is coupled to an inlet 30 of the second tangential flow filter 18.

Perfusion bioprocessing system 10 also includes a recirculation pump 36, a first feed flow control device 38, and a second feed flow control device 40 coupled to recirculation flow path 14. In the illustrated embodiment, the first and second feed flow control devices 38, 40 are referred to herein as first and second feed flow control valves. In particular, a first supply flow control valve 38 is coupled to first branch portion 20 and is disposed downstream of recirculation pump 36 and upstream of first tangential flow filter 16. A second feed flow control valve 40 is coupled to the main section 19 and is arranged downstream of the recirculation pump 36 and upstream of the second tangential flow filter 18. For example, bioreactor 12 is used to store process fluid 42 associated with cell culture. In particular, recirculation pump 36 is used to supply process fluid 42 at a predetermined flow rate from bioreactor 12 to either first tangential flow filter 16 or second tangential flow filter 18 via recirculation flow path 14. The first and second feed flow control valves 38, 40 are used to control the flow of the process fluid 42 to the first or second tangential flow filters 16, 18 via the recirculation flow path 14. If the first supply flow control valve 38 is open and the second supply flow control valve 40 is closed, a first quantity 39 of process fluid 42 is transmitted through the first tangential flow filter 16. If the first supply flow control valve 38 is closed and the second supply flow control valve 40 is open, a second quantity 41 of process fluid 42 is passed through the second tangential flow filter 18.

In addition, perfusion bioprocessing system 10 includes a permeate collection unit 44, the permeate collection unit 44 being coupled to the first outlet 26 of the first tangential flow filter 16 via a first permeate flow path 46 and a second permeate flow path 48. The first permeate flow path 46 and the second permeate flow path 48 may also be collectively referred to as a permeate flow path. Further, the permeate collection unit 44 is coupled to the first outlet 32 of the second tangential flow filter 18 via a second permeate flow path 48. The first permeate flow path 46 is coupled to the second permeate flow path 48 at a location 50 downstream of the second tangential flow filter 18. The perfusion bioprocessing system 10 also includes a permeate pump 52 coupled to the second permeate flow path 48. In addition, perfusion bioprocessing system 10 includes a first permeate flow control device 54 coupled to first permeate flow path 46 and a second permeate flow control device 56 coupled to second permeate flow path 48. The first permeate stream control means 54 and the second permeate stream control means 56 are referred to herein as a first permeate stream control valve and a second permeate stream control valve. A second permeate flow control valve 56 is disposed upstream of the location 50. The first tangential flow filter 16 is used to separate a first quantity 58 of permeate fluid 60 from a first quantity 39 of process fluid 42 by utilizing a pressure differential across the first tangential flow filter 16. If the first permeate flow control valve 54 is open and the second permeate flow control valve 56 is closed, the permeate pump 52 is operable to supply a first quantity 58 of permeate fluid 60 to the permeate collection unit 44 via the first permeate flow path 46 and the second permeate flow path 48 at a predetermined flow rate. If the first permeate flow control valve 54 is closed and the second permeate flow control valve 56 is open, the permeate pump 52 is operable to supply a second quantity 59 of permeate fluid 60 to the permeate collection unit 44 via the second permeate flow path 48 at a predetermined flow rate.

Further, the bioreactor 12 is coupled to the second outlet 28 of the first tangential flow filter 16 and the second outlet 34 of the second tangential flow filter 18 via a retentate flow path 62. In particular, the retentate flow path 62 has a main portion 64, a first branch portion 66 and a second branch portion 68. Second outlet 28 of first tangential flow filter 16 is coupled to bioreactor 12 via first branching section 66 and main section 64. Similarly, the second outlet 34 of the second tangential flow filter 18 is coupled to the bioreactor 12 via a second branch portion 68 and the main portion 64. A first retentate flow control device 70 is coupled to the first branch portion 66 and a second retentate flow control device 72 is coupled to the main portion 64. The first retentate flow control means 70 and the second retentate flow control means 72 are referred to herein as a first retentate flow control valve and a second retentate flow control valve. In particular, a second retentate flow control valve 72 is provided downstream of the second branch portion 68 and upstream of a location 75 where the first branch portion 66 connects to the main portion 64. If the first retentate flow control valve 70 is open and the second retentate flow control valve 72 is closed, a first quantity 71 of retentate fluid 73 flows to the bioreactor 12 via the second outlet 28, the first branch portion 66 and the main portion 64 of the first tangential flow filter 16. First quantity 71 of retentate fluid 73 is the remainder of first quantity 39 of process fluid 42 after separation of first quantity 58 of permeate fluid 60. If the first retentate flow control valve 70 is closed and the second retentate flow control valve 72 is open, a second amount 74 of retentate fluid 73 flows to the bioreactor 12 via the second outlet 34 of the second tangential flow filter 18, the second branch portion 68 and the main portion 64. Second quantity 74 of retentate fluid 73 is the remainder of second quantity 41 of process fluid 42 after separation of second quantity 59 of permeate fluid 60. It should be noted herein that the illustrated perfusion bioprocessing system 10 is an exemplary embodiment and should not be construed as limiting. The configuration of the perfusion bioprocessing system 10 may vary depending on the application. In other embodiments, the number of tangential flow filters, valves, and pumps may vary depending on the application and process needs.

In another embodiment, instead of using recirculation pump 36, pressurized gas may be supplied from a gas source (not shown) to bioreactor 12 via a filter (not shown) for supplying process fluid 42 from bioreactor 12 to first tangential flow filter 16 and second tangential flow filter 18 via recirculation flow path 14. In such embodiments, the permeate pump 52 may not be required.

In the illustrated embodiment, perfusion bioprocessing system 10 also includes a control system 76, with control system 76 having a supply pressure sensor 78 coupled to recirculation flow path 14. In particular, supply pressure sensor 78 is coupled to main portion 19 of recirculation flow path 14. The supply pressure sensor 78 is located downstream of the recirculation pump 36 and upstream of the first and second branch portions 20, 22. Supply pressure sensor 78 is used to sense the pressure of process fluid 42 flowing through main portion 19 of recirculation flow path 14. The control system 76 additionally includes a retentate pressure sensor 80 coupled to the main portion 64 of the retentate flow path 62. In particular, the retentate pressure sensor 80 is disposed downstream of the first and second branch portions 66, 68 of the retentate flow path 62. Retentate pressure sensor 80 is used to sense the pressure of retentate fluid 73 flowing through main portion 64 of retentate flow path 62.

In addition, the control system 76 includes a permeate pressure sensor 84 and a permeate flow sensor 82 coupled to the second permeate flow path 48. A permeate flow sensor 82 is located downstream of the permeate pump 52. The permeate flow sensor 82 is used to measure the flow rate of the permeate fluid 60 flowing through the second permeate flow path 48. In one embodiment, the permeate flow sensor 82 may output a signal indicative of the flow rate of the permeate fluid 60 flowing through the second permeate flow path 60. In another embodiment, the permeate flow sensor 82 may output a signal indicative of a parameter (e.g., volume or velocity) of the permeate fluid 60 for use in calculating the flow rate of the permeate fluid 60. Any type of flow sensor that may be used to measure the flow rate of the osmotic fluid 60 is contemplated. The permeate pressure sensor 84 is located upstream of the permeate pump 52 and downstream of the location 50. The permeate pressure sensor 84 is used to sense the pressure of the permeate fluid 60 flowing through the second permeate flow path 48.

In addition, the control system 76 includes a revolutions per minute (rpm) sensor 86 coupled to the feed pump 36 and another rpm sensor 88 coupled to the permeate pump 52. An rpm sensor 86 is used to measure the rpm of the feed pump 36. The rpm sensor 88 is used to measure the rpm of the permeate pump 52.

Further, in the illustrated embodiment, the control system 76 includes a control unit 90, the control unit 90 having a processor 92 and a memory unit 94 coupled to the processor 92. In some embodiments, the control unit 90 is used to control at least one function of the perfusion bioprocessing system 10. In certain embodiments, the control unit 90 may include more than one processor that work in conjunction with each other to perform the intended functions. The control unit 90 is further configured to store content into the memory unit 94 and retrieve content from the memory unit 94. In one embodiment, control unit 90 is configured to initiate and control the functions of perfusion bioprocessing system 10.

In one embodiment, the control unit 90 includes at least one of a general purpose computer, a Graphics Processing Unit (GPU), a digital signal processor, and a controller. In other embodiments, the control unit 90 contains custom processor elements such as, but not limited to, Application Specific Integrated Circuits (ASICs) and Field Programmable Gate Arrays (FPGAs). In some embodiments, the control unit 90 may be communicatively coupled with at least one of a keyboard, a mouse, and any other input device, and configured to receive commands and/or parameters from an operator via a console.

In one embodiment, memory unit 94 is a Random Access Memory (RAM), Read Only Memory (ROM), flash memory, or any other type of computer-readable memory accessible by processor 92. Furthermore, in certain embodiments, memory unit 94 may be a non-transitory computer readable medium encoded with a program having a plurality of instructions to instruct processor 92 to execute a sequence of steps to operate perfusion bioprocessing system 10.

In the illustrated embodiment, the control unit 90 is communicatively coupled to the permeate stream sensor 82. In one embodiment, the control unit 90 is configured to receive an output signal from the permeate stream sensor 82 indicative of the flow rate of the permeate fluid 60. In another embodiment, the control unit 90 is configured to receive an output signal from the permeate stream sensor 82 indicative of a parameter (e.g., volume or velocity) of the permeate fluid 60 for calculating the flow rate of the permeate fluid 60 according to known techniques.

The control unit 90 is also communicatively coupled to the rpm sensors 86, 88 and is configured to receive output signals indicative of the rpm of the feed pump 36 and the permeate pump 52. The control unit 90 is also configured to determine a change in rpm of the feed pump 36 and the permeate pump 52 based on the output signals from the rpm sensors 86, 88.

In addition, control unit 90 is communicatively coupled to supply pressure sensor 78, retentate pressure sensor 80, and permeate pressure sensor 84. In one embodiment, control unit 90 is communicatively coupled to supply pressure sensor 78, retentate pressure sensor 80, and permeate pressure sensor 84, and is configured to determine a transmembrane pressure (TMP) of first tangential flow filter 16 based on outputs from supply pressure sensor 78, retentate pressure sensor 80, and permeate pressure sensor 84. It should be mentioned here that TMP denotes the pressure required to pass the fluid (water) through the filter. In another embodiment, control unit 90 is configured to determine a pressure differential across second tangential flow filter 16 based on outputs from supply pressure sensor 78 and retentate pressure sensor 80.

Further, a control unit 90 is coupled to and configured to control the operation of the first and second supply flow control valves 38, 40, the first and second permeate stream control valves 54, 56, and the first and second retentate stream control valves 70, 72. In one embodiment, control unit 90 is configured to control first supply flow control valve 38 for controlling the flow of first quantity 39 of process fluid 42 from bioreactor 12 to first tangential flow filter 16 via main portion 19 and first branch portion 20 of recirculation flow path 14. Furthermore, the control unit 90 is configured to control the first and second supply flow control valves 38, 40 for controlling the flow of the second quantity 41 of the process fluid 42 from the bioreactor 12 bypassing the first tangential flow filter 16 via the main portion 19 and the second branch portion 22 of the recirculation flow path 14 to the second tangential flow filter 18 upon determining a condition of the first tangential flow filter 16 being clogged or substantially clogged.

As mentioned earlier, the control unit 90 facilitates automatically switching the flow of the process fluid 42 between the first tangential flow filter 16 and the second tangential flow filter 18. Thus, no user intervention is required. Furthermore, there is no need to manually replace the tangential flow filter depending on the needs of the process.

Fig. 2 is a flow diagram illustrating a method 96 for operating the perfusion bioprocessing system 10 according to the embodiment of fig. 1. As represented by step 98, method 96 includes causing a flow of a first quantity 39 of process fluid 42 from bioreactor 12 to first tangential flow filter 16 via recirculation flow path 14. In one embodiment, as represented by step 100, control unit 90 operates recirculation pump 36, opens first supply flow control valve 38, and closes second supply flow control valve 40 to control the flow of first quantity 39 of process fluid 42 from bioreactor 12 to first tangential flow filter 16 via main portion 19 and first branch portion 20 of recirculation flow path 14. In another embodiment, instead of using recirculation pump 36, pressurized gas may be supplied from a gas source to bioreactor 12 via a filter for supplying a first quantity 39 of process fluid 42 from bioreactor 12 to first tangential flow filter 16 via main portion 19 and first branch portion 20 of recirculation flow path 14. As represented by step 102, first tangential flow filter 16 separates first quantity 39 of process fluid 42 into first quantity 58 of permeate fluid 60 and first quantity 71 of retentate fluid 73. In particular, a first quantity 39 of process fluid 42 traverses the first tangential flow filter 16 tangentially at a positive pressure relative to the permeate side of the first tangential flow filter 16. The control unit 90 operates the permeate pump 52 to open the first permeate flow control valve 54 and close the second permeate flow control valve 56 to supply a first amount 58 of permeate fluid 60 to the permeate collection unit 44 via the first permeate flow path 46 and the second permeate flow path 48. Further, the control unit 90 opens the first retentate flow control valve 70 and closes the second retentate flow control valve 72 to supply a first amount 71 of retentate fluid 73 to the bioreactor 12 through the first branch portion 66 and the main portion 64 of the retentate flow path 62.

According to embodiments herein, the control unit 90 is configured to determine a condition of clogging or substantial clogging of the first tangential flow filter 16 based on at least one process parameter discussed herein, as represented by step 104. In one embodiment, the control unit 90 determines the permeate flux rate of the first tangential flow filter 16 based on the flow rate of the first quantity 58 of permeate fluid 60 determined by the permeate flow sensor 82. It should be noted here that the permeate flux rate of the first tangential flow filter 16 is defined as the flow rate of the first quantity 58 of permeate fluid 60 measured per unit area of the first tangential flow filter 16. In one embodiment, the control unit 90 determines a plugged or substantially plugged condition of the first tangential flow filter 16 if the determined permeate flux rate is less than the threshold permeate flux rate. In one example, the threshold permeate flux rate is 70%.

In another embodiment, the control unit 90 determines a change in rpm of the permeate pump 52, e.g., an increase in rpm, based on at least one of the flow rate of the first quantity 58 of permeate fluid 60 and the determined revolutions per minute of the permeate pump 52. In particular, in such embodiments, the control unit 90 determines a plugged or substantially plugged condition of the first tangential flow filter 16 based on the determined permeate flux rate of the first tangential flow filter 16 and the change in rpm of the permeate pump 52. In one such particular embodiment, if the determined permeate flux rate is less than the threshold permeate flux rate, and based on the change in rpm of the permeate pump 52, the controller 90 determines a condition of clogging or a substantially clogged condition of the first tangential flow filter 16.

In yet another embodiment, the control unit 90 determines a plugged or substantially plugged condition of the first tangential flow filter 16 based on the pressure of the first quantity 58 of the permeate fluid 60 determined by the permeate pressure sensor 84. In particular, if the determined pressure of the first quantity 58 of the osmotic fluid 60 is less than the threshold pressure, the control unit 90 determines a clogged or substantially clogged condition of the first tangential flow filter 16.

In yet another embodiment, the control unit 90 determines a clogged or substantially clogged condition of the first tangential flow filter 16 based on the rpm of the recirculation pump 36 as determined by the rpm sensor 86. In yet another embodiment, the control unit 90 determines a clogged or substantially clogged condition of the first tangential flow filter 16 if the determined rpm of the recirculation pump 36 is greater than a threshold rpm.

In another embodiment, the control unit 90 determines a condition or substantial clogging of the first tangential flow filter 16 based on the pressure differential across the first tangential flow filter 16 (based on the outputs from the supply and retentate pressure sensors 78, 80, 84). In particular, if the pressure differential across the first tangential flow filter 16 is greater than the threshold pressure, the control unit 66 determines that the first tangential flow filter 16 is clogged or substantially clogged.

In yet another embodiment, the control unit 90 determines a plugged or substantially plugged condition of the first tangential flow filter 16 based on the determined TMP of the first tangential flow filter 16 (calculated based on the outputs from the supply pressure sensor 78, the retentate pressure sensor 80, and the permeate pressure sensor 84). TMP is calculated by the control unit 90 based on the following relation:

TMP=((p₂+p₃)/2)-p₁

wherein p is₁Is the output of the permeate pressure sensor 84, p₂Is the output of the supply pressure sensor 78, p₃Is the output of retentate pressure sensor 80. If the TMP is greater than the threshold pressure, the control unit 90 determines that the first tangential flow filter 16 is clogged or substantially clogged. In one embodiment, the control unit 90 determines the threshold pressure based on a plurality of parameters, such as, but not limited to, the determined flow rate of the first quantity 58 of permeate fluid 60 in the first permeate flow path 46, cell viability, cell densityAnd the determined permeate flux rate of the first tangential flow filter 16. In a particular embodiment, the ratio of TMP to threshold pressure is in the range of 1.5 to 2.

It should be noted here that the threshold pressures/flow rates/rpm/flux discussed herein are set based on predetermined process optimization values. If a blocked or substantially blocked condition of the first tangential flow filter 16 is determined, as represented by step 106, the method 96 further comprises causing a flow of a second quantity 41 of the process fluid 42 from the bioreactor 12 to the second tangential flow filter 18 via the recirculation flow path 14 bypassing the first tangential flow filter 16. In one embodiment, as represented by step 108, the control unit 90 operates the recirculation pump 36, closes the first supply flow control valve 38, and opens the second supply flow control valve 40 to control the flow of the second quantity 41 of the process fluid 42 from the bioreactor 12 to the second tangential flow filter 16 via the main portion 19 and the second branch portion 22 of the recirculation flow path 14. In another embodiment, instead of using recirculation pump 36, pressurized gas may be supplied from a gas source to bioreactor 12 via a filter for supplying a second amount 41 of process fluid 42 from bioreactor 12 to second tangential flow filter 16 via main portion 19 and second branch portion 20 of recirculation flow path 14. As represented by step 102, second tangential flow filter 18 separates second quantity 41 of process fluid 42 into second quantity 59 of permeate fluid 60 and second quantity 74 of retentate fluid 73. In particular, a first quantity 39 of process fluid 42 traverses the first tangential flow filter 16 tangentially at a positive pressure relative to the permeate side of the first tangential flow filter 16. The control unit 90 operates the permeate pump 52 to open the first permeate flow control valve 54 and close the second permeate flow control valve 56 to supply a first amount 58 of permeate fluid 60 to the permeate collection unit 44 via the first permeate flow path 46 and the second permeate flow path 48. In addition, the control unit 90 closes the first retentate flow control valve 70 and opens the second retentate flow control valve 72 to supply a second amount 74 of retentate fluid 73 to the bioreactor 12 through the second branch portion 68 and the main portion 64 of the retentate flow path 62.

In accordance with embodiments herein, the control unit 90 allows for monitoring of a number of process parameters discussed herein above for determining that the first tangential flow filter 16 is clogged or substantially clogged. Thereby, it is possible to divert the flow of the process fluid 42 through the second tangential flow filter 18. Thus, it is possible to extend the duration of the perfusion process for a longer period of time.

While only certain features of the specification have been illustrated and described herein, many modifications and changes will occur to those skilled in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the specification.

The invention described and illustrated above provides one example of the invention, while in practice other examples will be apparent to the skilled person. In addition, modifications that will readily occur to the skilled person include the provision of more than two filters. For example, three, four or more filters may be provided, along with a controller that determines the performance of each filter used, and the flow is sequentially switched in the same manner as the flow is controlled for the first and second filters mentioned above.