WO2015153618A1

WO2015153618A1 - System and method for concentrating plasma

Info

Publication number: WO2015153618A1
Application number: PCT/US2015/023603
Authority: WO
Inventors: Osman Akcakir
Original assignee: Haemonetics Corporation
Priority date: 2014-03-31
Filing date: 2015-03-31
Publication date: 2015-10-08

Abstract

A system for concentrating plasma includes a plasma reservoir, and a filter having a housing and a filter membrane that separates the plasma into retentate and filtrate as the plasma recirculates and until sufficient filtrate is produced. The filter housing may have a feed inlet, a retentate outlet, and a filtrate outlet. A feed tube fluidly connects the plasma reservoir and the feed inlet. A retentate tube fluidly connects the plasma reservoir and the retentate outlet and is configured to return retentate to the plasma reservoir. The system also includes a filtrate storage container fluidly connected to the filtrate outlet via a filtrate line. The filtrate storage container collects filtrate exiting the filter via the filtrate line. A flow sensor located on the filtrate line measures the flow of filtrate through the filtrate line, and a controller controls the speed of a pump based on the measured filtrate flow.

Description

SYSTEM AND METHOD FOR CONCENTRATING PLASMA

Priority

[0001] This patent application claims priority from United States Provisional Patent Application number 61/973,004, filed March 31, 2014, entitled, "System and Method for Concentrating Plasma," assigned attorney docket number 1611/C17, and naming Osman Akcakir as inventor, the disclosure of which is incorporated herein, in its entirety, by reference.

Technical Field

[0002] The present invention relates to processing a plasma product, and more particularly to concentrating plasma.

Background Art

[0003] During plasmapheresis, whole blood is withdrawn from a donor and separated into its constituent components (e.g., red blood cells, platelets, plasma, etc.). The plasma may be collected in a plasma container, and the remaining components may be similarly collected or returned to the donor. In some applications, the collected plasma may be further processed prior to storage.

Summary of the Embodiments

[0004] In a first embodiment of the invention there is provided a system for concentrating plasma product. The system may include a plasma reservoir, and a filter having a housing and a filter membrane. The filter membrane may separate the plasma into retentate and filtrate, thereby concentrating the plasma flowing through the filter. The filter housing may have a feed inlet, a retentate outlet, and a filtrate outlet. To provide for fluid flow through the system, the system may include a feed tube fluidly connecting the plasma reservoir and the feed inlet, and a retentate tube fluidly connecting the plasma reservoir and the retentate outlet. The retentate tube may be configured to return retentate to the plasma reservoir.

[0005] The system may also have a filtrate storage container fluidly connected to the filtrate outlet via a filtrate line, and a pump located on the feed line. The filtrate storage container may be configured to collect filtrate exiting the filter via the filtrate line, and the filtrate line may have a filtrate flow sensor configured to measure the flow of filtrate through the filtrate line. The pump may draw plasma from the plasma reservoir and into the filter via the feed line. A controller in communication with the filtrate flow sensor may control the speed of the pump based, at least in part, on the measured filtrate flow.

[0006] In some embodiments, the system may include a feed pressure sensor and/or a retentate pressure sensor. The feed pressure sensor may be located on and configured to measure the pressure within the feed line. The retentate pressure sensor may be located on and configured to measure the pressure within the retentate line. The controller may be configured to control the speed of the pump based on the feed line pressure and/or the retentate line pressure. The system may also have a pinch valve that is located on the retentate line and configured to control the flow of retentate through and the pressure within the retentate line. In such embodiments, the controller may control the pinch valve based on the retentate line pressure.

[0007] In accordance with further embodiments, the system may include a scale that measures the weight of the plasma reservoir and/or the filtrate storage container, a plasma volume sensor that measures the volume of plasma within the plasma reservoir, a filtrate volume sensor that measures the volume of filtrate within the filtrate storage container, and/or a filtrate pressure sensor that measures a pressure within the filtrate line. The controller may control the pump based on the measured weight, the measured plasma volume, the measured filtrate volume, and/or the measured filtrate line pressure.

[0008] The system may also include a wash solution container that is configured to hold wash solution, and that is fluidly connected to the plasma reservoir via a wash line. In some embodiments, the plasma reservoir may be a plasma bag from a plasmapheresis device, and the system may also include a plasma concentrate bottle that is connected to the plasma reservoir via a concentrated plasma transfer line. In other embodiments, the plasma reservoir may be a plasma concentrate bottle. In such embodiments, the plasma concentrate bottle may include an inlet fluidly connected to a plasma bag containing plasma. The plasma bag may be configured to supply the plasma concentrate bottle with plasma. The filter may be held/contained within a manifold that applies a force to the filter housing. The manifold may have a first plate and a second plate that are moveable relative to one another, and the filter may be located between the first and second plate.

[0009] In further embodiments, the system may be in-line with a plasmapheresis system that processes blood withdrawn from a subject. In such embodiments, the plasma reservoir may be a plasma storage container that is fluidly connected to the plasmapheresis system and collects plasma from the plasmapheresis system. The system may also have a return line that fluidly connects the filtrate container and a subject, and returns filtrate within the filtrate container to the subject. In some embodiments, a return pump located on the return line may be used to return the filtrate to the subject via the return line.

[0010] In accordance with additional embodiments, a system for concentrating plasma may include a plasma reservoir configured to hold plasma, and a filter having a housing and a filter membrane configured separate the plasma flowing through the filter into retentate and filtrate (e.g., to concentrate the plasma flowing through the filter). The system may also have (1) a feed tube fluidly connecting the plasma reservoir and a feed inlet on the filter housing, (2) a retentate tube fluidly connecting the plasma reservoir and a retentate outlet on the filter housing, and (3) a filtrate storage container fluidly connected to a filtrate outlet on the housing via a filtrate line. The filtrate storage container may collect filtrate exiting the filter via the filtrate line.

[0011] The system may also have at least one pressure sensor located on the feed tube and/or retentate tube, and a pump located on the feed line for drawing plasma from the plasma reservoir and into the filter via the feed line. The pressure sensor(s) may measure a pressure within the feed tube and/or retentate tube, and the controller (in communication with the pressure sensor(s)) may control the speed of the pump based on the measured pressure.

[0012] In some embodiments, the at least one pressure sensor may include a feed pressure sensor located on the feed line and/or a retentate pressure sensor located on the retentate line. The feed pressure sensor may measure a pressure within the feed line, and the controller may control the speed of the pump based on the feed line pressure. Similarly, the retentate pressure sensor may measure a pressure within the retentate line, and the controller may control the speed of the pump based on the retentate line pressure. Additionally or alternatively, the system may include a filtrate flow sensor located on the filtrate line. The filtrate flow sensor may measure a flow of filtrate through the filtrate line, and the controller may control the speed of the pump based on the measured flow of filtrate.

[0013] In accordance with still further embodiments, a method for concentrating plasma may include providing a plasma reservoir configured to store plasma, drawing plasma from the plasma reservoir and through a feed line using a pump located on the feed line, and flowing the plasma through a tangential flow filter. The tangential flow filter may have a housing and a filter membrane that filters the plasma to create a retentate and a filtrate. The method may then (1) return the retentate to the plasma reservoir through a retentate line fluidly connecting the plasma reservoir with a retentate outlet on the filter housing, and (2) transfer the filtrate to a filtrate storage container through a filtrate line fluidly connecting the filtrate container with a filtrate outlet on the filter housing. During the filtering process, the method may measure the flow of filtrate through the filtrate line, and control the operation of the pump based, at least in part, on the measured filtrate flow. The method may repeat the above steps until a target plasma concentration is achieved in the plasma reservoir.

[0014] In some embodiments, the target plasma concentration may be determined based upon the measured flow of filtrate through the filtrate line, and/or based upon a volume of filtrate collected within the filtrate storage container. Additionally or alternatively, the method may measure the weight and/or volume of concentrated plasma within the plasma reservoir, and the target plasma concentration may be determined based upon the measured weight and/or the measured volume.

[0015] Once the target plasma concentration is achieved, the method may transfer concentrated plasma within the plasma reservoir to a plasma concentrate bottle. The method may then (1) transfer wash solution from a wash solution container to the plasma reservoir, (2) recirculate the wash solution through the filter via the feed line and back into the plasma reservoir via the retentate line, and (3) transfer the recirculated wash solution to the plasma concentrate bottle. [0016] In some embodiments, the plasma reservoir may be a plasma concentrate bottle. In such embodiments, the method may transfer plasma from a plasma bag to the plasma concentrate bottle prior to drawing plasma from the plasma concentrate bottle. The retentate may be returned to the plasma concentrate bottle. The method may then transfer additional plasma from the plasma bag to the plasma concentrate bottle as the plasma is drawn from the plasma concentrate bottle and filtered by the tangential flow filter. During a wash step, the method may transfer wash solution from a wash solution container to the plasma bag, and recirculate the transferred wash solution through the filter and into the plasma concentrate bottle via the feed line and retentate line.

[0017] Additionally or alternatively, the method may measure a pressure within the feed line and/or the retentate line, and control the speed of the pump based on the measured pressure. Furthermore, the retentate line may include a pinch valve for controlling the flow of retentate through the retentate line and the method may adjust the pinch valve based, at least in part, on the retentate line pressure (e.g., to adjust the retentate line pressure). Additionally or alternatively, the method may also measure a pressure within the filtrate line, and control the operation of the pump based, at least in part, on the filtrate line pressure. In some embodiments, the method may include placing the filter within a manifold that is configured to hold the filter and apply a force to the filter housing. The manifold may include a first plate and a second plate that are moveable relative to one another. The filter may be placed/located between the first and second plate.

[0018] The plasma reservoir may be a plasma storage container from a

plasmapheresis system and may be fluidly connected to a blood component separation device within the plasmapheresis system. The plasmapheresis system may process blood withdrawn from a subject, and the method may return filtrate within the filtrate storage container to the subject via a filtrate return line.

[0019] In further embodiments, a method for concentrating plasma includes (1) providing a plasma reservoir configured to store plasma, (2) drawing plasma from the plasma reservoir and through a feed line using a pump located on the feed line, and (3) flowing the plasma through a tangential flow filter. The tangential flow filter may have a housing and a filter membrane that filters the plasma to create a retentate and a filtrate. The method may then return the retentate to the plasma reservoir through a retentate line fluidly connecting the plasma reservoir with a retentate outlet on the filter housing, and transfer the filtrate to a filtrate storage container through a filtrate line fluidly connecting the filtrate container with a filtrate outlet on the filter housing. During filtering, the method may measure a pressure the feed line and/or retentate line, and control the operation of the pump based on the measured pressure. The method may continue filtering (e.g., the method may repeat the above steps) until a target plasma concentration is achieved in the plasma reservoir.

Brief Description of the Drawings

[0020] The foregoing features of embodiments will be more readily understood by reference to the following detailed description, taken with reference to the accompanying drawings, in which:

[0021] Fig. 1 schematically shows a system for filtering and concentrating plasma using a tangential flow filter, in accordance with some embodiments of the present invention.

[0022] Fig. 2 schematically shows a cross-sectional view of the tangential flow filter of Figure 1 in accordance with some embodiments of the present invention.

[0023] Figure 3 is a flowchart showing a method of concentrating plasma, in accordance with some embodiments of the present invention.

[0024] Figs. 4A-4E schematically show the steps of the method of concentrating plasma shown in Figure 3, in accordance with some embodiments of the present invention.

[0025] Figure 5 is a flowchart showing an alternative method of concentrating plasma, in accordance with additional embodiments of the present invention.

[0026] Figs. 6A-6D schematically show the steps of the alternative method of concentrating plasma shown in Figure 5, in accordance with additional embodiments of the present invention.

[0027] Figs 7A and 7B schematically show a manifold for the tangential flow filter of Figure 1, in accordance with some embodiments of the present invention.

[0028] Figs. 8A and 8B show an alternative embodiment of a manifold for the tangential flow filter of Figure 1, in accordance with additional embodiments of the present invention.

[0029] Figure 9 is a flowchart showing a method for in-line plasma concentration, in accordance with some embodiments of the present invention [0030] Figs 10A and 10B schematically show the steps of the method for in-line plasma concentration shown in Figure 9, in accordance with some embodiments of the present invention.

Detailed Description of Specific Embodiments

[0031] Figure 1 shows an automated plasma concentration/filtration system 100 in accordance with some embodiments of the present invention. The plasma to be filtered can be stored within a plasma reservoir 110 that is fluidly connected to a filter 120 (e.g., a feed inlet 122) via a feed line 130. The filter 120 also includes a retentate outlet 124 and a filtrate outlet 126. The retentate outlet 124 is fluidly connected to the plasma reservoir 110 via a retentate line 140, and the filtrate outlet 126 is fluidly connected to a filtrate container 150 via a filtrate line 160. To control the flow through and the pressure within the retentate line 140, the system 100 can include a variable pinch valve 144 located on the retentate line 140.

[0032] As shown in Figure 2, in some embodiments, the filter 120 may be a tangential flow filter with a housing 128 made from two end caps 21 OA/210B that define the structure of the filter 120. Within the housing 128, the filter 120 may have one or more layers of a filter membrane 220 that divide the interior of the housing into feed channel(s) 230 and permeate (e.g., filtrate) channel(s) 240. The filter membrane 220 may have pores sizes small enough so that proteins of interest (e.g., IgG and coagulation factors) remain within the plasma as it flows through the filter 120, but unwanted components (e.g., water, ions, and small proteins) pass through the filter membrane 220. Therefore, as the plasma flows through the filter 120 (e.g., through the feed channel(s)) and across the face of the filter membrane 220 (which prevents the build-up of plasma within the filter housing 128), the plasma will become more concentrated (e.g., the retentate) as the filtrate passes through the membrane 220 and into the permeate/filtrate channel(s) 240.

[0033] It is important to note that the type and pore size of the filter membrane 220 can be selected based upon the desired application. For example, if the system 100 is going to be filtering plasma, and the user is seeking to ensure that the IgG (which has a size of approximately 130-150 kilodaltons) and coagulation factors remain with the plasma (e.g., the retentate), a filter membrane having a pore size of approximately 5-100 kilodaltons may be selected. This pore size will ensure that the undesired components (e.g., water, ions, small proteins) pass through the filter membrane 220, but the IgG and coagulation factors remain within the retentate (e.g., the concentrated plasma). When selecting a filter membrane 220, it should also be noted that in some applications, concentrated proteins may form a gel layer on the face of the filter membrane 220 that effectively decreases the pore size.

[0034] In addition to the filter membrane 220, in some embodiments, the filter 120 may have a divider 250 that divides the feed channel 230 (extending down the center of the filter 120) into two channels that meet/join near the retentate outlet 124. Each of the channel(s) (e.g., the feed channel(s) 230 and/or the permeate channel(s) 240) can have a mesh screen layer (not shown). This mesh screen layer creates turbulence within the channels and may improve filtration.

[0035] Returning to Figure 1, the system 100 also includes a number of other components that help control the operation of the system 100. For example, to measure the pressures within each of the fluid lines, the system 100 can includes a feed pressure sensor 132 located on the feed line 130, a retentate pressure sensor 142 located on the retentate line 140, and a filtrate pressure sensor 162 located on the filtrate line 160. Additionally or alternatively, the system 100 can include a filtrate flow rate sensor 164 (also located on the filtrate line 160) that measures the flow rate through the filtrate line 160. Furthermore, to measure the volume of plasma within the plasma reservoir 110, the system 100 can include a volume sensor 115 (e.g., an optical sensor or an ultrasonic sensor) and/or a scale located on or connected to the plasma reservoir 110. Similarly, the system 100 can also have a volume sensor or scale located on/connected to the filtrate container 150 (e.g., filtrate volume sensor 155) to measure the volume of filtrate collected within the filtrate container 150.

[0036] Each of the above mentioned sensors and measurement devices (e.g., the pressure sensors 132/142/162, the flow rate sensor 164, the volume sensor(s) 115/155, the scales, etc.) can be electrically connected to a controller 170 that controls the operation of the system 100 and the pump 134 used to recirculate the plasma through the system 100. The controller 170 may monitor the overall operation of the system 100, and adjust the operating parameters based upon one or more of the signals received from the sensors, scales, etc. For example, the controller 170 can monitor the flow rate of filtrate through the filtrate line 160 (e.g., via the filtrate flow rate sensor 164), and speed up, slow down, or stop the pump 134 based upon the measured flow rate (e.g., the controller 170 may stop the pump 134 and filtration process if the flow through the filtrate line 160 stops, which is an indication that the plasma has reaches max concentration). Similarly, the controller can monitor the pressure within the feed line 130, retentate line 140, and filtrate line 160 (e.g., based upon pressure sensors 132/142/162) and control the operation of the pump 134 and/or the variable pinch valve 144 based on one or more of the measured pressures.

[0037] Any number of types of pumps can be used to draw the plasma from the plasma reservoir 110. However, a steady fluid flow through the system 100 and filter 120 improves filtration. Therefore, if the pump 134 is a peristaltic pump (which produces a pulsatile flow), it is preferable that a peristaltic pump be chosen that minimizes pressure and flow excursions. Additionally, in embodiments in which a peristaltic pump is used, it may be beneficial to choose a tubing material that resists shredding (e.g., shredding of the tubing material into the feed flow). To that end, the entire feed line 130 or the portion of the feed line where the pump 134 resides, may be made from a shred-resistant material.

[0038] As discussed in greater detail below, the plasma reservoir 110 can be any number of containers depending on the application. For example, in some embodiments, the plasma reservoir 110 may be the plasma storage container (e.g., a plasma bottle or a plasma bag) in which the plasmapheresis device collected the plasma. However, in other

embodiments, the plasma reservoir 110 may be a plasma concentrate container 410 supplied with a disposable set for the system 100. In such embodiments, the disposable set may include, among other things, the plasma concentrate container 410, the feed line 130, the filter 120, the retentate line 140 with or without the variable pinch valve 144, filtrate line 160, the filtrate container 130, and a wash solution container 330 and line 335.

[0039] Figure 3 is a flowchart depicting a method for concentrating plasma using a plasma concentration/filtration system 100. Figures 4A-4E schematically show the system 100 at various stages of the filtration and concentration method. As shown in Figure 4A, in this embodiment, the plasma reservoir is a plasma bag 310 in which the plasma was collected during plasmapheresis. After the plasmapheresis process is complete and the plasma is collected within the bag 310, the plasma bag 310 may be connected to the filtration system 100 (Step 301) (e.g., using a sterile connections). For example, the feed tube 130 and the retentate tube 140 may be connected to sterile connections located on the plasma bag 310. It is important to note that, in order to ensure the plasma bag 310 can be completely emptied, it is beneficial to connect the feed tube 130 to a port on the bottom of the plasma bag 310. Conversely, to ensure that the pump 134 is not drawing out the retentate that has just returned to the plasma bag 310, it is beneficial to connect the retentate tube 140 to a port on the top of the bag 310.

[0040] Once the plasma bag 310 is connected to the system 100, the pump 134 may begin to draw plasma from the plasma bag 310 (Step 302) and recirculate the plasma through the system 100 (Step 303). As mentioned above, as the plasma enters the feed inlet 122 and passes through the tangential flow filter 120, the plasma will be separated into retentate (e.g., a more concentrated version of the plasma) and filtrate/permeate. The retentate will remain within the feed channel(s) 230 in the filter 120, and the filtrate will pass through the filter membrane 220 and into the filtrate/permeate channel(s) 240. The retentate will then exit the filter 120 through the retentate outlet 124, flow through the rententate line 140 and back into the plasma bag 310. The filtrate will exit the filter 120 through the filtrate outlet 126, flow through the filtrate line 160, and into the filtrate container 150.

[0041] The flow rate at which the pump 134 withdraws the plasma from the plasma bag 310 (which may be determined based upon the number of rotations of the pump per minute) may depend on a number of factors including, but not limited to the volume of plasma to be processed, the viscosity of the plasma, the desired processing time, and the size of the filter 120 being used. For example, in some applications, the pump 134 will draw plasma from the bag 310 at approximately 50-1000 ml/min. This will result in retentate and filtrate flow rates of approximately 45-900 ml/min and 5-100 ml min, respectively.

[0042] Additionally, in order to prevent a back-up of plasma to be

filtered/concentrated within laboratory and/or donation setting, the flow rates may be based upon the time it takes to collect the plasma from the donor (e.g., the plasmapheresis process). For example, a flow rate (and other system/operational parameters) may be chosen that allows the filtration concentration process to be completed in a time similar to that of the plasmapheresis process. Therefore, once a subsequent bag of plasma is collected from the donor/subject, the filtration concentration of the prior bag of plasma will be complete. This will avoid a backlog of plasma needing to be filtered/concentrated.

[0043] During the filtration concentration process, the controller 170 will monitor the outputs from the various sensors mentioned above (e.g., the pressure sensors 132/142/162, flow rate sensor 164, volume sensors/scales 115/155, etc.) and control the operation of the pump 134 based upon at least one of the outputs. For example, the controller 170 may monitor the pressures within the feed line 130 and retentate line 140 (e.g., using pressure sensors 132/142) and increase speed of the pump 134 if the pressure is below a threshold pressure (e.g., the max feed pressure of the filter, which may be between 40 and 100 psi depending on the filter), or decrease the speed of the pump 134 if the pressure is above the threshold. Additionally, it should be noted that the viscosity of the plasma being recirculated through the system 100 increases as the plasma becomes more concentrated. This increase in viscosity, in turn, increases the pressure within the system 100. The controller 170 can compensate for this increase in pressure by adjusting the speed of the pump 134 and/or adjusting the pinch valve 144 on the retentate line 140. In such embodiments, as the increasing viscosity increases the pressure within the system (e.g., within the retentate line 140), the controller can open the valve to compensate for the increased viscosity and decrease the pressure within the system/retentate line 140.

[0044] The system 100 will continue to recirculate the plasma through the system 100 and filter 120 until a desired plasma concentration is obtained (e.g., 2-3 times the concentration of the original/starting plasma) (Step 304). For example, the

concentration/filtration process can be stopped when a target volume of filtrate is collected within the filtrate container 150 (e.g., as measured by the flow sensor 164, the volume sensor, and/or the scale) or the flow through the filtrate line 160 stops. Alternatively, the concentration/filtration process can be stopped when a target volume of concentrated plasma is collected within the plasma bag 310 (e.g., as measured by the volume sensor and/or scale).

[0045] It should be noted that the volume collected within the plasma bag 310 and/or the filtrate bag 150 is related to the increase in concentration of the plasma. For example, if after filtering/concentrating the plasma, the volume within the plasma bag 310 is half of the starting volume, then the final plasma product is two times more concentrated that the starting plasma. Similarly, if the volume of filtrate collected within the filtrate container 150 is equal to half of the original volume of the plasma (e.g., meaning that the volume remaining in the plasma bag 310 is also half of the starting volume), the concentrated plasma is two times more concentrated than the starting plasma. [0046] Once the filtration/concentration process is stopped and the concentrated plasma is contained within the plasma bag 310, the system 100 may then transfer the concentrated plasma from the plasma bag 310 to a plasma concentrate bottle 320 (via a transfer line 325; Figure 4C) that will be used to transport and store the concentrated plasma (Step 305). It should be noted that, because the volume of concentrated plasma is less than that of the starting plasma, the plasma concentrate bottle 320 can be considerably smaller than the plasma bag 310. This smaller size will reduce transportation and storage costs for the concentrated plasma.

[0047] During the filtration process, the proteins within the plasma may create a layer of concentrated proteins on the filter membrane 220. The proteins remaining in the filter 120 and lines (e.g., feed line 130 and retentate line 140) can account for a significant percentage (e.g., 1-2%) of the proteins within the plasma. Therefore, in some embodiments, the system 100 may perform a wash step to rinse the lines 130/140 and filter 120 to collect these proteins (Step 306). In such embodiments, the system 100 may transfer wash solution (e.g., 100 ml of a PBS buffer solution) from a wash solution container 330 into the plasma bag 310 (e.g., gravity drain through a wash solution line 335), and then recirculate the wash solution through the system 100 (e.g., through the feed line 130, filter 120, and retentate line 140), and back into the plasma bag 310 (Fig. 4D). This, in turn, will wash the proteins remaining in the lines 130/140 and filter 120 into the plasma bag 310. The system 100 may then transfer the recirculated wash solution (now within the plasma bag 310) into the plasma concentrate bottle 320 (Step 307).

[0048] As mentioned above, in some embodiments, the plasma reservoir from which the plasma is drawn may be a plasma concentrate bottle. In such embodiments, as shown in Figures 6 A to 6D, the plasma concentrate bottle 410 may have two inlets on the top of the bottle 410 (a plasma inlet 412 and a retentate inlet 414) and an outlet 416 on the bottom of the bottle through which the pump 134 can draw plasma to be filtered/concentrated. Figure 5 is a flowchart depicting a method for concentrating plasma using a plasma concentrate bottle 410 with two inlets 412/414. In particular prior to filtration/concentration, the plasma bag 310 containing the plasma collected during the plasmapheresis process, may be fluidly connected to the plasma inlet 412 via a plasma transfer tube 420 (and a sterile connection) (Step 401), and plasma from the plasma bag 310 can be transferred to the plasma concentrate bottle 410 (Step 402).

[0049] As also mentioned above, the plasma concentrate bottle 410 may be smaller than the plasma bag 310. Therefore, not all of the plasma within the plasma bag 310 can be transferred to the plasma concentrate bottle 410 at once. However, as the system 100 draws plasma from the plasma concentrate bottle 410 (Step 403) and recirculates the plasma through the filter 120 (Step 404) and filtrate is collected within the filtrate container 150 (and the retentate is returned to the plasma concentrate bottle 410 via the retentate line 140 and retentate inlet 414), the plasma level within the plasma concentrate bottle 410 decreases. As the level in the plasma concentrate bottle 410 decreases, the system 100 can continue to add more plasma to the bottle 410 until no plasma remains in the plasma bag 310 (Step 405). Additionally, like the embodiment discussed above and shown in Figures 4A to 4E, the system 100 may continue to recirculate the plasma within the plasma concentrate bottle 410 (sending the retentate back to the plasma concentrate bottle 410 and the filtrate to the filtrate container 150) until the desired concentration is obtained (e.g., the filtrate volume limit is detected, filtrate flow stops, or other limit detected) (Step 406).

[0050] As shown in figure 6D, in this embodiment, during the wash step (Step 407), the wash solution may be transferred from the wash solution container 330 to the plasma bag 310 (e.g., via a wash solution transfer line 335). The pump 134 may then draw the wash solution from the plasma bag 310 via a wash line 430 that fluidly connects the plasma bag 310 and the feed line 130 (e.g., upstream of the pump 134) and recirculate the wash solution through filter 120 and lines. However, it is important to note that, because the retentate line 140 is connected to the plasma concentrate bottle 410, the wash solution will return directly to the plasma concentrate bottle 410 (e.g., as opposed to back to the plasma bag 310) (Step 408).

[0051] It is important to note that, in some embodiments, prior to

filtration/concentration and during system set-up, the filter 120 may be placed within a manifold 510 (Figs. 7A and 7B) that includes two plates 520A/B (e.g., steel plates) that are moveable relative to one another. For example, the manifold 510 can have lever 530 that can be manipulated to move the plates relative to one another (e.g., a user can move the lever 530 down to bring the plates 520A/B together or move the lever up to move the plates 520A/B apart). To load the filter 120, the user may move the lever 530 up to "open" the plates 520A/B (Figure 7A), place the filter 120 between the plates 520A/B, and move the lever 530 down to bring the plates 520A/B closer to one another and clamp the filter between the plates 520A/B (Figure 7B). Alternatively, as shown in Figures 8A and 8B, instead of a lever 530, in some embodiments, the manifold 610 can be automated such that the plates 620A/B can be opened and closed by simply pressing a button 630 located on the manifold 610.

[0052] In addition to holding the filter 120 in place during filtration/concentration, the manifold 510/610 also reduces the need to use heavy materials for the filter 120 and filter housing. For example, because the filter 120 is clamped between and supported by the manifold plates (e.g., plates 720A/B or plates 820A/B), the pressure within the filter 120 is effectively translated through the filter housing material to the plates, which can handle greater operating pressures than the filter 120. In other words, by placing the filter 120 into the manifold, the operating pressure of the filter 120 and system 100 is essentially increased. Furthermore, in some embodiments, because the pressures are effectively translated to the manifold plates (e.g., plates 520A/B or plates 620A/B), the wall thicknesses of the filter housing may be reduced and/or weaker materials may be used.

[0053] Although the above described embodiments are systems that filter the plasma off-line (e.g., they are not connected to the plasmapheresis system, and do not filter the plasma during plasma collection and while the subject is still connected to the

plasmapheresis system), other embodiments of the present invention may be in-line systems. For example, as shown in Figures 9, 10A and 10B, the plasma filtration/concentration system 100 may be connected to the plasmapheresis system 710 and, in particular, to the plasma container 720 of the plasmapheresis system 710. In such embodiments, the plasmapheresis system 710 will draw whole blood from a donor/subject 730, separate the whole blood using a blood component separation device 740, collect plasma within the plasma container 720 (Step 701), and, perhaps, return the other components to the donor/subject 730.

[0054] Once some plasma has been collected within the plasma container 720 (which will be used as the plasma reservoir), the filtration/concentration system 100 may then begin to filter/concentrate the plasma in a manner similar to that described above. For example, the system 100 (e.g., the pump 134) may draw plasma from the plasma container 720 (Step 702), and recirculate the plasma (Step 703) through the feed line 130 and the filter 120, where the plasma is separated into rententate and filtrate. The retentate may then be returned to the plasma container 720 for further concentration, and the filtrate may be sent to the filtrate container 150 where it will be stored until it is returned to the donor 720 via a return line 750. Alternatively, the filtrate may be returned directly to the subject via the return line 750 (e.g., the system may not include a filtrate container 150).

[0055] The system will continue filtering/concentrating the plasma collected within the plasma container 720 until the desired concentration is reached (as described above) (Step 704). If the filtrate has not yet been returned to the donor/subject 730, the system may then return the filtrate to the donor/subject 730 via the return line 750 (Step 705). For example, the system 100 may include a return pump 760 located on the return line 750 that draws the filtrate from the filtrate container 150, through the return line 750 and back to the donor/subject 730. It is important to note that, although Figures 10A and 10B show the return line 750 returning the filtrate to a different arm than where the whole blood is drawn from, to minimize the number of needle sticks that the donor/subject 730 must endure, in some embodiments, the return line 750 can connect to the same needle as the line through which the whole blood is drawn. In some embodiments, the system may then transfer the concentrated plasma, which has collected within the plasma container 720 to a plasma concentrate container (Step 706). Alternatively, the plasma container 720 may be the plasma concentrate container, and the plasma concentrate may be collected directly in the plasma concentrate container.

[0056] It is important to note that, in some embodiments, it may be necessary to wet the filter and/or prime the system 100 prior to filtration/concentration. To that end, some embodiments may include (or may be connected to) a priming solution container 190 that, in turn, is fluidly connected to the feed line 130 via a priming solution line 192 (Fig. 1). In such embodiments, the pump 134 on the feed line 130 may draw priming solution from the priming solution container 190 and recirculate the priming solution through the system 100 to prime the system 100 and/or wet the filter 120.

[0057] It is important to note that the feedback system utilized by various

embodiments of the present invention allow the plasma filtration/concentration to be optimized. For example, embodiments of the present invention are able to keep the system 100 operating at or near the maximum operating pressure of the filter 120 (without over- pressurizing any of the components of the system 100) and are able to detect as soon as filtration/concentration is complete. This, in turn, reduces the overall filtration/concentration time and improves system efficiency. Additionally, the feedback also allows the system 100 to account for variability in the starting viscosity of the plasma (which may differ from donor to donor). For example, by monitoring the feed pressure, retentate pressure, and filtrate pressure and flow rate, embodiments of the present invention can ensure that the system 100 is optimized, regardless of the starting viscosity.

[0058] It is should be noted that, particularly in the in-line embodiments, it may be possible to process more whole blood and collect more plasma than typical plasmapheresis devices by returning filtrate or a compensation fluid (e.g., a saline solution) to the donor/subject 730. By returning the filtrate or compensation fluid to the donor, some embodiments of the present invention are able to maintain/control the net loss of fluids from the patient. For example, in off-line systems (e.g., like those shown in Figures 4A-4E and 6A-6D), a saline solution can be returned to the donor/subject 730 during the plasmapheresis process to off-set the additional volume of plasma collected. Similarly, for in-line systems that return the filtrate to the donor/subject 730 (e.g., like that shown in Figures 10A and 10B), the filtrate will off-set the additional volume of plasma collected.

[0059] The removal of additional plasma may result in some secondary therapeutic benefits for the donor/subject 730. For example, when plasma is removed from the donor/subject 730, cholesterol is also removed from the subject. Therefore, by removing additional plasma from the donor/subject 730, additional cholesterol will also be removed. This, in turn, will lower the donor's cholesterol level. Furthermore, because embodiments of the present invention are able to collect more plasma from the donor/subject during each donation, the number of needle sticks required to collect a given volume of plasma is reduced. This, in turn, improves donor/subject 730 comfort and reduces the risk of infection.

[0060] It is also important to note that, although the embodiments described above filter plasma in order to obtain a concentrated plasma product, other embodiments of the present invention may be utilized to selectively remove components of the plasma (e.g., as opposed to concentrating the plasma). For example, in some embodiments, a filter pore size can be chosen that will selectively remove some fraction of the proteins (e.g., albumin) within the plasma as it recirculates through the system 100. [0061] The embodiments of the invention described above are intended to be merely exemplary; numerous variations and modifications will be apparent to those skilled in the art. All such variations and modifications are intended to be within the scope of the present invention as defined in any appended claims.

Claims

What is claimed is:

1. A system for the concentration of plasma product comprising:

a plasma reservoir configured to hold plasma;

a filter having a housing and a filter membrane configured to separate the plasma into retentate and filtrate, thereby concentrating the plasma flowing through the filter, the filter housing having a feed inlet, a retentate outlet, and a filtrate outlet;

a feed tube fluidly connecting the plasma reservoir and the feed inlet;

a retentate tube fluidly connecting the plasma reservoir and the retentate outlet and configured to return retentate to the plasma reservoir;

a filtrate storage container fluidly connected to the filtrate outlet via a filtrate line, the filtrate storage container configured to collect filtrate exiting the filter via the filtrate line, the filtrate line having a filtrate flow sensor configured to measure a flow of filtrate through the filtrate line;

a pump located on the feed line and configured to draw plasma from the plasma reservoir and into the filter via the feed line; and

a controller in communication with the filtrate flow sensor and configured to control a speed of the pump based, at least in part, on the measured filtrate flow.

2. A system according to claim 1, further comprising a feed pressure sensor located on the feed line and configured to measure a pressure within the feed line, the controller also configured to control the speed of the pump based on the feed line pressure.

3. A system according to claim 1, further comprising a retentate pressure sensor located on the retentate line and configured to measure a pressure within the retentate line, the controller also configured to control the speed of the pump based on the retentate line pressure.

4. A system according to claim 3 further comprising a pinch valve located on the retentate line, the pinch valve configured to control the flow of retentate through the retentate line.

5. A system according to claim 4, wherein the controller is further configured to control the pinch valve based, at least in part on the retentate line pressure.

6. A system according to claim 1, further comprising a scale configured to measure a weight of at least one of the plasma reservoir and the filtrate storage container, the controller configured to control the pump based on the measured weight.

7. A system according to claim 1, further comprising a plasma volume sensor configured to measure a volume of plasma within the plasma reservoir, the controller also configured to control the speed of the pump based on the measured volume.

8. A system according to claim 1, further comprising a filtrate volume sensor configured to measure a volume of filtrate within the filtrate storage container, the controller also configured to control the speed of the pump based on the measured volume.

9. A system according to claim 1, further comprising a filtrate pressure sensor located on the filtrate line and configured to measure a pressure within the filtrate line, the controller also configured to control the speed of the pump based on the filtrate line pressure.

10. A system according to claim 1, further comprising a wash solution container configured to hold wash solution and fluidly connected to the plasma reservoir via a wash line.

11. A system according to claim 1 , wherein the plasma reservoir is a plasma bag from a plasmapheresis device.

12. A system according to claim 11, further comprising a plasma concentrate bottle fluidly connected to the plasma reservoir via a concentrated plasma transfer line and configured to store concentrated plasma product.

13. A system according to claim 1, wherein the plasma reservoir is a plasma concentrate bottle.

14. A system according to claim 13, wherein the plasma concentrate bottle includes an inlet fiuidly connected to a plasma bag containing plasma, the plasma bag configured to supply the plasma concentrate bottle with plasma.

15. A system according to claim 1, further comprising a manifold configured to hold the filter and apply a force to the filter housing.

16. A system according to claim 15, wherein the manifold includes a first plate and a second plate, the first and second plate being moveable relative to one another, the filter being located between the first and second plate.

17. A system according to claim 1, wherein the system is in-line with a plasmapheresis system, the plasmapheresis system processing blood withdrawn from a subject.

18. A system according to claims 17, wherein the plasma reservoir is a plasma storage container fiuidly connected to the plasmapheresis system, the plasma storage container configured to collect plasma from the plasmapheresis system.

19. A system according to claim 18, further comprising:

a return line fiuidly connecting the filtrate container and a subject and configured to return filtrate within the filtrate container to the subject.

20. A system according to claim 19, further comprising a return pump located on the return line and configured to return the withdrawn filtrate to the subject via the return line.

21. A system for the concentration of plasma product comprising:

a plasma reservoir configured to hold plasma;

a filter having a housing and a filter membrane configured separate the plasma flowing through the filter into retentate and filtrate, thereby concentrating the plasma flowing through the filter, the filter housing having a feed inlet, a retentate outlet, and a filtrate outlet; a feed tube fluidly connecting the plasma reservoir and the feed inlet; a retentate tube fluidly connecting the plasma reservoir and the retentate outlet;

a filtrate storage container fluidly connected to the filtrate outlet via a filtrate line, the filtrate storage container configured to collect filtrate exiting the filter via the filtrate line; at least one pressure sensor located on at least one of the feed tube and retentate tube, and configured to measure a pressure;

a controller in communication with the at least one pressure sensor and configured to control a speed of the pump based, at least in part, on the measured pressure.

22. A system according to claim 21, wherein the at least one pressure sensor includes a feed pressure sensor located on the feed line, the feed pressure sensor configured to measure a pressure within the feed line, the controller configured to control the speed of the pump based on the feed line pressure.

23. A system according to claim 21, wherein the at least one pressure sensor includes a retentate pressure sensor located on the retentate line, the retentate pressure sensor configured to measure a pressure within the retentate line, the controller configured to control the speed of the pump based on the retentate line pressure.

24. A system according to claim 23 further comprising a pinch valve located on the retentate line, the pinch valve configured to control the flow of retentate through the retentate line.

25. A system according to claim 24, wherein the controller is further configured to control the pinch valve based, at least in part on the retentate line pressure.

26. A system according to claim 21, further comprising a filtrate flow sensor located on the filtrate line, the filtrate flow sensor configured to measure a flow of filtrate through the filtrate line, the controller further configured to control the speed of the pump based on the measured flow of filtrate.

27. A system according to claim 21, further comprising a scale configured to measure a weight of at least one of the plasma reservoir and the filtrate storage container, the controller configured to control the pump based on the measured weight.

28. A system according to claim 21, further comprising a plasma volume sensor configured to measure a volume of plasma within the plasma reservoir, the controller also configured to control the operation of the pump based on the measured volume.

29. A system according to claim 21, further comprising a filtrate volume sensor configured to measure a volume of filtrate within the filtrate storage container, the controller also configured to control the operation of the pump based on the measured volume.

30. A system according to claim 21, further comprising a filtrate pressure sensor located on the filtrate line and configured to measure a pressure within the filtrate line, the controller configured to control the speed of the pump based on the filtrate line pressure.

31. A system according to claim 21, further comprising a wash solution container configured to hold wash solution and fluidly connected to the plasma reservoir via a wash line.

32. A system according to claim 21, wherein the plasma reservoir is a plasma bag from a plasmapheresis device.

33. A system according to claim 32, further comprising a plasma concentrate bottle fluidly connected to the plasma reservoir via a concentrated plasma transfer line and configured to store concentrated plasma product.

34. A system according to claim 21, wherein the plasma reservoir is a plasma concentrate bottle.

35. A system according to claim 34, wherein the plasma concentrate bottle includes an inlet fiuidly connected to a plasma bag containing plasma, the plasma bag configured to supply the plasma concentrate bottle with plasma.

36. A system according to claim 21, further comprising a manifold configured to hold the filter and apply a force to the filter housing.

37. A system according to claim 36, wherein the manifold includes a first plate and a second plate, the first and second plate being moveable relative to one another, the filter being located between the first and second plate.

38. A system according to claim 21, wherein the system is in-line with a plasmapheresis system, the plasmapheresis system processing blood withdrawn from a subject.

39. A system according to claims 38, wherein the plasma reservoir is a plasma storage container fiuidly connected to the plasmapheresis system, the plasma storage container configured to collect plasma from the plasmapheresis system.

40. A system according to claim 39, further comprising:

41. A system according to claim 39, further comprising a return pump located on the return line and configured to return the withdrawn filtrate to the subject via the return line.

42. A method for concentrating plasma product comprising:

(a) providing a plasma reservoir configured to store plasma;

(b) drawing plasma from the plasma reservoir and through a feed line using a pump located on the feed line; (c) flowing the plasma through a tangential flow filter, the tangential flow filter having a housing and a filter membrane, the filter membrane filtering the plasma to create a retentate and a filtrate;

(d) returning the retentate to the plasma reservoir through a retentate line fluidly connecting the plasma reservoir with a retentate outlet on the filter housing;

(e) transferring the filtrate to a filtrate storage container through a filtrate line fluidly connecting the filtrate container with a filtrate outlet on the filter housing;

(f) measuring the flow of filtrate through the filtrate line;

(g) controlling the operation of the pump based, at least in part, on the measured filtrate flow through the filtrate line; and

(h) repeating steps (a) to (g) until a target plasma concentration is achieved in the plasma reservoir.

43. A method according to claim 42 wherein the target plasma concentration is determined based upon the measured flow of filtrate through the filtrate line.

44. A method according to claim 42, wherein the target plasma concentration is determined based upon a volume of filtrate collected within the filtrate storage container.

45. A method according to claim 42, further comprising measuring at least one of a weight and a volume of concentrated plasma within the plasma reservoir, wherein the target plasma concentration is determined based upon at least one of the measured weight and the measured volume.

46. A method according to claim 42, further comprising:

transferring concentrated plasma within the plasma reservoir to a plasma concentrate bottle.

47. A method according to claim 46, further comprising:

transferring wash solution from a wash solution container to the plasma reservoir; and recirculating the wash solution through the filter via the feed line and back into the plasma reservoir via the retentate line.

48. A method according to claim 47, further comprising:

transferring the recirculated wash solution to the plasma concentrate bottle.

49. A method according to claim 42, wherein the plasma reservoir is a plasma concentrate bottle.

50. A method according to claim 49, further comprising:

transferring plasma from a plasma bag to the plasma concentrate bottle prior to drawing plasma from the plasma concentrate bottle, wherein step (d) includes returning the retentate to the plasma concentrate bottle.

51. A method according to claim 50, further comprising:

transferring additional plasma from the plasma bag to the plasma concentrate bottle as the plasma is drawn from the plasma concentrate bottle and filtered by the tangential flow filter.

52. A method according to claim 51, further comprising:

transferring wash solution from a wash solution container to the plasma bag; and recirculating the transferred wash solution through the filter and into the plasma concentrate bottle via the feed line and retentate line.

53. A method according to claim 42, further comprising:

measuring a pressure within at least one of the feed line and the retentate line; and controlling the speed of the pump based on the measured pressure.

54. A method according to claim 53, wherein the retentate line includes a pinch valve for controlling the flow of retentate through the retentate line.

55. A method according to claim 54, further comprising adjusting the pinch valve based, at least in part on the retentate line pressure, thereby adjusting the retentate line pressure.

56. A method according to claim 42, further comprising measuring a pressure within the filtrate line, controlling the operation of the pump including controlling operation of the pump based, at least in part, on the filtrate line pressure.

57. A method according to claim 42, further comprising placing the filter within a manifold configured to hold the filter and apply a force to the filter housing.

58. A method according to claim 57, wherein the manifold includes a first plate and a second plate, the first and second plate being moveable relative to one another, the filter being located between the first and second plate.

59. A method according to claim 42, wherein the plasma reservoir is a plasma storage container from a plasmapheresis system and is fluidly connected to a blood component separation device within the plasmapheresis system.

60. A method according to claim 59, wherein the plasmapheresis system processes blood withdrawn from a subject.

61. A method according to claim 60, further comprising:

returning filtrate within the filtrate storage container to the subject via a filtrate return line.

62. A method for concentrating plasma product comprising:

(a) providing a plasma reservoir configured to store plasma;

(b) drawing plasma from the plasma reservoir and through a feed line using a pump located on the feed line; (c) flowing the plasma through a tangential flow filter, the tangential flow filter having a housing and a filter membrane, the filter filtering the plasma to create a retentate and a filtrate;

(f) measuring a pressure in at least one of the feed line and retentate line;

(g) controlling the operation of the pump based, at least in part, on the measured pressure; and

63. A method according to claim 62, wherein the target plasma concentration is determined based upon the measured flow of filtrate through the filtrate line.

64. A method according to claim 62, wherein the target plasma concentration is determined based upon a volume of filtrate collected within the filtrate storage container.

65. A method according to claim 62, further comprising measuring at least one of a weight and a volume of concentrated plasma within the plasma reservoir, wherein the target plasma concentration is determined based upon at least one of the measured weight and the measured volume.

66. A method according to claim 62, further comprising:

67. A method according to claim 66, further comprising:

68. A method according to claim 67, further comprising:

transferring the recirculated wash solution to the plasma concentrate bottle.

69. A method according to claim 62, wherein the plasma reservoir is a plasma concentrate bottle.

70. A method according to claim 69, further comprising:

transferring plasma from a plasma bag to the plasma concentrate bottle prior to drawing plasma from the plasma reservoir, wherein step (d) includes returning the retentate to the plasma concentrate bottle.

71. A method according to claim 70, further comprising:

72. A method according to claim 71, further comprising:

73. A method according to claim 62, further comprising:

measuring the flow of filtrate through the filtrate line;

controlling the operation of the pump based, at least in part, on the measured filtrate flow through the filtrate line.

74. A method according to claim 62, wherein the retentate line includes a pinch valve for controlling the flow of retentate through the retentate line.

75. A method according to claim 74. further comprising adjusting the pinch valve based, at least in part on the retentate line pressure, thereby adjusting the retentate line pressure.

76. A method according to claim 62, further comprising measuring a pressure within the filtrate line, controlling the operation of the pump including controlling the operating of the pump based, at least in part, on the filtrate line pressure.

77. A method according to claim 62, further comprising placing the filter within a manifold configured to hold the filter and apply a force to the filter housing.

78. A method according to claim 77, wherein the manifold includes a first plate and a second plate, the first and second plate being moveable relative to one another, the filter being located between the first and second plate.

79. A method according to claim 62, wherein the plasma reservoir is a plasma storage container from a plasmapheresis system and is fluidly connected to a blood component separation device within the plasmapheresis system.

80. A method according to claim 79, wherein the plasmapheresis system processes blood withdrawn from a subject.

81. A system according to claim 80, further comprising: