Continuous tangent flow filtration system

Abstract

A tangential flow filtration system, and more specifically, a continuous tangential flow filtration (“cTFF”) system consisting of single pass modules, is disclosed herein. Each single pass module is configured to transition from a first process configuration to a second process configuration and / or operate under both the first process configuration and the second process configuration for customization of the cTFF system. Each of the modules has at least one break tank for regulation of flow and pressure across the module and, on a larger scale, the entire cTFF system.

Description

Technical Field

[0001] The present disclosure relates to a tangential flow filtration system, and more specifically, to a continuous tangential flow filtration (“cTFF”) system consisting of single-pass modules having two or more process configurations and at least one break tank for flow and pressure control.

Background Art

[0002] Conventional pharmaceutical and biopharmaceutical manufacturing processes require a series of separate batch operations arranged in a downstream configuration. For example, conventional systems can include cases of column chromatography, virus inactivation, virus filtration, tangential flow filtration, final filtration, and storage and transportation. Each of these operations may further require its own subset of operations. For example, a conventional way to complete tangential flow filtration is via batch tangential flow filtration (bTFF), which requires recirculation of the feed material through the same filter multiple times. This is done to increase the concentration of the solute of interest in the solution and / or to achieve the desired solution composition through diafiltration in which the solute of interest is transferred from the starting solution matrix to the exchange buffer. Such processes require several recirculation paths and can lead to inefficiencies in the system.

[0003] The continuous tangential flow filtration strategy can include using single-pass tangential flow filtration (spTFF) as a concentration operation and counter-current buffer exchange tangential flow filtration (CCBE-TFF) as a diafiltration operation, which enables continuous tangential flow filtration that can be used to achieve the same processing results as bTFF. For example, spTFF can achieve the same desired concentration by passing through the filter only once, rather than requiring the filter to pass through several times or even hundreds of times. By adding multiple consecutive concentration steps in series and collating with in-line dilution, spTFF can also be used for CCBE-TFF. However, CCBE-TFF requires multiple steps to improve efficiency, the feed flow is continuously supplied to the system, and the retentate is continuously collected at the outlet through a series of dilution and concentration steps. The diafiltration buffer is dispensed at the final diafiltration step. The permeate from the final step then serves as the diafiltration agent for the previous step, resulting in a "counter-current" flow with respect to the feed flow. However, the CCBE-TFF process involves a unique set of challenges, including complex process control, an increase in the number of pumps and other equipment required, and larger surface area requirements compared to conventional bTFF systems. Additionally, the requirements for a series of steps present process control challenges including, but not limited to, unstable flow rates, system overpressure, unwanted mixing, tightly coupled flow control loops between steps, and complex start-up and shutdown procedures, which further complicate situations that require disturbance response, necessitate system restart, and result in further inefficiencies. Summary of the Invention

[0004] The present disclosure relates to a tangential flow filtration system, and more specifically, to a continuous tangential flow filtration (“cTFF”) system consisting of single-pass modules configured to transition from a first process configuration to a second process configuration and / or to operate under both the first process configuration and the second process configuration for the customization of cTFF systems. Each of the modules has at least one break tank for the regulation of flow and pressure across the module and, on a larger scale, the entire cTFF system.

[0005] In a first aspect of the present disclosure, a tangential flow filtration module is described. The module includes a flow distributor including a module exchange buffer distributor and a module feed liquid distributor, a feed liquid break tank positioned downstream of the flow distributor, the feed liquid break tank including an electric stirrer, and a first filter positioned downstream of the feed liquid break tank.

[0006] In another aspect of the present disclosure, a tangential flow filtration module is described. The module includes a flow distributor including a module exchange buffer distributor and a module feed liquid distributor, a filter positioned downstream of the flow distributor and having two output portions including a permeate output portion and a retentate output portion, and a permeate break tank positioned downstream of the filter and supplied by the permeate output portion of the filter.

[0007] In yet another aspect of the present disclosure, a tangential flow filtration system is described. The tangential flow filtration system comprises a plurality of individual modules, each of the individual modules being configured to perform a process related to tangential flow filtration, and each individual module includes a plurality of valves and a control system. The operation of the plurality of valves is configured to change the flow path of the corresponding individual module. The control system is configured to calculate a current stage rejection coefficient for an individual module and automatically operate the plurality of valves to change the flow path so that the current stage rejection coefficient for the individual module approaches a target stage rejection coefficient. The current stage rejection coefficient is a ratio between any two of the permeate flow rate, feed flow rate, and retentate flow rate for an individual module.

[0008] In another aspect of the present disclosure, a tangential flow filtration system is described. The system comprises a plurality of modules, each module comprising a module flow distributor, a filter positioned downstream of the module flow distributor, and at least one of a feed interruption tank positioned between the module flow distributor and the filter and a permeate interruption tank positioned downstream of the filter.

[0009] In various aspects of the present disclosure, the module may further comprise a feed pump disposed between the feed interruption tank and the first filter. The feed pump may be configured to control the flow rate of the flow between the feed interruption tank and the first filter.

[0010] In various aspects of the present disclosure, the operation of the electric stirrer is configured to produce a homogeneous solution.

[0011] In various aspects of the present disclosure, the feed interruption tank may define voids.

[0012] In various aspects of the present disclosure, the feed interruption tank may define a vent in fluid communication with ambient pressure.

[0013] In various aspects of the present disclosure, the permeate interruption tank can be positioned downstream of the first filter.

[0014] In various aspects of the present disclosure, the module exchange buffer supply unit can consist of the permeate of a second filter positioned downstream of the first filter, and the feed solution supply unit of the second filter includes the retention liquid of the first filter.

[0015] In various aspects of the present disclosure, the module feed solution supply unit consists of the retention liquid of a third filter positioned upstream of the first filter.

[0016] In various aspects of the present disclosure, the feed solution interruption tank can be positioned between the flow distribution unit and the filter.

[0017] In various aspects of the present disclosure, the interior of the permeate interruption tank can define voids.

[0018] In various aspects of the present disclosure, the permeate interruption tank can include a vent in fluid communication with the ambient pressure.

[0019] In various aspects of the present disclosure, the valve can be positioned between the first filter and the permeate interruption tank. The valve can be configured to control the permeate pressure on the permeate side of the first filter.

[0020] In various aspects of the present disclosure, the permeate interruption tank can supply to a second filter positioned upstream of the feed solution supply unit. The feed solution supply unit can consist of the retention liquid of the second filter.

[0021] In various aspects of the present disclosure, the module exchange buffer supply unit can consist of the permeate of a third filter positioned downstream of the first filter, and the feed solution supply unit of the third filter includes the retention liquid of the first filter.

[0022] In various aspects of the present disclosure, the module may further include at least one valve, and the operation of the valve is configured to change the configuration of the tangential flow filtration module from a first flow path configuration to a second flow path configuration, or from the second flow path configuration to the first flow path configuration. The first flow configuration may be a countercurrent buffer exchange flow path configuration. The second flow configuration may be a single pass tangential flow filtration flow path configuration.

[0023] In various aspects of the present disclosure, the plurality of individual modules may include at least five modules.

[0024] In various aspects of the present disclosure, the last individual module of the plurality of individual modules may have a different target stage removal coefficient from at least one other individual module of the plurality of individual modules.

[0025] In various aspects of the present disclosure, the control system may be configured to maintain the tangential flow filtration system in a steady state where the current stage removal coefficient approaches the target stage removal coefficient. The system may be configured to allow a user to adjust at least one of a plurality of valves in a manner that deviates the current stage removal coefficient from the target stage removal coefficient when the tangential flow filtration system is in a steady state. The control system may be configured to automatically operate the remaining valves of the plurality of valves to compensate for the user's adjustment such that the current stage removal coefficient approaches the target stage removal coefficient again after the user's adjustment. Each of the plurality of individual modules may include a feed interruption tank positioned downstream of the flow distributor and upstream of the filter for the individual module, and a permeate interruption tank positioned downstream of the filter. The flow distributor may include a module feed liquid distributor and a module exchange buffer liquid distributor. The first flow rate output of the feed interruption tank and the second flow rate output of the permeate interruption tank may be individually adjustable during operation of the tangential flow filtration system. The control system may be configured to maintain the tangential flow filtration system in a steady state by automatically maintaining a substantially steady stage removal coefficient during adjustment of either the first flow rate output or the second flow rate output. The control system may be further configured to maintain a steady level in the feed interruption tank and a steady level in the permeate interruption tank.

[0026] In various aspects of the present disclosure, each module can have at least one of a first configuration corresponding to a single-pass tangential flow filtration (“spTFF”) process, a second configuration corresponding to a countercurrent buffer exchange tangential flow filtration (“CCBE-TFF”) process, and a third configuration corresponding to a combined spTFF and CCBE-TFF process. Each module of the plurality of modules can include a plurality of valves such that each module of the plurality of modules can selectively switch from the first configuration to at least one of the second configuration and the third configuration, selectively switch from the second configuration to at least one of the first configuration and the third configuration, and selectively switch from the third configuration to at least one of the first configuration and the second configuration. The first module of the plurality of modules can be in the first configuration, and the second module of the plurality of modules can be in the second configuration. The first plurality of modules including the first module can be in the first configuration, and the second plurality of modules including the second module can be in the second configuration. The last module of the plurality of modules can be operated in the third configuration. At least some of the permeate from the last module can be dispensed to a module exchange buffer dispenser for another module upstream of the last module, and at least some of the permeate from the last module can be sent to a waste section.

[0027] In various aspects of the present disclosure, each module of the plurality of modules can include a retentate flow path and a permeate flow path. A permeate interruption tank can be positioned along the permeate flow path.

[0028] In various aspects of the present disclosure, the system can comprise at least five modules.

[0029] In various aspects of the present disclosure, the first module of the plurality of modules includes a system feed dispenser. The last module of the plurality of modules includes a system buffer exchange dispenser.

[0030] In various aspects of the present disclosure, the system can be configured to operate as a diafiltration system that moves a solute of interest from within a feed solution distribution section from a starting solution matrix to an exchange buffer. The system can be configured to flush the filters of each module with the exchange buffer before initiating filtration of the feed solution distribution section.

[0031] In various aspects of the present disclosure, the system can be configured to compensate for outputting a product during system startup at a concentration lower than the process requirements by outputting the product during steady state at a concentration higher than the process requirements, whereby a mixture of the product output during startup and the product output during steady state has a concentration that meets the process requirements.

Brief Description of the Drawings

[0032] This patent document or this application document includes at least one drawing created in color. Copies of this patent or this patent application publication that include color drawings will be provided by the Patent Office upon request and payment of the required fees.

[0033] The above and other features and advantages of the present disclosure, and the manner in which they are achieved, will become more apparent and better understood by referring to the following description of embodiments of the invention in conjunction with the accompanying drawings.

Figure 1

Figure 2

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Figure 5

[0034] Throughout the several views, corresponding reference numerals indicate corresponding parts. The illustrations described herein illustrate exemplary embodiments of the invention and such illustrations are not to be construed as limiting the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

[0035] To facilitate an understanding of the principles of the present invention, reference will now be made to the embodiments illustrated in the drawings and this will be described using specific language. Nevertheless, it will be understood that no limitation of the scope of the present invention is thereby intended. Any modifications and further improvements to the embodiments described, as well as further applications of the principles of the invention disclosed herein, are contemplated as would normally occur to one of ordinary skill in the art related to the present invention. Although one embodiment of the present invention is shown in great detail, it will be apparent to those skilled in the art that some features not relevant to the present invention may not be shown for clarity.

[0036] FIG. 1 provides a schematic diagram of a fully integrated continuous tangential flow filtration (“cTFF”) system 100. The cTFF system 100 receives as input a system feed solution dispenser 103 and outputs a final system product 109. Optionally, the cTFF system 100 also receives as input a system exchange buffer dispenser 111. The system feed solution dispenser 103 may contain a solute of interest, such as a monoclonal antibody (mAB) suspended in a starting solution matrix. The cTFF system 100 may operate to increase the concentration of the solute of interest in the final system product 109. The cTFF system 100 may operate as a diafiltration system in which the solute of interest is transferred from the starting solution matrix to an exchange buffer. When operating as a diafiltration system, the final system product 109 may contain the solute of interest suspended in the exchange buffer supplied at 109 instead of the starting solution matrix. In some embodiments, the cTFF system may operate to both transfer the solute of interest to the exchange buffer and increase the concentration of the solute of interest in the final system product.

[0037] The cTFF system 100 may include a plurality of modules 102, each module 102 having a substantially identical operating structure to the remaining modules described herein, including some valves and / or other devices that allow for variations in the flow path configuration to perform various processes. As illustrated, the cTFF system 100 includes five modules 102; however, other embodiments may include more or fewer modules 102 to perform the processes as described.

[0038] Each of the modules 102 can be configured for performing a tangential flow filtration process. As illustrated, the first module 102a is configured to perform a primary concentration function using single-pass tangential flow filtration (“spTFF”), and the final module 102e is configured to perform a secondary concentration function using spTFF in cooperation with a countercurrent buffer exchange tangential flow filtration (“CCBE-TFF”) process, if necessary. The second module 102b, the third module 102c, and the fourth module 102d are each configured to perform CCBE-TFF. As described above, each module 102 has a substantially identical operating structure. Each module 102 can be configured to complete different processes by opening and closing certain on or off valves within the module 102. Thus, each module 102 can be easily operated in any configuration. Thus, the cTFF system 100 can be arranged with any number of modules as desired, and each module 102 can be configured for the same process or different processes as desired.

[0039] For example, in other embodiments, the cTFF system 100 can include six modules 102, where the second, third, fourth, and fifth modules are each configured to perform CCBE-TFF, while the sixth module is configured to perform a secondary concentration function using spTFF. Other embodiments are available that enable optimization of the system 100 for a particular process objective by using a fewer or greater number of modules 102 and configuring each module accordingly for a process (e.g., spTFF, CCBE-TFF, a combination of spTFF and CCBE-TFF, or other processes as desired).

[0040] The connections between the respective modules 102 are also illustrated in FIG. 1. For example, the retentate output of the first module 102a, or the primary concentration stage using the spTFF process, may provide a feed or retentate distribution section to the second module 102b along path 802, as further described herein. The retentate output of the second module 102b, or the retentate output of the first buffer exchange stage, may provide a feed or retentate distribution section to the third module 102c along path 804. The retentate output of the third module 102c, or the retentate output of the second buffer exchange stage, may provide a feed or retentate supply to the fourth module 102d along path 806, while the permeate output of the third module 102c may provide a permeate or diafiltration buffer distribution section to the second module 102b along path 808.

[0041] The retentate output of the fourth module 102d, or the retentate output of the third buffer exchange stage, may provide a feed or retentate distribution section to the fifth module 102e along path 812, while the permeate output of the fourth module 102d may provide a permeate or diafiltration buffer distribution section to the third module 102c along path 814. The retentate output of the fifth module 102e, which may serve as the fourth buffer exchange stage and / or the secondary concentration stage, is collected as the product, while the permeate output of the fifth module 102e provides a permeate distribution section to the fourth module 102d along path 824. Flow rate control for each path is further considered herein.

[0042] The system feed distribution section 103 may be distributed to the first module 102a. The final product 109 may be collected from the last module, i.e., the fifth module 102e. When the cTFF system is operated as a diafiltration system, the exchange buffer may also be provided to the final module, i.e., the fifth module 102e, as further described in more detail below.

[0043] FIG. 2 is a schematic diagram of module 102, its components, and the connections between them. As further discussed herein, flow path 104 (including flow paths 104a and 104b and possibly including flow paths 104c, 104d, 104e, and / or 104f) illustrates a permeate path, flow path 106 (including flow paths 106a and 106b) illustrates a retentate and / or feed path, and flow path 108 illustrates a supply path between a first break tank, or 110, and filter 112. For clarity, in both FIGS. 1 and 2, the permeate path is shown as a dotted line, the retentate and / or feed path is shown as a dashed line, while the path between the break tank and the filter is shown as a dash-dotted line. Each of flow paths 104, 106, and 108 can be controlled as further disclosed herein so as to form at least one of a first flow path configuration associated with an spTFF process and / or a second flow path configuration associated with a CCBE-TFF process such that the first and second flow path configurations can be active simultaneously or exclusively. In other words, module 102 can be configured to perform the spTFF process and the CCBE-TFF process simultaneously or exclusively.

[0044] The flow path 104a, which is the first part of the flow path 104, may start at the first input 114 with the diafiltration buffer or, alternatively, the permeate distribution section in each module 102, and the source of distribution of the module 102 may depend on the positioning of the module 102 within the cTFF system 100 (Figure 1). Where appropriate, the permeate distribution section or the diafiltration buffer provided at the first input 114 may be provided by a downstream module 102, as described above in relation to the cTFF system 100. The first input 114 may be regarded as a module exchange buffer distribution section. The operation of a flow valve, for example, the flow control valve 113, may prevent or enable the permeate distribution flow or the diafiltration buffer distribution flow to the flow path 104a as desired for the process configuration of the module 102. For example, the operation of the flow control valve 113 may further facilitate the control of the amount of the permeate distribution section or the diafiltration buffer entering the flow path 104a in order to maintain a stable system 100 (Figure 1), as further described herein. In other words, the flow control valve 113 may facilitate the control of the flow rate of the permeate distribution section or the diafiltration buffer into the module 102 as required by the state of the module 102 and / or the system 100 (Figure 1). When the flow control valve 113 is open and the flow path 104a is active, the diafiltration buffer or the permeate distribution section may enter the supply-side interruption tank 110 and terminate the flow path 104a. The flow rate of the diafiltration buffer or the permeate distribution section through the flow control valve 113 may be partially related to the extent to which the flow control valve 113 is opened. For example, a fully open valve may enable a maximum flow rate, while a half-open valve may enable a flow rate of approximately 50%. Varying the opening degree of the flow control valve 113 and the corresponding flow rate may be used as desired for the purpose of module operation.

[0045] The flow path 106a, which is the first part of the flow path 106, can start at each module 102 having a supply liquid distributor or, alternatively, a holding liquid distributor at the second input 124, and the distributor source of the module 102 can depend on the positioning of the module 102 within the cTFF system 100 (FIG. 1). Where appropriate, the holding liquid distributor or supply liquid distributor provided at the second input 124 can be provided by the upstream module 102 as described above in relation to the cTFF system 100. The second input 124 can be regarded as a module supply liquid distributor. The operation of the flow valve, for example, the flow control valve 115, can prevent or enable the holding liquid distribution flow or supply liquid distribution flow to the flow path 106a as desired for the process configuration of the module 102. For example, the operation of the flow control valve 115 can further facilitate the control of the amount of the holding liquid distributor or supply liquid distributor entering the flow path 106a to maintain a stable system 100 (FIG. 1) as further described herein. In other words, the flow control valve 115 can facilitate the control of the flow rate of the holding liquid distributor or supply liquid distributor to the module 102 as required by the state of the module 102 and / or the system 100 (FIG. 1). When the flow control valve 115 is open and the flow path 106a is active, the holding liquid distributor or supply liquid distributor can enter the supply-side interruption tank 100 and end the flow path 106a. The flow rate of the holding liquid distributor or supply liquid distributor through the flow control valve 115 can be partially related to the extent to which the flow control valve 115 is opened. For example, a fully open valve can enable a maximum flow rate, while a half-open valve can enable a flow rate of approximately 50%. Changing the opening degree of the valve 115 and the corresponding flow rate can be used as desired for the purpose of module operation.

[0046] The supply liquid interruption tank 110 can initiate the flow path 108. The supply liquid interruption tank 110 can receive a fluid flow from at least one of the flow paths 104a and 106a. An electric stirrer 128, such as an impeller, can be housed within the supply liquid interruption tank 110 to mix the fluid and ensure a homogeneous flow. The supply liquid interruption tank 110 can include a vent 129 that communicates with the ambient pressure to allow the pressure to return to the ambient pressure between the modules 102 and remain at the ambient pressure. The vent 129 facilitates the capacity of each module 102 to utilize the full pressure range of the filter 112 and otherwise reduces any pressure cascades that can occur throughout the cTFF system 100 (FIG. 1).

[0047] For example, during the CCBE process, the permeate from each stage can be reinjected into the feed stream of the preceding stage, similar to the permeate flow path described above with reference to FIG. 1. Generally, in certain embodiments that do not include the supply liquid interruption tank 110, the outlet pressure of the permeate can be higher than the feed liquid pressure of the preceding stage, resulting in a pressure cascade where the pressure of the final stage is the highest and the pressure of the initial stage is the lowest. Thus, the maximum pressure of the system can be constrained by the pressure rating of the system. That maximum pressure of the system must be shared across all stages within the system. An increase in the number of stages can improve the exchange efficiency that reduces the buffer requirements. However, as the number of stages increases, the maximum pressure of the system must be shared across more stages, and as a result, the pressure available to drive permeation at each individual stage becomes smaller, and thus the effectiveness of each stage is limited. By including the supply liquid interruption tank 110 and using the vent 129 to stabilize the pressure within the module 102, the pressure cascade can be reduced.

[0048] Ideally, the residence time in the supply liquid interruption tank 110 is relatively short, for example, about 30 to 120 seconds. The relatively short residence time in the supply liquid interruption tank 110 can minimize the system time constant required to reach the steady-state operation described herein, including start-up time, stop time, and response time to disturbances. An interruption tank of appropriate size can provide sufficient capacity to absorb disturbances while maintaining a reasonable hold-up volume. Longer or shorter retention times in the supply liquid interruption tank 110 can also be considered.

[0049] A pump 130, such as a positive displacement pump, can be positioned downstream of the supply liquid interruption tank 110 to facilitate a homogeneous mixture flow from the supply liquid interruption tank 110 to the filter 112. A flow transmitter 132 can be positioned downstream of the pump 130 to measure the flow rate of the homogeneous mixture from the supply liquid interruption tank 110 to the filter 112. The flow transmitter 132 can be operably communicated with a flow controller 133 configured to control the flow according to the required level adjustment in the supply liquid interruption tank 110 communicated by a level transmitter 136 and a level controller 137 as described below. The flow controller 133 is operably communicated with a speed controller 134 of the pump 130 as indicated by a process control loop 141, and as a result, the speed of the pump 130 can be adjusted as desired for each measured flow rate by the flow transmitter 132 and the flow controller 133. As used herein, the process control loop 141 refers to all dashed-line process control connections interconnecting the level transmitter 136, the level controller 137, the flow controller 133, the speed controller 134, and the flow transmitter 132 as shown in FIG. 2.

[0050] As shown by process control loop 141, speed controller 134 can be further operably coupled to level transmitter 136 and level controller 137, which are configured to cooperate to measure and control the amount of mixture present in supply interruption tank 110 to maintain the amount within a threshold range. Supply interruption tank 110 is ensured to include a void to facilitate control of the pressure within supply interruption tank 110 as described above. The void can further enable the interruption tank to absorb flow control disturbances and disconnect flow control between modules 102. As described above, speed controller 134 can adjust the speed of pump 130 as desired for each measurement value obtained and provided by the level transmitter to maintain the mixture level of supply interruption tank 110 within the desired level as determined by level controller 137 and flow controller 133. For example, if the level of the mixture in supply interruption tank 110 exceeds the upper threshold amount, pump 130 can enter from supply interruption tank 110 into the remaining flow path 108 and increase the flow rate through module 102 as further described herein. If the level of the mixture in supply interruption tank 110 falls below the lower threshold amount, pump 130 can decrease the flow rate from supply interruption tank 110, thus enabling supply interruption tank 110 to be refilled. In other embodiments, a weight transmitter (not shown) can be operably coupled to supply interruption tank 110 to measure the contents of supply interruption tank 110 via weight in addition to, or instead of, measuring the contents via level. The weight transmitter and the level transmitter can operate in cooperation or separately to measure the contents of supply interruption tank 110 in various embodiments.

[0051] As described above, the homogeneous mixture can be pumped from the supply liquid interruption tank 110 to the filter 112. The first pressure transmitter 138 is positioned between the pump 130 and the filter 112 and can be configured to measure the pressure drop across the filter 112 in cooperation with the second pressure transmitter 142 and the third pressure transmitter 144 for monitoring and optimizing the filter performance, as further described herein.

[0052] The flow path 106b, which is the second part of the flow path 106, may start from the filter 112. As described above, the second pressure transmitter 142 may be positioned within the flow path 106b to facilitate the measurement of the pressure drop across the filter 112. The flow transmitter 126 may be positioned within the flow path 106b downstream of the filter 112 to measure the flow rate of the retained liquid from the filter 112. The flow transmitter 126 may be operably coupled to a flow controller 127 that can control the flow control valve 146 according to an input received from the flow transmitter 126, as indicated by the process control loop 117. The process control loop 117 refers to all the dashed process control connections that interconnect the flow controller 127, the flow control valve 146, and the flow transmitter 126. The flow control valve 146 may also be positioned within the flow path 106b to impede or enable the flow of the retained liquid from the filter 112 to the first output 148 of the module 102 as desired for the process configuration of the module 102. The flow control valve 146 may facilitate the control of the flow of the retained liquid as required by the state of the module 102 and / or the system 100 (FIG. 1) according to the flow controller 127. When the flow control valve 146 is open and the flow path 106b is active, the retained liquid may exit the module 102 at the first output 148 and terminate the flow path 106b. The flow rate of the retained liquid through the flow control valve 146 may be partially related to the extent to which the flow control valve 146 is open. For example, a fully open valve may allow a maximum flow rate, while a half-open valve may allow a flow rate of approximately 50%. Varying the opening degree of the valve 146 and the corresponding flow rate may be used as desired for the purpose of module operation. The first output 148 may be in fluid communication with a supply input of another module within the cTFF system 100 (FIG. 1) as described above, or may facilitate the collection of the retained liquid as a product.

[0053] Ratio controllers such as gamma controller 180, further contemplated herein, are generally represented by process control loop 181 and, as further described herein, can adjust flow controller 127 of process control loop 117 for holding liquid flow path 106b based on flow controller 133 of process control loop 141 for filter flow path 108.

[0054] Flow path 104b, a second portion of flow path 104, can also begin at filter 112. As described above, third pressure transmitter 144 can be positioned within flow path 104b to facilitate measurement of the pressure drop across filter 112. Pressure control valve 150 can also be positioned within flow path 104b to improve the holding liquid flow control function as described above and further described herein under certain process conditions. Third flow transmitter 154 can be positioned between filter 112 and pressure control valve 150 to measure the flow rate of the permeate from filter 112 to permeate break tank 152. Pressure control valve 150 can facilitate control of the permeate pressure as required by the state of module 102 and / or system 100 (FIG. 1). When pressure control valve 150 is open and flow path 104b is active, the permeate can enter permeate break tank 152 as further described herein. In some embodiments, pressure control valve 150 can be a passive control valve. The flow through pressure control valve 150 can be determined by the overall mass balance of the system as further described herein. The permeate pressure upstream of pressure control valve 150 can be partially related to the extent to which flow control valve 150 is open. For example, a fully open valve can allow for a minimum permeate pressure while a half-open valve can allow for an elevated permeate pressure. Varying the opening of valve 150 and the corresponding permeate pressure can be used as desired for the purpose of module operation. Thus, the flow rate of flow path 104b or the permeate flow path is obtained from the overall mass balance around filter 112. Thus, any change to the flow rate within flow path 108 or flow path 106b results in a responsive change in the flow rate within flow path 104b to maintain mass conservation within module 102.

[0055] In some situations, the flow rate in flow path 104b is too high relative to the target flow rate set by gamma controller 180. Gamma controller 180 may attempt to compensate by further opening valve 146 to divert flow from flow path 104b to flow path 106. However, in some cases, valve 146 cannot be opened further (e.g., it is already fully open). In this situation, the permeate pressure can be applied if manual or automatic adjustment of permeate 150 is completed by the user or control system to move valve 150 towards the closed position, change the dynamics within filter 112, and push more flow into flow path 106b, which, as further discussed herein, enables valve 146 to regain active control of the flow rate in flow path 104b.

[0056] The permeate interruption tank 152 can receive the permeate flow from the filter 112 as determined by the cooperation of the first flow control valve 146 and the pressure control valve 150. The permeate interruption tank 152 can serve both to collect the permeate from the module 102 and as a reservoir for dispensing the permeate as a diafiltration solution to the upstream module 102 of the cTFF system 100 (FIG. 1) as described above. Under ideal steady-state conditions, the level in the permeate interruption tank 152 can remain substantially stable since the amount of permeate flowing into the permeate interruption tank 152 can be substantially the same as the amount of diafiltration agent flowing out into the next module supplied from the permeate interruption tank 152. The level transmitter 156 can be configured to measure the amount of permeate present in the permeate interruption tank 152 and operate in conjunction with the level controller 157 to ensure that the amount is within a threshold range. The threshold range of the permeate interruption tank 152 can facilitate including voids within the permeate interruption tank 152, enabling the interruption tank to absorb flow control disturbances and decouple the flow control between the modules 120. The permeate interruption tank 152 can further include a corresponding second vent 153 in fluid communication with the ambient pressure to allow the pressure to return to and remain at the ambient pressure between the modules 102, which can be further facilitated by the voids for the reasons provided above in connection with the feed interruption tank 110.

[0057] A pump 131, such as a positive displacement pump, may be positioned downstream of the permeate break tank 152 to facilitate the flow of permeate from the permeate break tank 152 to the second output 160 of the module 102. The pump 131 may be operably coupled to a speed controller 155, which may be further operably coupled to a level transmitter 156 and a level controller 157, as indicated by the process control loop 159. The process control loop 159 refers to all dashed process control connections that interconnect the speed controller 155, the level controller 157, and the level transmitter 156. The speed controller 155 may adjust the speed of the pump 131 as desired for each measurement obtained and provided by the level transmitter 156 to maintain the permeate level of the permeate break tank 152 within a level threshold range determined by the level controller 157. In other embodiments, a weight transmitter (not shown) may be operably coupled to the permeate break tank 152 to measure the contents of the permeate break tank 152 via weight, in addition to or instead of level. The weight transmitter and the level transmitter may operate in concert or separately to measure the contents of the permeate break tank 152 in various embodiments. In some situations, if the level of the permeate in the permeate break tank 152 exceeds an upper threshold amount, the permeate may be discharged to a waste section along the flow path 104c, and access to the flow path may be facilitated by a valve 105. If the level of the permeate in the permeate break tank 152 drops below a lower threshold amount, the diafiltration buffer may be added along the flow path 104d, and access to the flow path may be facilitated by a valve 107.

[0058] Valve 162 can be positioned downstream of pump 131 along flow path 104e. Valve 162 can be operable to permit or prevent the flow of permeate to the second outlet 160. The second outlet 160 can be in fluid communication with the permeate distribution section of the upstream module of system 100 (FIG. 1) as described above. Control valve 164 can also be positioned downstream of pump 131 along flow path 104f. Control valve 164 can be operable to permit or prevent the flow of permeate to the waste section 170 as further discussed herein. Control valve 164 can be operably coupled to flow controller 166 and / or flow transmitter 168 to measure and control the flow of permeate from the permeate break tank 152 to the waste section 170. Flow transmitter 168 can be operable to measure the flow rate of the permeate between the permeate break tank 152 and control valve 164, while flow controller 166 operates control valve 164 to maintain, decrease, or increase the flow rate measured by flow transmitter 168.

[0059] As described above, each module 102 can be operated to perform a particular process as desired through the operation of a plurality of valves as described above to close and / or open the flow paths described herein when necessary. A first path configuration that can conform to the spTFF process can include a fluid flow directed through flow path 104a, flow path 108, and each of flow paths 104b and 106b as necessary, such that flow path 106a is closed in the first path configuration. A second path configuration that can conform to the CCBE-TFF process can include a fluid flow directed through each of flow paths 104a, 106a, 108, and each of flow paths 104b and 106b as necessary. A third path configuration that enables substantially simultaneous CCBE-TFF and spTFF processes can include a fluid flow directed through each of flow path 104a, flow path 106a, flow path 108, and each of flow paths 104b and 106b as necessary.

[0060] The control of the cTFF system 100 to maintain a steady state within the system and facilitate stability and efficiency may depend at least in part on the monitoring and control of the flow ratio within the system 100, which can be established based on the desired degree of solution / buffer exchange. The desired degree of solution / buffer exchange may depend on the type of process being performed. For example, some processes may require an exchange efficiency of nearly 100% (e.g., 99.996%) between the solution and the buffer. Other processes may require a lower exchange efficiency, such as 99%. Even lower exchange efficiency requirements are also possible. As the number of CCBE stages increases within the cTFF system 100, the exchange efficiency may also increase, which can reduce the amount of diafiltration solution and / or buffer required.

[0061] The degree of buffer exchange required can be expressed as an impurity removal value (derivation not shown). As used herein, "impurity" is generally used to represent any species intended to be removed by the TFF diafiltration process. From this impurity removal value, an impurity removal coefficient ("α") can be calculated as a function of the number of CCBE stages present within the system using the following equation.

[0062]

Equation

[0063] The flow ratio of the exchange buffer to the feed solution to the CCBE section of the cTFF system can then be calculated from the impurity removal coefficient using the following equation.

[0064]

Equation

[0065] For many, but not all, tangential flow filtration processes, it is understood that the sieve coefficient for small, readily permeable solutes is equal to or close to 1. In the five-module cTFF system as described above, the impurity removal coefficient is calculated as the ratio of the diafiltration buffer flow rate entering module 102e to the flow rate of the product stream entering module 102b. For process control purposes, a stage removal coefficient ("γ") is introduced in the present disclosure. The stage removal coefficient (γ) can be the ratio between any two of the following three parameters: (i) the feed solution flow rate, as measured, for example, by flow transmitter 132; (ii) the permeate flow rate; and (iii) the retentate flow rate. The permeate flow rate and the retentate flow rate can each be measured for each individual module using flow transmitters 154, 126 (Figure 2) downstream of the filter as described above. One of the permeate flow rate and the retentate flow rate can be further calculated using at least two of flow transmitters 154, 126, and 132 (Figure 2). For example, the permeate flow rate can be calculated by subtracting the retentate flow rate measured by flow transmitter 126 (Figure 2) from the feed solution interruption tank flow rate measured by flow transmitter 132 (Figure 2). Similarly, the retentate flow rate can be calculated by subtracting the permeate flow rate measured by flow transmitter 154 (Figure 2) from the feed solution interruption tank flow rate measured by flow transmitter 126 (Figure 2).

[0066] In the CCBE-TFF process where the concentration of the holding solution exiting each module matches the concentration of the feed material entering the CCBE-TFF module, the numerical values of the stage removal coefficient ("γ") and the impurity removal coefficient ("α") are equal. In modules where a higher holding solution concentration is desired, such as at the final stage of the system, the numerical value of the stage removal coefficient ("γ") can be greater than the impurity removal coefficient ("α"). In other words, the cTFF system can approach a steady state as the stage removal coefficient approaches the impurity removal coefficient. However, these values do not necessarily have to be equal to maintain a steady state, depending on the desired result of the cTFF system process.

[0067] Referring again to FIG. 2, as described above, the gamma controller 180 is operably communicating with the flow controller 133 and the flow controller 127. As described above, the gamma controller adjusts the flow rate of the flow path 106b via the flow control valve 146, and adjusts the flow rate of the flow path 104b based on the flow rate of the flow path 108 controlled by the flow controller 133 by the resulting mass balance, so that the calculated stage removal coefficient of each module 102 approaches a predetermined target stage removal coefficient set point. The target stage removal coefficient set point can be determined according to the process requirements and how the module 102 is being used. For example, if the module 102 is operating only as an spTFF module, the stage removal coefficient (γ) set point can be established based on the degree of concentration required from the module 102. If the module 102 is operating as a CCBE-only module, the stage removal coefficient (γ) set point can be determined based on the desired exchange efficiency. For example, in one exemplary non-limiting embodiment, when the stage removal coefficient (γ) is defined as the ratio of the permeate flow rate to the holding solution flow rate, the stage removal coefficient set point is set to the impurity removal coefficient (α) required to achieve the desired exchange efficiency, as calculated using the above formula and / or determined / confirmed experimentally. In the combined CCBE and additional concentration modules, the stage removal coefficient (γ) set point can be set at a point that achieves both the desired amount of concentration and the desired exchange efficiency.

[0068] The predetermined target stage rejection coefficient can be pre-programmed in the gamma controller 180, and the predetermined target stage rejection coefficient is the stage rejection coefficient at which the module maintains a steady state. In other words, the gamma controller 180 can be configured to automatically maintain the module in a steady state by automatically and individually adjusting the hold-up liquid path 106b via the operation of the flow controller 127 as described above, thereby automatically maintaining a substantially steady stage rejection coefficient at or near the predetermined target stage rejection coefficient. In this way, the gamma controller 180 keeps the ratio of the feed liquid flow rate, the permeate liquid flow rate, and / or the hold-up liquid flow rate at a steady target steady state necessary to achieve process-specific objectives.

[0069] In some embodiments, the gamma controller 180 can also be configured to compensate for manual or automatic adjustment of the pump 130 or associated controller and / or the flow control valve 146 in a manner similar to that described above. For example, if the user notices that the level in the feed interruption tank 110 is too high, manual adjustment to the speed controller 134, the pump 130, and / or the flow controller 133 can be performed. Such adjustment changes the calculated stage rejection coefficient of the module 102. The gamma controller 180 can then operate the flow control valve 146 via the flow controller 127 so that the calculated stage rejection coefficient approaches the predetermined target stage rejection coefficient to compensate for the manual adjustment. Thus, the manual adjustment and the resulting automatic adjustment can be performed without requiring the shutdown of the module 102 or the system 100 (FIG. 1).

[0070] In some embodiments, the gamma controller 180 may be configured to automatically adjust the flow control valve 146 according to the setpoint target of the flow controller 133 of the flow path 108. As described above, the setpoint target of the flow controller 133 is adjusted according to the level of the supply liquid interruption tank 110 measured by the level transmitter 136. For example, if the level transmitter 136 measures that the level in the supply liquid interruption tank 110 is too high according to the level threshold of the level controller 137, the level controller 137 may communicate this to the flow controller 133. The flow controller 133 may adjust the speed of the pump 130 via the speed controller 134 in response to adjusting the level of the mixture in the supply liquid interruption tank 110. Such adjustment changes the calculated stage removal coefficient of the module 102. Then, the gamma controller 180 may operate the flow control valve 146 via the flow controller 122 so that the calculated stage removal coefficient approaches a predetermined target stage removal coefficient to compensate for the adjustment.

[0071] In a cTFF system similar to the cTFF system 100 illustrated in FIG. 1, the secondary concentration process of the final module, such as the fifth module 102e, is performed by setting the target stage removal coefficient to a value higher than the target stage removal coefficients of the intermediate modules 102b, 102c, and 102d. For example, the stage removal coefficient and the flow removal coefficient of each of the modules 102b, 102c, and 102d may be substantially equal, but the stage removal coefficient of the module 102e may be greater than the flow removal coefficient. This is because in the retention liquid of the module 102e, or in a system having more than five modules, the retention liquid of the final module is collected as the product. The permeate of the final module is split, for example, between a small waste stream via the flow path 104f and the permeate distributor of the immediately preceding module via the flow path 104e. The small waste stream removes the excess permeate resulting from the secondary concentration of the final module and is facilitated by a higher predetermined target stage removal coefficient. This is interpreted as a cTFF system having a smaller or larger number of modules in which the final module has a higher stage removal coefficient than the intermediate modules.

[0072] As described above, the feed liquid distributor 103 for the entire cTFF system 100 can be provided to the feed liquid distributor of the first module 102a. More specifically, the feed liquid distributor 103 can be provided in the flow path 106a of the first module 102a. The diafiltration buffer distributor 111 for the entire cTFF system 100 can be supplied to the exchange buffer or permeate distributor of the last module 102e, more specifically to the flow path 104a. This diafiltration buffer distributor can contain a buffer that is desired to be exchanged with the buffer currently present in the feed liquid distributor. The final product 109 of the entire cTFF system 100 can be collected from the flow path 102e of the last module 106b.

[0073] The steady-state operation of each module 102 is managed and generally controllable by interruption tank level controllers 137 and 157 and gamma controller 180. Maintaining the steady-state operation within each module 102 of system 100 (FIG. 1) facilitates the steady-state operation of the entire system 100 (FIG. 1). Due to the interconnection of the modules 102 within system 100 as described and illustrated above in connection with FIG. 1, a change in the total or average flow rate through each of the flow paths 104a, 106a, 108, 104b, and / or 106b of module 102 can result in a change in the total flow rate of the remaining modules within system 100.

[0074] In some cTFF systems, the filters can exhibit different filtration rates over different stages within the system. Conventionally, in a single-stage spTFF system, different filtration rates could be compensated for by changing the total flow rate within an individual stage, e.g., by changing the flow rate within the stage to run the process faster or slower in order to achieve a desired level of concentration. However, in the cTFF system 100 as described herein, such an interruption in the flow rate in one stage (e.g., the stage operated by module 102b) interrupts the flow rate in other stages (e.g., the stages operated by modules 102a, 102c, 102d, 102e), and since this interrupts steady-state operation, the flow rate cannot be changed to adjust the filtration rate.

[0075] Taking the above into consideration and additionally referring to FIG. 5, the filter 112 of each module 102b operates at an operating pressure level within a pressure-dependent region, e.g., within region 1000, and an increase in the supply flow pressure (i.e., the flow pressure measured by pressure transmitter 138) increases the filtration rate, while a decrease in the operating flow pressure decreases the filtration rate. In order for the level controller, flow controller, and gamma controller to successfully maintain a stable state, the transmembrane pressure changes resulting from controller operation must not affect the filtration rate or permeate flux in such a way as to disrupt the steady-state operation of the entire system 100 without changing the flow rate. The region with low pressure dependence is illustrated in region 1002 of FIG. 5. In still other embodiments, parameters such as the surface area of the filter or the configuration of the surface area of the filter can be manipulated at the individual stage level to affect the filtration rate of a particular stage without disturbing the remaining stages or the overall system.

[0076] Generally, the product collected during the start-up and shut-down of a continuous system may not meet the concentration or buffer exchange efficiency requirements, and such product collected during start-up or shut-down is discarded. To reduce or eliminate these losses, specific procedures may be followed.

[0077] For example, when the system is operating as a diafiltration system, the system is generally provided with a feed liquid distributor for a material containing a solute of interest suspended in a starting solution matrix. As in any diafiltration operation, the purpose of this system is to transfer the solute of interest from the starting solution matrix to the exchange buffer. In such a diafiltration system, the filters of the system can be flushed with the target exchange buffer solution before introducing the feed liquid distributor of the material to be filtered into the system. Then, all the materials collected from the initial start-up to the steady state are over-diluted by the exchange buffer already present in the system until the steady state is achieved, exceeding the desired impurity removal coefficient. Since the excess exchange buffer is typically not the cause of material rejection, the materials collected from the initial start-up to the steady state do not need to be discarded, thus reducing the waste section.

[0078] Regarding concentration, the materials collected during start-up can be concentrated lower than required by the process requirements. To compensate for this, the concentration during steady-state operation can be set at a level slightly higher than the process requirements such that the combination of (i) the lower-concentration product collected during start-up and (ii) the higher-concentration product collected during steady state together meets the concentration specified by the process requirements. The time required to bring the system to the steady state can be predicted mathematically and / or experimentally, and the total amount of product to be processed can be known in advance, so the amount by which the steady-state concentration must not exceed the process requirements can be calculated based on the overall mass balance. In this way, the product collected during start-up may not need to be discarded into the waste section.

Example

[0079] Example 1 The operating goals for the test cTFF system were selected according to Table 1 below.

[0080]

Table 1

[0081] Each of the tested steps that corresponded to Steps 2-4 described above in connection with System 100 was configured for the CCBE process. The feed material contained 107 g / L of mAb in an aqueous buffer solution having a higher conductivity. This material was prepared using a standard single-module spTFF configuration prior to use in this Example 1. At a given point in time, the following events then occurred. At 0 minutes, a buffer flush was performed. At 9 minutes, the process was started with the introduction of the mAb feed material. At 320 minutes, the process ended with a second buffer flush. At 330 minutes, a water flush was performed. At 340 minutes, a wash flush was performed. At 350 minutes, the shutdown of the test cTFF system was completed.

[0082] Figure 3 illustrates the parameters monitored to evaluate steady-state operation and the measurements of those parameters over the time of the experimental operation. Image 200 illustrates the direct and cross-flow fluxes and the transmembrane pressure (i.e., the difference between the average feed / retentate-side pressure and the average permeate-side pressure across the filter) for each step over the execution time of each step, line 202 illustrates the target direct and cross-flow flux, line 204 illustrates the direct and cross-flow flux of Step 2, line 206 illustrates the direct and cross-flow flux of Step 3, and line 208 illustrates the direct and cross-flow flux of Step 4. Line 210 illustrates the transmembrane pressure of Step 2, line 212 illustrates the transmembrane pressure of Step 3, and line 214 illustrates the transmembrane pressure of Step 4.

[0083] Image 300 illustrates the outlet concentration in g / L compared to the target outlet concentration, line 302 illustrates the target outlet concentration, and line 304 illustrates the achieved outlet concentration. Image 400 illustrates the flow ratio for each step, or the ratio of the permeate flow rate to the retentate flow rate, line 402 illustrates the target flow ratio, line 404 illustrates the flow ratio of Step 2, line 406 illustrates the flow ratio of Step 3, and line 408 illustrates the flow ratio of Step 4. Image 500 illustrates the conductivity for each step, line 502 illustrates the conductivity of Step 2, line 504 illustrates the conductivity of Step 3, and line 506 illustrates the conductivity of Step 4.

[0084] Steady-state operation was achieved over 5.5 hours, with only minor flow rate adjustments required every 30 - 60 minutes. As shown in Images 200 and 400, the AC and DC flow rates and flow ratios remained stable near the target values over the duration of the run. The conductivity decreased over Stages 2 - 4, as shown in Image 500, which was expected to demonstrate the occurrence of buffer exchange. At the end of Stage 4, a hold liquid product with an overall concentration of 108 g / L, containing pre- and post-steady-state materials pooled with the steady-state hold liquid, was collected, and it was demonstrated that the feed concentration was similar to the outlet concentration across the three CCBE modules, as expected for a module operating only in buffer exchange mode.

[0085] Example 2 The operating targets for the test cTFF system were selected according to Table 2 below.

[0086]

Table 2

[0087] The test stage corresponding to Stage 5 described above in relation to System 100 was configured for simultaneous CCBE and spTFF (i.e., the secondary concentration process). The feed material contained 108 g / L of mAb in an aqueous buffer solution. At a given point in time, the following subsequent events occurred. At 0 minutes, a buffer flush was performed. At 1 minute, the process was started with the introduction of the mAb feed material. At 170 minutes, the process ended with a second buffer flush. At 188 minutes, a water flush was performed. At 200 minutes, a wash flush was performed. At 210 minutes, the shutdown of the test cTFF system was completed.

[0088] Figure 4 illustrates the parameters monitored to evaluate steady-state operation and the measurement of such parameters over the time of experimental operation. Image 600 illustrates the direct and alternating fluxes and the transmembrane pressure (i.e., the difference between the average supply / hold-side pressure and the average permeate-side pressure across the filter) for each stage over the execution time of the stage, line 602 illustrates the target direct and alternating flux, and line 604 illustrates the direct and alternating flux of stage 5. Line 606 illustrates the transmembrane pressure of stage 5.

[0089] Image 700 illustrates the outlet concentration in g / L compared to the target outlet concentration, line 702 illustrates the target outlet concentration, and line 704 illustrates the achieved outlet concentration. Image 800 illustrates the flow ratio of stage 5 compared to the target flow ratio, or the ratio of the direct and alternating flow rate to the hold liquid flow rate, line 802 illustrates the target flow ratio for buffer exchange, and line 804 illustrates the flow ratio of stage 5. As previously explained, since this is the combined CCBE and spTFF stage, the flow ratio is higher than the target. Image 900 illustrates the conductivity of stage 5, and line 902 illustrates the conductivity of stage 5.

[0090] Stable steady-state operation was achieved over approximately 3 hours. Only minor flow rate adjustments were required every 30 - 60 minutes. As shown in Images 600 and 800, the direct and alternating flow rate, flow ratio, concentration, and conductivity were stable over the duration of the execution.

[0091] The present invention has been described as having an exemplary design, but the present invention can be further modified within the spirit and scope of the present disclosure. Accordingly, this application is intended to cover any variations, uses, or adaptations of the present invention using the general principles of the present invention. Furthermore, this application is intended to cover such departures from the present disclosure as come within known or customary practice within the technical field to which the present invention pertains.

Claims

1. A tangential flow filtration module, wherein the module comprises a flow distribution unit including a module exchange buffer solution distribution unit and a module feed solution distribution unit, a feed solution interruption tank positioned downstream of the flow distribution unit, the feed solution interruption tank including an electric stirrer, and a first filter positioned downstream of the feed solution interruption tank. A tangential flow filtration module comprising the above.

2. The tangential flow filtration module according to claim 1, further comprising a feed solution pump positioned between the feed solution interruption tank and the first filter, the feed solution pump being configured to control the flow rate of the flow between the feed solution interruption tank and the first filter.

3. The tangential flow filtration system according to claim 1, wherein the operation of the electric stirrer is configured to generate a homogeneous solution.

4. The tangential flow filtration system according to claim 1, wherein the feed solution interruption tank defines voids.

5. The tangential flow filtration system according to claim 1, wherein the feed solution interruption tank defines a vent in fluid communication with the ambient pressure.

6. The tangential flow filtration system according to claim 1, further comprising a permeate interruption tank positioned downstream of the first filter.

7. The tangential flow filtration system according to claim 1, wherein the module exchange buffer solution distribution unit consists of the permeate of a second filter positioned downstream of the first filter, and the feed solution distribution unit of the second filter includes the retentate of the first filter.

8. The tangential flow filtration module according to claim 1, wherein the module feed solution distribution unit consists of the retentate of a third filter positioned upstream of the first filter.

9. A tangential flow filtration module, wherein the module comprises a flow distribution unit including a module exchange buffer solution distribution unit and a module feed solution distribution unit, a filter positioned downstream of the flow distribution unit and having two output units including a permeate output unit and a retentate output unit, and a permeate interruption tank positioned downstream of the filter and supplied by the permeate output unit of the filter. A tangential flow filtration module comprising the above.

10. The tangential flow filtration module according to claim 9, further comprising a feed solution interruption tank positioned between the flow distribution unit and the filter.

11. The interior of the permeate break tank defines a void, the tangential flow filtration system according to claim 9.

12. The permeate break tank includes a vent in fluid communication with ambient pressure, the tangential flow filtration system according to claim 9.

13. Further comprising a valve positioned between the first filter and the permeate break tank, the valve being configured to control the permeate pressure on the permeate side of the first filter, the tangential flow filtration system according to claim 9.

14. The permeate break tank distributes to a second filter positioned upstream of the feed liquid distribution section, the tangential flow filtration system according to claim 9.

15. The feed liquid distribution section consists of the holding liquid of the second filter, the tangential flow filtration module according to claim 14.

16. The module exchange buffer liquid distribution section consists of the permeate of a third filter positioned downstream of the first filter, and the feed liquid distribution section of the third filter includes the holding liquid of the first filter, the tangential flow filtration system according to claim 9.

17. Further comprising at least one valve, the operation of the valve configures the tangential flow filtration module from a first flow path configuration to a second flow path configuration, or is configured to change the configuration of the tangential flow filtration module from the second flow path configuration to the first flow path configuration, The first flow configuration is a countercurrent buffer liquid exchange flow path configuration, The second flow configuration is a single pass tangential flow filtration flow path configuration, the tangential flow filtration module according to claim 9.

18. A tangential flow filtration system, the tangential flow filtration system comprises a plurality of individual modules, each of the individual modules being configured to perform a process related to tangential flow filtration, and each individual module a plurality of valves, the operation of the plurality of valves being configured to change the flow path of the corresponding individual module, a plurality of valves, and a control system, calculates a current stage rejection coefficient for the individual module, the current stage rejection coefficient being a ratio between any two of the permeate flow rate, feed liquid flow rate, and holding liquid flow rate for the individual module, the current stage rejection coefficient for the individual module, A control system configured to automatically operate the plurality of valves to change the flow path so that the current stage removal coefficient for each of the individual modules approaches the target stage removal coefficient, and a tangential flow filtration system including the same.

19. The tangential flow filtration system according to claim 18, wherein the plurality of individual modules include at least five modules.

20. The tangential flow filtration system according to claim 18 or 19, wherein the last individual module of the plurality of individual modules has a target stage removal coefficient different from that of at least one other individual module of the plurality of individual modules.

21. The tangential flow filtration system according to claim 18, wherein the control system is configured to maintain the tangential flow filtration system in a steady state in which the current stage removal coefficient approaches the target stage removal coefficient.

22. The system is configured to allow a user to adjust at least one of the plurality of valves in a manner that deviates the current stage removal coefficient from the target stage removal coefficient when the tangential flow filtration system is in the steady state, The tangential flow filtration system according to claim 21, wherein the control system is configured to automatically operate the remaining valves of the plurality of valves to compensate for the user adjustment so that the current stage removal coefficient approaches the target stage removal coefficient again after the user adjustment.

23. Each of the plurality of individual modules includes A supply liquid interruption tank positioned downstream of the flow distribution section for the individual module and upstream of the filter, wherein the flow distribution section includes a module supply liquid distribution section and a module exchange buffer liquid distribution section, and a supply liquid interruption tank; A permeate interruption tank positioned downstream of the filter, and A first flow rate output section of the supply liquid interruption tank and a second flow rate output section of the permeate interruption tank are individually adjustable during operation of the tangential flow filtration system, The tangential flow filtration system according to claim 21, wherein the control system is configured to maintain the tangential flow filtration system in a steady state by automatically maintaining a substantially steady stage removal coefficient during adjustment of either the first flow rate output section or the second flow rate output section.

24. The tangential flow filtration system according to claim 23, wherein the control system is further configured to maintain a steady level in the feed liquid interruption tank and a steady level in the permeate liquid interruption tank.

25. A tangential flow filtration system, wherein the system comprises a plurality of modules, and each module comprises a module flow distributor, a filter positioned downstream of the module flow distributor, a feed liquid interruption tank positioned between the module flow distributor and the filter, and at least one of a permeate liquid interruption tank positioned downstream of the filter.

26. Each module has at least one of a first configuration corresponding to a single pass tangential flow filtration ("spTFF") process, a second configuration corresponding to a countercurrent buffer exchange tangential flow filtration ("CCBE-TFF") process, and a third configuration corresponding to a combined spTFF and CCBE-TFF process, according to the tangential flow filtration of claim 25.

27. Each module of the plurality of modules includes a plurality of valves such that each module of the plurality of modules can selectively switch from the first configuration to at least one of the second configuration and the third configuration, from the second configuration to at least one of the first configuration and the third configuration, and from the third configuration to at least one of the first configuration and the second configuration, according to the tangential flow filtration system of claim 26.

28. The first module of the plurality of modules is in the first configuration, and the second module of the plurality of modules is in the second configuration, according to the tangential flow filtration system of claim 26.

29. The first plurality of modules including the first module is in the first configuration, and the second plurality of modules including the second module is in the second configuration, according to the tangential flow filtration system of claim 28.

30. The last module of the plurality of modules is operated in the third configuration, according to the tangential flow filtration system of claim 26.

31. At least some of the permeate from the last module is dispensed to a module exchange buffer dispenser for another module upstream of the last module, and at least some of the permeate from the last module is sent to a waste section, the tangential flow filtration system of claim 30.

32. Each module of the plurality of modules includes a holding liquid flow path and a permeate flow path, and the permeate interruption tank is positioned along the permeate flow path, the tangential flow filtration system of claim 25.

33. The tangential flow filtration system of claim 25, further comprising at least five modules.

34. The first module of the plurality of modules includes a system feed liquid dispenser, and the last module of the plurality of modules includes a system buffer exchange dispenser, the tangential flow filtration system of claim 25.

35. The system is configured to operate as a diafiltration system that transfers a solute of interest from a starting solution matrix to an exchange buffer from within a feed liquid dispenser, and the system is configured to flush the filter of each module with the exchange buffer before starting filtration of the feed liquid dispenser, the tangential flow filtration system of claim 25.

36. The system is configured to compensate for outputting a product during system startup at a concentration lower than the process requirement by outputting the product at a concentration higher than the process requirement during steady state, whereby a mixture of the product output during startup and the product output during steady state has a concentration that meets the process requirement, the tangential flow filtration system of claim 25.

Images