Continuous tangential flow filtration system

Abstract

Tangential flow filtration systems are disclosed herein, and more particularly, continuous tangential flow filtration ("cTFF") systems that include a single pass module are disclosed herein. Each one-pass module is configured to transition from a first process configuration to a second process configuration and / or operate in both the first process configuration and the second process configuration to customize the cTFF system. Each of the modules has at least one cutoff box for regulating flow and pressure throughout the module and, over a greater scale, regulating the cTFF system.

Description

Technical Field

[0001] The present disclosure relates to tangential flow filtration systems, and more particularly, to continuous tangential flow filtration ("cTFF") systems including a single pass module with more than one process configuration and at least one break box for flow and pressure control. Background Art

[0002] Conventional pharmaceutical and biopharmaceutical manufacturing processes require a series of discrete batch operations arranged in downstream configurations. For example, conventional systems may include examples of column chromatography, virus inactivation, virus filtration, tangential flow filtration, final filtration, and storage and transportation. Each of these operations may also require a subset of its own operation. For example, the conventional way to complete tangential flow filtration is via batch tangential flow filtration (bTFF), which requires that the feed-in material be repeatedly recycled by the same filter. This is done to increase the concentration of the solute of interest in the solution or to achieve the desired solution composition by diafiltration, wherein the solute of interest is converted into an exchange buffer from the starting solution matrix. Such a process requires several recirculations, and may cause system inefficiency.

[0003] Continuous tangential flow filtration strategies can include using single-pass tangential flow filtration ("spTFF") as a concentration operation and using countercurrent buffer exchange tangential flow filtration ("CCBE-TFF") as a diafiltration operation, which allows continuous tangential flow filtration to be used to achieve the same processing results as bTFF. For example, spTFF can achieve the same desired concentration with a single pass through the filter without requiring several or even hundreds of passes through the filter. With the continuous addition of multiple continuous concentration steps and in contrast to in-line dilution, spTFF can also be used for CCBE-TFF. However, CCBE-TFF requires multiple stages to improve efficiency, in which the feed stream is continuously fed into the system and the retentate is continuously collected at the discharge through a series of dilution and concentration stages. The diafiltration buffer is supplied at the final diafiltration stage. The permeate from the final stage is then used as the diafiltration agent for the previous stage, resulting in a flow that is "countercurrent" with the feed stream. However, the CCBE-TFF process also comes with its own set of challenges, including complex process control, an increased number of necessary pumps and other instrumentation, and a higher surface area requirement relative to conventional bTFF systems. In addition, the requirement for serial stages presents process control challenges, including but not limited to unstable flow rates, system overpressure, undesirable mixing, tightly coupled flow control loops between stages, and complex startup and shutdown procedures, which also complicates situations requiring upset response, where restarting the system is necessary, leading to additional inefficiencies. Summary of the invention

[0004] The present disclosure relates to tangential flow filtration systems, and more particularly, to continuous tangential flow filtration ("cTFF") systems comprising single-pass modules configured to transition from a first process configuration to a second process configuration and / or to operate in both the first process configuration and the second process configuration to customize the cTFF system. Each of the modules has at least one break box to regulate flow and pressure throughout the module and, on a larger scale, the cTFF system.

[0005] In a first aspect of the present disclosure, a tangential flow filtration module is described. The module includes: a flow supply including a module exchange buffer supply and a module feed supply; a feed break box positioned downstream of the flow supply, the feed break box including a powered agitator; and a first filter positioned downstream of the feed break box.

[0006] In another aspect of the present disclosure, a tangential flow filtration module is described. The module includes: a flow supply including a module exchange buffer supply and a module feed supply; a filter positioned downstream of the flow supply and having two outputs including a permeate output and a retentate output; and a permeate break box positioned downstream of the filter and supplied by the permeate output of the filter.

[0007] In yet another aspect of the present disclosure, a tangential flow filtration system is described. The tangential flow filtration system includes a plurality of individual modules, each of the individual modules being configured to perform a process associated with tangential flow filtration, wherein each individual module includes a plurality of valves and a control system. Actuation 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 removal factor for the individual modules and automatically operate the plurality of valves to change the flow path so that the current stage removal factor for the individual modules approaches a target stage removal factor. The current stage removal factor is a ratio between any two of the permeate flow rate, the feed flow rate, and the retentate flow rate for the individual modules.

[0008] In another aspect of the present disclosure, a tangential flow filtration system is described. The system includes: a plurality of modules, each module including a module flow supply; a filter positioned downstream of the module flow supply; and at least one of a feed break box positioned between the module flow supply and the filter and a permeate break box positioned downstream of the filter.

[0009] In various aspects of the present disclosure, the module may further include a feed pump positioned between the feed break box and the first filter. The feed pump may be configured to control a flow rate of flow between the feed break box and the first filter.

[0010] In various aspects of the present disclosure, the operation of the dynamic agitator is configured to produce a homogenous solution.

[0011] In various aspects of the present disclosure, the feed break box may define an air gap.

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

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

[0014] In various aspects of the present disclosure, the module exchange buffer supply may include permeate of a second filter positioned downstream of the first filter, and the feed supply of the second filter includes retentate of the first filter.

[0015] In various aspects of the present disclosure, the module feed supply includes the retentate of a third filter positioned upstream of the first filter.

[0016] In various aspects of the present disclosure, a feed break box may be positioned between the flow supply and the filter.

[0017] In various aspects of the present disclosure, the interior of the permeate break box may define an air gap.

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

[0019] In various aspects of the present disclosure, a valve can be positioned between the first filter and the permeate break 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 break box can supply a second filter positioned upstream of the feed supply. The feed supply can include the retentate of the second filter.

[0021] In various aspects of the present disclosure, the module exchange buffer supply may include permeate of a third filter positioned downstream of the first filter, and the feed supply of the third filter includes the retentate of the first filter.

[0022] In various aspects of the present disclosure, the module can include at least one valve, wherein 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 to change the configuration of the tangential flow filtration module from a second flow path configuration to a first flow path configuration. The first flow configuration can be a countercurrent buffer exchange flow path configuration. The second flow configuration can 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, a last single module of the plurality of single modules may have a different target phase removal factor than at least one other single module of the plurality of single modules.

[0025] In various aspects of the present disclosure, a control system may be configured to maintain a tangential flow filtration system in a stable state, wherein a current stage removal factor is close to a target stage removal factor. The system may be configured to allow a user to adjust at least one of a plurality of valves in a manner that causes the current stage removal factor to deviate from the target stage removal factor when the tangential flow filtration system is in a stable 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, so that the current stage removal factor is close to the target stage removal factor again after the user's adjustment. Each of a plurality of individual modules may include: a feed break box positioned downstream of a flow supply and upstream of a filter for an individual module; and a permeate break box positioned downstream of the filter. The flow supply may include a module feed supply and a module exchange buffer supply. A first flow rate output of the feed break box and a second flow rate output of the permeate break box may be individually adjusted during operation of the tangential flow filtration system. The control system may be configured to maintain the tangential flow filtration system in a stable state by automatically maintaining a substantially constant stage removal factor during adjustment of either the first flow rate output or the second flow rate output. The control system may also be configured to maintain a constant liquid level in the feed break box and a constant liquid level in the permeate break box.

[0026] In various aspects of the present disclosure, each module can have at least one of the following: 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 of the plurality of modules can include a plurality of valves such that each 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. A first module of the plurality of modules can be in a first configuration, and a second module of the plurality of modules can be in a second configuration. A first plurality of modules including the first module can be in a first configuration, and a second plurality of modules including the second module can be in a second configuration. A last module of the plurality of modules can be operated in a third configuration. At least some of the permeate from the last module can be supplied to a module exchange buffer supply of another module upstream of the last module, and at least some of the permeate from the last module can be sent to waste.

[0027] In various aspects of the present disclosure, each module in the plurality of modules may include a retentate flow path and a permeate flow path. A permeate break box may be positioned along the permeate flow path.

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

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

[0030] In various aspects of the present disclosure, the system can be configured to operate as a diafiltration system that transfers solutes of interest from within a feed supply from a starting solution matrix into an exchange buffer. The system can be configured to flush the filter of each module with the exchange buffer prior to commencing filtration of the feed supply.

[0031] In various aspects of the present disclosure, the system can be configured to compensate for the system outputting a product having a concentration lower than the process requirement during startup by outputting a product having a concentration higher than the process requirement during steady state, so that a mixture of the product output during startup and the product output during steady state has a concentration that meets the process requirement. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] The patent or application file contains at least one drawing printed in color. Copies of this patent or patent application publication with color drawings will be provided by the Office upon request and payment of the necessary fee.

[0033] The above-mentioned and other features and advantages of the present disclosure and the manner of achieving them will become more apparent and will be better understood through the following description of embodiments of the present invention with reference to the accompanying drawings, in which:

[0034] Figure 1 is a schematic illustration of a continuous tangential flow filtration ("cTFF") system comprising substantially similar modules;

[0035] Figure 2 yes Figure 1 Schematic illustration of the modules of the cTFF system;

[0036] Figure 3 is a series of graphical representations of various monitoring parameters used to evaluate steady state operation of an experimental cTFF system module implementing a CCBE-TFF or buffer exchange process;

[0037] Figure 4 is a series of graphical representations of various monitoring parameters used to evaluate steady state operation of an experimental cTFF module implementing both CCBE-TFF and spTFF secondary concentration processes; and

[0038] Figure 5 is a graphical representation of regions of pressure dependence relative to permeate flux and retentate concentration and regions of less pressure dependence relative to permeate flux and retentate concentration.

[0039] Corresponding reference characters indicate corresponding parts throughout the several views.The exemplifications set out herein illustrate exemplary embodiments of the invention, and such exemplifications should not be construed as limiting the scope of the invention in any way. DETAILED DESCRIPTION

[0040] For the purpose of promoting understanding of the principles of the present invention, reference will now be made to the embodiments illustrated in the accompanying drawings and specific language will be used to describe the embodiments. However, it will be understood that this is not intended to limit the scope of the present invention thereby. Those skilled in the art to which the present invention relates will generally contemplate any changes and other modifications in the described embodiments, as well as any other applications of the principles of the present invention as described herein. An embodiment of the present invention is shown in great detail, although it will be apparent to those skilled in the relevant art that, for the sake of clarity, some features unrelated to the present invention may not be shown.

[0041] Figure 1A schematic illustration of a fully integrated continuous tangential flow filtration ("cTFF") system 100 is provided. The cTFF system 100 accepts a system feed supply 103 as an input and outputs a finished system product 109. Optionally, the cTFF system 100 also accepts a system exchange buffer supply 111 as an input. The system feed supply 103 may include a solute of interest (such as a monoclonal antibody (mAB)) suspended in a starting solution matrix. The cTFF system 100 may be operated to increase the concentration of the solute of interest in the finished system product 109. The cTFF system 100 may be operated as a diafiltration system, wherein the solute of interest is transferred from the starting solution matrix to the exchange buffer. When operated as a diafiltration system, the finished system product 109 may include a solute of interest suspended in the exchange buffer supplied at 109 instead of in the starting solution matrix. In some embodiments, the cTFF system may be operated both to transfer the solute of interest to the exchange buffer and to increase the concentration of the solute of interest in the finished system product.

[0042] The cTFF system 100 can include a plurality of modules 102, wherein each module 102 has substantially the same operating structure as the remaining modules further described herein, including a number of valves and / or other instruments, thereby allowing the flow path configuration to be changed to implement various processes. As illustrated, the cTFF system 100 includes five modules 102; however, other embodiments can include a greater or lesser number of modules 102 to implement the described processes.

[0043] Each of the modules 102 can be configured to perform 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"); the final module 102e is configured to perform a secondary concentration function in conjunction with a countercurrent buffer exchange tangential flow filtration ("CCBE-TFF") process using spTFF (if necessary); and the second module 102b, the third module 102c, and the fourth module 102d are each configured to perform CCBE-TFF. As noted above, each module 102 has substantially the same operating structure. Each module 102 can be configured to complete different processes by closing or opening certain normally open valves or normally closed valves within the module 102. In this way, each module 102 can be easily operated in either configuration. Therefore, the cTFF system 100 can be arranged with any number of modules as desired, wherein each module 102 can be configured for the same or different processes as desired.

[0044] For example, in other embodiments, the cTFF system 100 may include six modules 102, wherein the second module, the third module, the fourth module, and the fifth module are each configured to perform CCBE-TFF, while the sixth module is configured to perform a secondary concentration function using spTFF. Other embodiments may be used that allow the system 100 to be optimized for specific process goals 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).

[0045] Figure 1 804. The connections between each module 102 are also illustrated. For example, the retentate output of the first module 102a, or the primary concentration stage using the spTFF process, can provide a feed or retentate supply to the second module 102b along route 802, as further described herein. The retentate output of the second module 102b, or the first buffer exchange stage, can provide a feed or retentate supply to the third module 102c along route 804. The retentate output of the third module 102c, or the second buffer exchange stage, can provide a feed or retentate supply to the fourth module 102d along route 806, while the permeate output of the third module 102c can provide a permeate or diafiltration buffer supply to the second module 102b along route 808.

[0046] The retentate output or third buffer exchange stage of the fourth module 102d can provide a feed or retentate supply to the fifth module 102e along route 812, while the permeate output of the fourth module 102d can provide a permeate or diafiltration buffer supply to the third module 102c along route 814. The retentate output of the fifth module 102e (which can be used as a fourth buffer exchange stage and / or a secondary concentration stage) is collected as a product, while the permeate output of the fifth module 102e provides a permeate supply to the fourth module 102d along route 824. The flow rate control of each route is further discussed herein.

[0047] The system feed supply 103 can be supplied to the first module 102a. The final product 109 can be collected from the last module (i.e., the fifth module 102e). When the cTFF system is operated as a diafiltration system, an exchange buffer can also be provided to the final module (i.e., the fifth module 102e), as described in further detail below.

[0048] Figure 21 is a schematic illustration of module 102, its components, and the connections therebetween. Flow path 104 (including flow paths 104a and 104b, which may also include flow paths 104c, 104d, 104e, and / or 104f) illustrates a permeate route, flow path 106 (including flow paths 106a and 106b) illustrates a retentate and / or feed route, and flow path 108 illustrates a feed route between first break box or 110 and filter 112, as further discussed herein. For clarity, in Figure 1 and Figure 2 In both, the permeate route is shown by a dotted line, the retentate and / or feed route is shown by a dashed line, and the route between the break box and the filter is shown by a dash-dot-dash line. Each of the flow paths 104, 106, and 108 can be controlled as further disclosed herein to form at least one of a first flow path configuration associated with a spTFF process and / or a second flow path configuration associated with a CCBE-TFF process, such that the first flow path configuration and the second flow path configuration can function simultaneously or exclusively. In other words, the module 102 can be configured to perform a spTFF process and a CCBE-TFF process simultaneously or exclusively.

[0049] The first portion of the flow path 104 (flow path 104a) may begin at each module 102 with a diafiltration buffer or, alternatively, a permeate supply at a first input 114, wherein the supply source for a module 102 may depend on the module 102 in the cTFF system 100 ( Figure 1 ) is positioned within. Where appropriate, the permeate supply or diafiltration buffer provided at the first input 114 may be provided by the downstream module 102, as described above with respect to the cTFF system 100. The first input 114 may be considered as a module exchange buffer supply. For the process configuration of the module 102, the operation of a flow valve (e.g., a flow control valve 113) may prohibit or allow the permeate supply flow or the diafiltration buffer supply flow to enter the flow path 104a as desired. For example, the operation of the flow control valve 113 may also facilitate the control of the amount of permeate supply or diafiltration buffer entering the flow path 104a to maintain a stable system 100 ( Figure 1 ), as further described herein. In other words, the flow control valve 113 can be configured to flow in accordance with the module 102 and / or the system 100 ( Figure 1) to facilitate control of the flow rate of the permeate supply or diafiltration buffer entering the module 102 as required by the state of the flow control valve 113. When the flow control valve 113 is open and the flow path 104a is active, the diafiltration buffer or permeate supply can enter the feed side break box 110, thereby ending the flow path 104a. The flow rate of the diafiltration buffer or permeate supply through the flow control valve 113 may be partially related to the degree of opening of the flow control valve 113. For example, a fully open valve can allow a maximum flow rate, while a half-open valve can allow a flow rate of about 50%. For the purpose of module operation, different degrees of opening of the flow control valve 113 and corresponding flow rates can be used as desired.

[0050] The first portion of flow path 106 (flow path 106a) may start at each module 102 with a feed supply or, interchangeably, a retentate supply at second input 124, wherein the supply source for module 102 may depend on the module 102 in the cTFF system 100 ( Figure 1 ) is positioned within. Where appropriate, the retentate supply or feed supply provided at the second input 124 may be provided by the upstream module 102, as described above with respect to the cTFF system 100. The second input 124 may be considered a module feed supply. For the process configuration of the module 102, the operation of a flow valve (e.g., a flow control valve 115) may be used to prohibit or allow the flow of a retentate supply or a feed supply into the flow path 106a as desired. For example, the operation of the flow control valve 115 may also facilitate control of the amount of the retentate supply or feed supply entering the flow path 106a to maintain a stable system 100 ( Figure 1 ), as further described herein. In other words, the flow control valve 115 can be as module 102 and / or system 100 ( Figure 1 ) state into the module 102. When the flow control valve 115 is open and the flow path 106a is active, the retentate supply or feed supply enters the feed side break box 100, thereby ending the flow path 106a. The flow rate of the retentate supply or feed supply through the flow control valve 115 may be partially related to the degree of opening of the flow control valve 115. For example, a fully open valve may allow a maximum flow rate, while a half-open valve may allow a flow rate of about 50%. For the purpose of module operation, different degrees of opening of the valve 115 and corresponding flow rates may be used as desired.

[0051] The feed break box 110 can begin the flow path 108. The feed break box 110 can receive fluid flow from at least one of the flow path 104a and the flow path 106a. A dynamic agitator 128 (such as an impeller) can be included in the feed break box 110 to mix the fluid to ensure a homogeneous flow. The feed break box 110 can include a vent 129 that communicates with ambient pressure to allow the pressure to return to and remain at ambient pressure between modules 102. The vent 129 facilitates the ability of each module 102 to utilize the entire pressure range of the filter 112, thereby mitigating pressure that may otherwise be present throughout the cTFF system 100 ( Figure 1 ) any pressure cascades generated.

[0052] For example, during a CCBE process, the permeate from each stage can be reinjected into the feed stream of the previous stage, similar to the above reference Figure 1 102. The flow path of the permeate described herein. Typically, in certain embodiments that do not include a feed break box 110, the outlet pressure of the permeate may be higher than the feed pressure of the previous stage, resulting in a pressure cascade, wherein the pressure at the final stage is the highest and the pressure at the initial stage is the lowest. Therefore, the maximum pressure of the system may be constrained by the pressure rating of the system. This maximum pressure of the system must be shared throughout all stages in the system. An increase in the number of stages can improve exchange efficiency, which reduces buffer requirements; however, in the case of a larger number of stages, the maximum pressure of the system must be shared throughout a larger number of stages, resulting in less pressure available to drive permeation at each single stage, thereby limiting the efficiency of each stage. Pressure cascades can be mitigated by including a feed break box 110 and using vents 129 to stabilize the pressure within the module 102.

[0053] Ideally, the residence time within the feed break box 110 is relatively short (e.g., about 30-120 seconds). A relatively short residence time within the feed break box 110 can minimize system time constants required to achieve steady state operation as described herein, including startup time, shutdown time, and response time to disturbances. An appropriately sized break box can provide sufficient capacity to absorb disturbances while maintaining a reasonable hold-up volume. Longer or shorter residence times within the feed break box 110 are also contemplated.

[0054] A pump 130, such as a positive displacement pump, may be positioned downstream of the feed break box 110 to facilitate flow of the homogeneous mixture from the feed break box 110 to the filter 112. A flow transmitter 132 may be positioned downstream of the pump 130 to measure the flow rate of the homogeneous mixture from the feed break box 110 to the filter 112. The flow transmitter 132 may be in operative communication with a flow controller 133 configured to control the flow rate based on a desired level adjustment within the feed break box 110 as communicated by a level transmitter 136 and a level controller 137, as described below. The flow controller 133 is in operative communication with a speed controller 134 of the pump 130, as shown by a process control loop 141, so that the speed of the pump 130 may be adjusted as desired by the flow transmitter 132 and the flow controller 133 based on the measured flow rate. As used herein, the process control loop 141 refers to all dashed 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, such as Figure 2 As shown in .

[0055] The speed controller 134 may also be operably coupled to a level transmitter 136 and a level controller 137, as shown by a process control loop 141, which may be configured to work in concert to measure and control the amount of the mixture present in the feed break box 110 so as to maintain the amount within a threshold range, thereby ensuring that the feed break box 110 includes an air gap, thereby facilitating control of the pressure within the feed break box 110, as described above. The air gap may also allow the break box to absorb flow control disturbances and disconnect flow control between modules 102. The speed controller 134 may adjust the speed of the pump 130 as desired based on the measurements obtained and provided by the level transmitter to maintain the mixture level of the feed break box 110 within a desired level as determined by the level controller 137 and the flow controller 133, as described above. For example, if the level of the mixture in the feed break box 110 exceeds an upper threshold amount, the pump 130 may increase the flow rate from the feed break box 110 into the remaining flow path 108 and through the module 102, as further described herein. If the level of the mixture in the feed break box 110 drops below a minimum threshold amount, the pump 130 may reduce the flow rate from the feed break box 110, thereby allowing the feed break box 110 to refill. In other embodiments, a weight transmitter (not shown) may be operably coupled to the feed break box 110 to measure the contents of the feed break box 110 via weight (in addition to or in lieu of measuring the contents via level). In various embodiments, the weight transmitter and the level transmitter may work in conjunction or separately to measure the contents of the feed break box 110.

[0056] As described above, the homogeneous mixture may be pumped from the feed break box 110 to the filter 112. The first pressure transmitter 138 may be positioned between the pump 130 and the filter 112 and configured to cooperate with the second pressure transmitter 142 and the third pressure transmitter 144 (as further described herein) to measure the pressure drop across the filter 112 in order to monitor and optimize filter performance.

[0057] The second portion of the flow path 106 (flow path 106b) may begin at the filter 112. As mentioned 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 retentate from the filter 112. The flow transmitter 126 may be operably coupled to a flow controller 127 (as shown by the process control loop 117), which may control a flow control valve 146 based on input received from the flow transmitter 126. The process control loop 117 refers to all of the dashed-line type process control connections that interconnect the flow controller 127, the flow control valve 146, and the flow transmitter 126. For the process configuration of module 102, flow control valve 146 can also be positioned in flow path 106b as desired to prohibit or allow retentate from filter 112 to flow to first output 148 of module 102. Flow control valve 146 can be positioned in flow path 106b as desired to prohibit or allow retentate from flowing from filter 112 ... according to flow controller 127, such as module 102 and / or system 100. Figure 1 ) state. When the flow control valve 146 is open and the flow path 106b is active, the retentate can leave the module 102 at the first output 148, thereby ending the flow path 106b. The flow rate of the retentate through the flow control valve 146 can be partially related to the degree of opening of the flow control valve 146. For example, a fully open valve can allow a maximum flow rate, while a half-open valve can allow a flow rate of about 50%. For the purpose of module operation, different degrees of opening of the valve 146 and corresponding flow rates can be used as desired. The first output 148 can be connected to the cTFF system 100 ( Figure 1 ) to facilitate feed input fluid communication with another module within the module (as described above), or to facilitate collection of the retentate as a product.

[0058] A ratio controller, such as a gamma controller 180 discussed further herein, can typically regulate a flow controller 127 of a process control loop 117 for a retentate flow path 106b based on a flow controller 133 of a process control loop 141 for a filter flow path 108, as shown by process control loop 181 and further described herein.

[0059] The second portion of flow path 104 (flow path 104b) may also begin at filter 112. As mentioned above, third pressure transmitter 144 may be positioned within flow path 104b to facilitate measuring the pressure drop across filter 112. Pressure control valve 150 may also be positioned within flow path 104b to improve retentate flow control functionality under certain process conditions, as described above and further described herein. Third flow transmitter 154 may be positioned between filter 112 and pressure control valve 150 to measure the flow rate of permeate from filter 112 to permeate break box 152. Pressure control valve 150 may be positioned as module 102 and / or system 100 ( Figure 1 ) state as required by the control of the permeate pressure. When the pressure control valve 150 is open and the flow path 104b is active, the permeate can enter the permeate break box 152, as further described herein. In some embodiments, the pressure control valve 150 can be a passive control valve. The flow through the pressure control valve 150 can be determined by the overall mass balance of the system, as further described herein. The permeate pressure upstream of the pressure control valve 150 can be partially related to the degree of opening of the flow control valve 150. For example, a fully opened valve can allow a minimum permeate pressure, while a half-open valve can allow an elevated permeate pressure. For the purpose of module operation, different degrees of opening of the valve 150 and corresponding permeate pressures can be used as desired. In this way, the flow rate of the flow path 104b or the permeate flow path is generated by the overall mass balance around the filter 112. Thus, any change in the flow rate in the flow path 108 or the flow path 106b results in a responsive change in the flow rate in the flow path 104b to maintain mass conservation in the module 102.

[0060] In some circumstances, the flow rate within flow path 104b is too high relative to the target flow rate set using gamma controller 180. Gamma controller 180 can 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., is already fully open). In such circumstances, osmotic pressure can be applied, wherein manual or automatic adjustment of valve 150 can be accomplished by a user or a control system to move valve 150 toward a closed position, thereby changing the dynamics within filter 112 and forcing more flow into flow path 106b, which allows valve 146 to regain active control of the flow rate within flow path 104b, as further discussed herein.

[0061] The permeate break tank 152 may 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 break tank 152 may be used to both collect the permeate from the module 102 and to serve as a reservoir to supply the permeate as a diafiltration solution to the cTFF system 100 ( Figure 1 ) upstream module 102, as described above. Under ideal steady-state conditions, the liquid level in the permeate break box 152 can remain substantially stable because the amount of permeate flowing into the permeate break box 152 may be substantially the same as the amount of percolate flowing out of the permeate break box 152 into the next supplied module. The level transmitter 156 can be configured to measure the amount of permeate present in the permeate break box 152 and work in conjunction with the level controller 157 to ensure that the amount is within a threshold range. The threshold range of the permeate break box 152 can facilitate the inclusion of an air gap within the permeate break box 152, thereby allowing the break box to absorb flow control disturbances and disconnect flow control between modules 120. For the reasons provided above in relation to the feed break box 110, the permeate break box 152 can also include a corresponding second vent 153 in fluid communication with ambient pressure to allow pressure to return between modules 102 and remain at ambient pressure, which can be further facilitated by the air gap.

[0062] 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 also be operably coupled to a level transmitter 156 and a level controller 157, as indicated by a process control loop 159. The process control loop 159 refers to all of the dashed-line type process control connections interconnecting 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 based on measurements taken 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 in lieu of liquid level). In various embodiments, the weight transmitter and the liquid level transmitter may work in conjunction or separately to measure the contents of the permeate break tank 152. In certain circumstances, if the level of permeate in the permeate break tank 152 exceeds an upper threshold amount, the permeate may be discharged to waste along flow path 104c, access to which may be facilitated by valve 105. If the level of permeate in the permeate break tank 152 drops below a minimum threshold amount, supplemental diafiltration buffer may be added along flow path 104d, access to which may be facilitated by valve 107.

[0063] Valve 162 can be positioned downstream of pump 131 along flow path 104e. Valve 162 can be operated to allow or prohibit permeate from flowing to second output 160. Second output 160 can be connected to system 100 ( Figure 1 ) upstream module of the permeate supply fluid communication, as discussed above. The control valve 164 can also be positioned downstream of the pump 131 along the flow route 1046f. The control valve 164 is operable to allow or prohibit the flow of permeate to the waste 170, as further discussed herein. The control valve 164 is operably connected to the flow controller 166 and / or the flow transmitter 168 to measure and control the flow of permeate from the permeate break box 152 to the waste 170. The flow transmitter 168 can be operable to measure the flow rate of the permeate between the permeate break box 152 and the control valve 164, while the flow controller 166 operates the control valve 164 to maintain, reduce or increase the flow rate as measured by the flow transmitter 168.

[0064] As discussed above, each module 102 can be manipulated via the operation of a plurality of valves to accomplish a particular process as desired, as discussed above, the plurality of valves closing and / or opening the flow paths described herein as desired. A first route configuration that may be consistent with a spTFF process may include fluid flow directed through each of flow path 104a, flow path 108, and flow paths 104b and 106b as desired, such that flow path 106a is closed in the first route configuration. A second route configuration consistent with a CCBE-TFF process may include fluid flow directed through each of flow paths 104a, 106a, 108, and flow paths 104b and 106b as desired. A third route configuration that allows substantially simultaneous CCBE-TFF and spTFF processes may include fluid flow directed through each of flow path 104a, flow path 106a, flow path 108, and flow paths 104b and 106b as desired.

[0065] Controlling the cTFF system 100 to maintain a steady state within the system and promote stability and efficiency may rely at least in part on monitoring and controlling the flow ratio within the system 100, which can be established based on the desired solution / buffer exchange degree. The desired solution / buffer exchange degree may depend on the type of process being implemented. For example, some processes may require an exchange efficiency between the solution and the buffer of almost 100% (e.g., 99.996%). Other processes may require a lower exchange efficiency, such as 99%. Lower exchange efficiency requirements are also possible. As the number of CCBE stages in the cTFF system 100 increases, the exchange efficiency may also increase, which can reduce the amount of diafiltration solution and / or buffer required.

[0066] 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 refer to any species that is intended to be removed by a TFF diafiltration process. From this impurity removal value, an impurity removal factor ("ɑ") can be calculated as a function of the CCBE stages present in the system using the following formula:

[0067]

[0068] in:

[0069] FR = Impurity Removal Value

[0070] C F = concentration of component in the feed

[0071] C N = concentration of the component in the retentate from the final stage

[0072] ɑ=Impurity removal factor

[0073] N = number of buffer exchange stages (modules)

[0074] The flow ratio of exchange buffer to feed to the CCBE portion of the cTFF system can then be calculated based on the impurity removal factor using the following formula:

[0075]

[0076] in:

[0077] ɑ=Impurity removal factor

[0078] Q DF = Flow rate of diafiltration buffer entering the countercurrent system

[0079] Q F = Flow rate of feed entering the countercurrent system

[0080] S = sieving coefficient

[0081] It will be appreciated that for many (but not all) tangential flow filtration processes, the sieving coefficient for small, easily permeable solutes is equal to or close to 1. In the five-module cTFF system described above, the impurity removal factor is calculated as the ratio of the flow rate of the diafiltration buffer entering module 102e divided by the flow rate of the product stream entering module 102b. For the purpose of process control, a stage removal factor ("γ") is introduced in the present disclosure. The stage removal factor (γ) can be the ratio between any two of the following three parameters: (i) feed flow rate, such as measured by flow transmitter 132, (ii) permeate flow rate, and (iii) retentate flow rate. Flow transmitters 154, 126 ( Figure 2 ) The permeate flow rate and the retentate flow rate are measured for each individual module, as described above. One of the permeate flow rate and the retentate flow rate can also be measured using flow transmitters 154, 126, and 132 ( Figure 2 ) is calculated. For example, the permeate flow rate may be calculated from the flow transmitter 132 ( Figure 2 ) is subtracted from the feed break box flow rate measured by flow transmitter 126 ( Figure 2 ) measured by flow transmitter 126 ( Figure 2 ) is subtracted from the feed break box flow rate measured by flow transmitter 154 ( Figure 2 ) is calculated from the permeate flow rate measured.

[0082] In a CCBE-TFF process, where the retentate concentration leaving each module matches the concentration of the feed material entering the CCBE-TFF module, the values ​​of the stage removal factor ("γ") and the impurity removal factor ("ɑ") are equal. In modules where higher retentate concentrations are desired (e.g., the final stage of the system), the value of the stage removal factor ("γ") may be greater than the impurity removal factor ("ɑ"). In other words, the cTFF system may approach steady state when the stage removal factor approaches the impurity removal factor. However, these values ​​do not always need to be equal to maintain steady state, depending on the desired outcome of the cTFF system process.

[0083] Reference again Figure 2 (and as described above), the gamma controller 180 is in operative communication with the flow controller 133 and the flow controller 127. As described above, the gamma controller is configured to operate the flow controller 127 to adjust the flow rate of the flow path 106b via the flow control valve 146, and to adjust the flow rate of the flow path 104b through the mass balance generated thereby, the flow rate of the flow path 104b being based on the flow rate of the flow path 108 controlled by the flow rate controller 133, so that the calculated stage removal factor of each module 102 approaches a predetermined target stage removal factor set point. The target stage removal factor set point can be determined based on the process requirements and the manner in which the module 102 is used. For example, if the module 102 is operated only as a spTFF module, the stage removal factor (γ) set point can be established based on the desired degree of concentration of the module 102. If the module 102 is operated only as a CCBE module, the stage removal factor (γ) set point can be determined based on the desired exchange efficiency. For example, in one exemplary non-limiting embodiment, if the stage removal factor (γ) is defined as the ratio of the permeate flow rate to the retentate flow rate, then the stage removal factor set point can be set to the impurity removal factor (α) required to achieve the desired exchange efficiency, as calculated using the above equation and / or determined / confirmed experimentally. In a combined CCBE and additional concentration module, the stage removal factor (γ) set point can be set to a point that achieves both the desired amount of concentration and the desired exchange efficiency.

[0084] The predetermined target phase removal factor may be preprogrammed into the gamma controller 180, wherein the predetermined target phase removal factor is the phase removal factor at which the module maintains a steady state. In other words, the gamma controller 180 may be configured to maintain the module in a steady state by automatically maintaining a substantially constant phase removal factor at or near the predetermined target phase removal factor by automatically and individually adjusting the retentate route 106b via operating the flow controller 127 as described above. In this manner, the gamma controller 180 maintains the ratio of the feed flow rate, the permeate flow rate, and / or the retentate flow rate at a constant target steady state necessary to achieve a process-specific goal.

[0085] In some embodiments, the gamma controller 180 may also be configured to compensate for manual or automatic adjustments 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 a user notices that the liquid level within the feed break box 110 is too high, a manual adjustment may be performed to the speed controller 134, the pump 130, and / or the flow controller 133. With such an adjustment, the calculated phase removal factor of the module 102 is altered. The gamma controller 180 may then operate the flow control valve 146 via the flow controller 127 so that the calculated phase removal factor approaches a predetermined target phase removal factor to compensate for the manual adjustment. In this manner, the manual adjustment and the resulting automatic adjustment may be performed without shutting down the module 102 or the system 100 ( Figure 1 ).

[0086] In some embodiments, the gamma controller 180 may be configured to automatically adjust the flow control valve 146 based on a set point target of the flow controller 133 of the flow path 108. As described above, the set point target of the flow controller 133 is adjusted based on the liquid level of the feed break box 110 as measured by the level transmitter 136. For example, if the level transmitter 136 measures that the liquid level within the feed break box 110 is too high based on the liquid level threshold of the level controller 137, the level controller 137 may communicate this information to the flow controller 133. In response to adjusting the liquid level of the mixture in the feed break box 110, the flow controller 133 may adjust the speed of the pump 130 via the speed controller 134. In the case of such an adjustment, the calculated phase removal factor of the module 102 is altered. The gamma controller 180 may then operate the flow control valve 146 via the flow controller 122 so that the calculated phase removal factor approaches the predetermined target phase removal factor to compensate for the adjustment.

[0087] In a similar Figure 1In the cTFF system of the cTFF system 100 illustrated in , by setting the target stage removal factor to a higher value than the target stage removal factor of the intermediate modules 102b, 102c and 102d, the secondary concentration process of the final module (such as the fifth module 102e) can be performed. For example, although the stage removal factor and the flow removal factor of each of the modules 102b, 102c and 102d may be substantially equal, the stage removal factor of the module 102e may be greater than the flow removal factor. This is because the retentate of module 102e (or the retentate of the final module in a system with more than five modules) is collected as a product. The permeate of the final module is distributed between the small waste stream (e.g., via flow path 104f) and the permeate supply of the module immediately preceding (e.g., via flow path 104e). The small waste stream removes excess permeate caused by the secondary concentration of the final module under the promotion of the higher predetermined target stage removal factor. This translates into cTFF systems with fewer or greater numbers of modules, where the final module has a higher stage removal factor than the intermediate modules.

[0088] As mentioned above, the feed supply 103 of the overall cTFF system 100 can be provided to the feed supply of the first module 102a; more specifically, the feed supply 103 can be provided to the flow path 106a of the first module 102a. The diafiltration buffer supply 111 of the overall cTFF system 100 can be supplied to the exchange buffer or permeate supply of the last module 102e, and more specifically, to the flow path 104a. The diafiltration buffer supply can include a buffer that is desired to be exchanged with the buffer currently present in the feed supply. The finished product 109 of the overall cTFF system 100 can be collected from the flow path 106b of the last module 102e.

[0089] Steady state operation of each module 102 may be managed and generally controlled by break tank level controllers 137 and 157 and gamma controller 180. Figure 1 ) promotes the maintenance of steady state operation within each module 102 of the overall system 100 ( Figure 1 ) steady state operation. Due to the interconnection of modules 102 within system 100 (as described above with respect to Figure 1 As described and shown), a change in the average flow rate or total flow rate of each of the flow paths 104a, 106a, 108, 104b and / or 106b through module 102 may result in a change in the total flow rate of the remaining modules within system 100.

[0090] In some cTFF systems, filters may exhibit different filtration rates throughout different stages within the system. Conventionally, for a single-stage spTFF system, different filtration rates can be compensated for by changing the overall flow rate within a single stage, for example, by changing the flow rate within a stage to run the process faster or slower to achieve a desired degree of concentration. However, in a cTFF system 100 as described herein, the flow rate cannot be changed to adjust the filtration rate because such a disturbance in the flow rate at one stage (e.g., the stage operated by module 102b) will disturb the flow rates of other stages (e.g., the stages operated by modules 102a, 102c, 102d, 102e), which disturbs steady-state operation.

[0091] In view of the above and with additional reference to Figure 5 , the filter 112 of each module 102b operates at an operating pressure level within a region of pressure dependence (e.g., region 1000), wherein an increase in feed flow pressure (i.e., flow pressure measured by pressure transmitter 138) increases filtration rate, while a decrease in operating flow pressure decreases filtration rate. In order for the level controller, flow controller, and gamma controller to successfully maintain steady state, changes in transmembrane pressure caused by controller action must affect filtration rate or permeate flux, but will not alter flow rate in a manner that disrupts steady state operation of the overall system 100. Figure 5 An area of ​​less pressure dependence is shown at area 1002. 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 perturbing the remaining stages or the overall system.

[0092] Often, products collected during startup and shutdown of a continuous system may not meet concentration or buffer exchange efficiency requirements, and such products collected during startup or shutdown are discarded. Specific procedures can be followed to mitigate or eliminate these losses.

[0093] For example, when the system is operated as a diafiltration system, the system is provided with a feed supply comprising a material of the solute of interest suspended in the starting solution matrix. As in any diafiltration operation, the target of the system is to transfer the solute of interest from the starting solution matrix to the exchange buffer. In this type of diafiltration system, before the feed supply of the material to be filtered is introduced into the system, the filter of the target exchange buffer solution flushing system can be used. Then, all materials collected from the initial start-up to the stable state will exceed the desired impurity removal factor, because the material is excessively diluted by the exchange buffer already present in the system, until the stable state is realized. Because excessive exchange buffer is not usually the reason for material rejection, there is no need to abandon the material collected from the initial start-up to the stable state, thus reducing waste.

[0094] With respect to concentration, the concentration of the material collected during startup may be lower than that required by the process requirements. To compensate for this, the concentration during steady-state operation may be set to a level slightly higher than the process requirements, so that a combination of (i) products collected during startup with a concentration lower than required and (ii) products collected during steady-state with a concentration higher than required will together meet the concentration dictated by the process requirements. Since the time required for the system to reach steady state can be predicted mathematically and / or experimentally, and the total amount of product to be processed can be known in advance, the amount by which the steady-state concentration must exceed the process requirements can be calculated based on an overall mass balance. In this way, the products collected during startup may not need to be discarded to cause waste.

[0095] Example

[0096] Example 1

[0097] Select the operational objectives of the cTFF system to be tested according to Table 1 below:

[0098] parameter unit Target Feed concentration Gram / liter (g / L) 100 Surface Area <![CDATA[Square meters per stage (m 2 / stage)]]> 1x0.24 #Phase number not applicable 3 alpha not applicable 7.115 Cross flow rate (flux) Milliliters / minute (mL / min, LMM) 144.0(0.6) Feed / Retentate Milliliters / minute (mL / min) 17.7 Diafiltration buffer / permeate Milliliters / minute (mL / min) 126.3

[0099] Table 1: Example Operational Parameter Targets

[0100] Each of the tested stages (consistent with stages two through four as discussed above with respect to system 100) was configured for a CCBE process. The feed material included 107 g / L mAb in an aqueous buffer solution having a higher conductivity. The material was prepared using a standard single module spTFF configuration prior to use in this Example 1. The following events occurred at given time points: at 0 minutes, a buffer rinse was performed; at 9 minutes, the process was started with the introduction of the mAb feed material; at 320 minutes, the process was ended with a second buffer rinse; at 330 minutes, a water rinse was performed; at 340 minutes, a cleaning rinse was performed; and at 350 minutes, shutdown of the test cTFF system was completed.

[0101] Figure 3 Parameters monitored for evaluating steady-state operation and measurements of the parameters over time of the experimental operation are illustrated. Graph 200 illustrates cross flux and transmembrane pressure (i.e., the difference between the average feed / retentate side pressure and the average permeate side pressure on the filter) for each stage over time of operation of each stage, wherein line 202 illustrates the target cross flux, line 204 illustrates the cross flux of stage two, line 206 illustrates the cross flux of stage three, and line 208 illustrates the cross flux of stage four. Line 210 illustrates the transmembrane pressure of stage two, line 212 illustrates the transmembrane pressure of stage three, and line 214 illustrates the transmembrane pressure of stage four.

[0102] Graph 300 illustrates the outlet concentration (in g / L) compared to the target outlet concentration, where line 302 illustrates the target outlet concentration and line 304 illustrates the achieved outlet concentration. Graph 400 illustrates the flow ratio, or the ratio of the permeate flow rate to the retentate flow rate, for each stage, where line 402 illustrates the target flow ratio, line 404 illustrates the flow ratio for stage two, line 406 illustrates the flow ratio for stage three, and line 408 illustrates the flow ratio for stage four. Graph 500 illustrates the conductivity for each stage, where line 502 illustrates the conductivity for stage two, line 504 illustrates the conductivity for stage three, and line 506 illustrates the conductivity for stage four.

[0103] Achieve more than 5 and a half hours of stable steady state operation, wherein every 30-60 minutes only need to carry out slight flow rate adjustment.As shown in images 200 and 400, during the duration of operation, cross flow rate and flow ratio remain stable near target value.Conductivity declines from stage two to stage four, as shown in image 500, and this expects to show that buffer exchange has occurred.At the end of stage four, collect retentate product, it has the overall concentration of 108g / L, including the material before the steady state and the material after the steady state that gather with the steady state retentate), thereby show that feed concentration is similar to the outlet concentration on three CCBE modules, as expected for the module that operates only in buffer exchange mode.

[0104] Example 2

[0105] The operational objectives for testing the cTFF system were selected according to Table 2 below:

[0106]

[0107]

[0108] Table 2: Operational parameter targets

[0109] The tested stage (consistent with stage five as discussed above with respect to system 100) was configured for both CCBE and spTFF (i.e., a two-stage concentration process). The feed material included 108 g / L mAb in an aqueous buffer solution. The following events occurred at given time points: at 0 minutes, a buffer rinse was performed; at 1 minute, the process began with the introduction of the mAb feed material; at 170 minutes, the process ended with a second buffer rinse; at 188 minutes, a water rinse was performed; at 200 minutes, a cleaning rinse was performed; and at 210 minutes, shutdown of the test cTFF system was completed.

[0110] Figure 4Parameters monitored for evaluating steady state operation and measurements of the parameters over time of experimental operation are illustrated. Graph 600 illustrates cross flux and transmembrane pressure (i.e., the difference between the average feed / retentate side pressure and the average permeate side pressure on the filter) for a stage over time of operation of the stage, wherein line 602 illustrates the target cross flux and line 604 illustrates the cross flux for stage five. Line 606 illustrates the transmembrane pressure for stage five.

[0111] Graph 700 illustrates the outlet concentration (in g / L) compared to the target outlet concentration, where line 702 illustrates the target outlet concentration and line 704 illustrates the achieved outlet concentration. Graph 800 illustrates the flow ratio of stage five compared to the target flow ratio, or the ratio of the crossflow flow rate to the retentate flow rate, where line 802 illustrates the target flow ratio for buffer exchange and line 804 illustrates the flow ratio of stage five. The flow ratio is higher than the target because this is a combined CCBE and spTFF stage, as explained previously. Graph 900 illustrates the conductivity of stage five, where line 902 illustrates the conductivity of stage five.

[0112] Nearly three hours of stable steady state operation was achieved. Only minor flow rate adjustments were made every 30-60 minutes. As shown in images 600 and 800, the cross flow rate, flow ratio, concentration and conductivity were stable for the duration of the run.

[0113] Although the present invention has been described as having an exemplary design, the present invention may be further modified within the spirit and scope of the present disclosure. Therefore, this application is intended to cover any changes, uses or adaptations of the present invention using its general principles. In addition, this application is intended to cover such content that deviates from the present disclosure, as long as the content belongs to the known or customary practice of the field to which the present invention belongs.

Claims

1. A tangential flow filtration module, comprising: flow supply, which includes module exchange buffer supply and module feed supply; a feed break box positioned downstream of the flow supply, the feed break box including a powered agitator; and A first filter is positioned downstream of the feed break box.

2. The tangential flow filtration module of claim 1, further comprising a feed pump positioned between the feed break box and the first filter, the feed pump configured to control a flow rate of flow between the feed break box and the first filter.

3. The tangential flow filtration system according to claim 1, wherein: The operation of the dynamic agitator is configured to produce a homogeneous solution.

4. The tangential flow filtration system according to claim 1, wherein: The feed break box defines an air gap.

5. The tangential flow filtration system according to claim 1, wherein: The feed break box defines a vent in fluid communication with ambient pressure.

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

7. The tangential flow filtration system according to claim 1, wherein: The module exchange buffer supply comprises the permeate of a second filter positioned downstream of the first filter, and the feed supply of the second filter comprises the retentate of the first filter.

8. The tangential flow filtration module according to claim 1, wherein: The module feed supply includes the retentate of a third filter positioned upstream of the first filter.

9. A tangential flow filtration module, comprising: flow supply, which includes module exchange buffer supply and module feed supply; a filter positioned downstream of the flow supply and having two outputs including a permeate output and a retentate output; as well as A permeate break tank is positioned downstream of the filter and is supplied by the permeate output of the filter.

10. The tangential flow filtration module of claim 9 further comprising a feed break box positioned between the flow supply and the filter.

11. The tangential flow filtration system according to claim 9, wherein: An interior of the permeate break tank defines an air gap.

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

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

14. The tangential flow filtration system according to claim 9, wherein: The permeate break tank supplies a second filter positioned upstream of the feed supply.

15. The tangential flow filtration module according to claim 14, wherein: The feed supply includes the retentate of the second filter.

16. The tangential flow filtration system according to claim 9, wherein: The module exchange buffer supply comprises permeate of a third filter positioned downstream of the first filter, and the feed supply of the third filter comprises retentate of the first filter.

17. The tangential flow filtration module of claim 9, further comprising at least one valve, wherein: The operating configuration of the valve is: changing the configuration of the tangential flow filtration module from a first flow path configuration to a second flow path configuration; or changing the configuration of the tangential flow filtration module from the second flow path configuration to the first flow path configuration; wherein the first flow configuration is a countercurrent buffer exchange flow path configuration; and Wherein, the second flow configuration is a single-pass tangential flow filtration flow path configuration.

18. A tangential flow filtration system, comprising: A plurality of individual modules, each of the individual modules being configured to perform a process associated with tangential flow filtration, wherein each individual module comprises: a plurality of valves, wherein actuation of the plurality of valves is configured to alter a flow path of a corresponding single module; and The control system is configured as follows: calculating a current stage removal factor for the single module, the current stage removal factor being a ratio between any two of a permeate flow rate, a feed flow rate, and a retentate flow rate for the single module; and The plurality of valves are automatically operated to modify the flow path so that a current phase removal factor for the single module approaches a target phase removal factor.

19. The tangential flow filtration system of claim 18, wherein: The plurality of individual modules comprises at least five modules.

20. The tangential flow filtration system according to any one of claims 18-19, wherein: A last single module of the plurality of single modules has a different target phase removal factor than at least one other single module of the plurality of single modules.

21. The tangential flow filtration system of claim 18, wherein: The control system is configured to maintain the tangential flow filtration system in a steady state, wherein the current stage removal factor is close to the target stage removal factor.

22. The tangential flow filtration system of claim 21, wherein: The system is configured to allow a user to adjust at least one of the plurality of valves in a manner that causes the current stage removal factor to deviate from the target stage removal factor when the tangential flow filtration system is in the stable state; and The control system is configured to automatically operate remaining valves of the plurality of valves to compensate for the user's adjustment so that the current phase removal factor again approaches the target phase removal factor after the user's adjustment.

23. The tangential flow filtration system of claim 21, wherein: Each of the plurality of individual modules comprises: a feed break box positioned for the individual module downstream of flow supplies including a module feed supply and a module exchange buffer supply and upstream of the filter; and a permeate break tank positioned downstream of the filter; wherein during operation of the tangential flow filtration system, a first flow rate output of the feed break tank and a second flow rate output of the permeate break tank are individually adjustable; and Wherein, the control system is configured to maintain the tangential flow filtration system in a stable state by automatically maintaining a substantially constant stage removal factor during adjustment of either the first flow rate output or the second flow rate output.

24. The tangential flow filtration system of claim 23, wherein: The control system is also configured to maintain a constant liquid level within the feed break tank and a constant liquid level within the permeate break tank.

25. A tangential flow filtration system, the system comprising: Multiple modules, each module includes: Module flow supply; a filter positioned downstream of the module flow supply; and At least one of the following: a feed break box positioned between the module flow supply and the filter; and A permeate break tank is positioned downstream of the filter.

26. Tangential flow filtration according to claim 25, wherein 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.

27. The tangential flow filtration system of claim 26, wherein: Each of the multiple modules includes multiple valves, so that each of the multiple 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.

28. The tangential flow filtration system of claim 26, wherein: A first module of the plurality of modules is in the first configuration and a second module of the plurality of modules is in the second configuration.

29. The tangential flow filtration system of claim 28, wherein: A first plurality of modules including the first module is in the first configuration, and a second plurality of modules including the second module is in the second configuration.

30. The tangential flow filtration system of claim 26, wherein: A last module of the plurality of modules operates in the third configuration.

31. The tangential flow filtration system of claim 30, wherein: At least some of the permeate from the last module is supplied to a module exchange buffer supply of another module upstream of the last module, and at least some of the permeate from the last module is sent to waste.

32. The tangential flow filtration system of claim 25, wherein: Each module of the plurality of modules includes a retentate flow path and a permeate flow path, and wherein the permeate break box is positioned along the permeate flow path.

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

34. The tangential flow filtration system of claim 25, wherein: A first module in the plurality of modules includes a system feed supply and a last module in the plurality of modules includes a system buffer exchange supply.

35. The tangential flow filtration system of claim 25, wherein: The system is configured to operate as a diafiltration system that transfers solutes of interest from a feed supply from a starting solution matrix into an exchange buffer, and wherein the system is configured to flush the filter of each module with the exchange buffer prior to commencing filtering of the feed supply.

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

Images