CA2083543A1 - Automated system and method for processing biological fluid - Google Patents

Abstract

ABSTRACT:

An automated system for collecting and processing donated includes a pressure differential generator; a biological fluid processing assembly, and an automated control arrangement coupled to at least one of the pressure differential generator and the biological fluid processing assembly.

Description

f~ J ~3 AUTOMATED SYSTEM AND NET~OD FOR
PROCESSING BIOLOGICAL FLUID

This application is a continuation-in-part application of U.S. Application Serial No. 07/788,787, filed November 6, 1991.

Technical Field:
This invention relates to a system for automatically processing biological fluid donated for the purpose of therapeutic transfusion and, particularly, to improved methods and apparatuses for preparing, from donated biological fluid such as whole blood, packed red cells (hereinafter PRC), platelet concentrate (hereinafter PC), and plasma.

Back~round of the Invention The development of plastic blood collection bags has facilitated the separation of donated whole blood into its various components and analogous products, thereby making these different blood products available as a transfusion product.
For this reason, the separation of blood into components has substantial therapeutic and monetary value, placing additional pressure on blood banks to increase component yield per unit of biological fluid and to reduce costs per unit of processed biological fluid.
In view of this, there is a growing need for an efficient system and method for separating a biological fluid (e.g., whole blood) into its components. Blood ~'' , ", : 2~83~3 bank personnel have responded to the increased need for blood components by attempting to increase the yields in a variety of ways. However, any savings resulting from increasing the yield may be offset by the -S increased labor cost, if the operator of the processingsystem must continuously and carefully monitor the system to increase the yield.
Because of the high cost and limited availability of blood components, a device comprising a porous medium used to deplete leukocytes from biological fluid should deliver the highest possible proportion of the component present in the donated blood and, at the same time, decrease or eliminate operator intervention during the processing. An ideal device for the leukocyte depletion of a blood component would be inexpensive, relatively small, and be capable of rapidly processing blood components obtained from about one unit or more of biological fluid (e.g., donated whole blood), in, for example, less than about one hour. Ideally, this device would reduce the leukocyte content to the lowest possible level, while maximizing the yield of a valuable blood component while minimizing an expensive, sophisticated, labor intensive effort by the operator of the system. The yield of the blood component should be maximized while at the same time delivering a viable and physiologically active component--e.g., by minimizing damage due to processing, and/or the presence of air or gas.

Summarv of the Invention In the devices and methods of this invention, separation of a biological fluid into one or more components is preferably carried out at the time of . ~ : ,~ - :

3~i~3 processing, which, in the ~nited States, is generally within about 6 to 8 hours of the time the blood is drawn. Preferably, the separated component is also leukocyte depleted during this interval. Thus, as a biological fluid is transferred from the bag in which it is contained, leukocytes may be removed by the appropriate porous mèdium, and leukocyte-depleted biological fluid may be collected in a satellite bag, without, or with minimal, operator intervention. In accordance with the invention, a system is provided whereby a biological fluid such as whole blood is automatically processed to form any desired component or fraction, such as platelet-rich plasma (PRP) and PRC.
Processes and systems according to the invention may also include a red cell barrier medium that allows the passage of one component of the biological fluid, but prevents the passage of red cells throùgh the medium, thereby eliminating the need for continuous monitoring by an operator and increasing the efficiency with which a biological fluid such as whole blood or PRP is separated into one or more components.

Definitions The following definitions are used in reference to the invention:
(A) Blood Product or Biological Fluid: refers to any treated or untreated fluid associated with living organisms, particularly blood, including whole blood, warm or cold blood, and stored or fresh blood; treated blood, such as blood diluted with a physiological solution, including but not limited to saline, nutrient, and/or anticoagulant solutions; one or more .,: .
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2~ aL3 blood components, such as platelet concentrate (PC), platelet-rich plasma (PRP), platelet~free plasma, platelet-poor plasma (PPP), plasma, packed red cells (PRC), or buffy coat (BC); and analogous blood products derived from blood or a blood component or derived from bone marrow. The biological fluid may include leuXocytes, or may be treated to remove leukocytes. As used herein, blood product or biological fluid refers to the components described above, and to similar blood products or biological fluids obtained by other means and with similar properties.
A "unit" typically refers to the quantity of biological fluid from a donor or derived from one unit of whole blood. It may also refer to the quantity drawn during a single donation. Typically, the volume of a unit varies, the amount differing from patient to patient and donation to donation. Multiple units of some blood components, particularl~ platelets and buffy coat, may be pooled or combined, typically by combining 4 or more units.
(B) Porous medium: refers to the porous medium through which one or more blood components or biological fluids pass. For example, the PRC porous medium depletes leukocytes from a red cell containing solution or suspension, e.g., from packed red cells.
The platelet or PRP porous medium refers generically to any one of the media which deplete leukocytes from the non-PRC fluids, e.g., from BC, PRP, or from PC. The red cell barrier medium is effective for separating the red cell containing component of blood from the non-red cell containing component, e.g., separating PRP from PRC, and is described in more detail below. As used herein, filter assembly refers to the porous medium ::
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2~3~'~3 positioned in a suitable housing.
The porous media are primarily intended for use with biological fluid obtained from donated blood soon after the blood is drawn, typically within about 8 hours. A porous medium may also be used to filter stored biological fluid, but, since the risk of clogging during filtration increases with ~torage age, the risk can be reduced, by for example, using pre-filters.
A porous medium may be pre-formed, multi-layered, and/or may be treated to modify the surface of the medium. If a fibrous medium is used, the fibers may be treated either before or after forming the fibrous lay-up. It is preferred to modify the fiber surfaces before forming the fibrous lay-up because a more cohesive, stronger product is obtained after hot compression to form an integral filter element.
The porous medium may be configured as a flat sheet, a corrugated sheet, a web, or a membrane. The porous medium may be a depth filter, a single layer, or a composite of at least two fiber and/or membrane layers. Preferably, the porous medium forms an interference fit at its edges when assembled into the housing.
(C) Separation Medium: A separation medium refers to a porous medium effective for separating one component of a biological fluid from another component.
The separation media according to the invention are suitable for passing at least one component of the blood product or biological fluid, particularly plasma, therethrough, but not other components of the blood product or biological fluid, particularly platelets and/or red cells.

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The separatio~ medium may be pre-formed, multi-layered, and/or may be treated to modify the surface of the medium. If a fibrous medium is used, the fibers may be treated either before or after forming the fibrous lay-up. It is preferred to modify the fiber surfaces before forming the fibrous lay-up because a more cohesive, stronger product is obtained after hot compression to form an integral filter element.
The separation medium may be configured in any suitable fashion, such as a flat sheet, a corrugated sheet, a web, hollow fibers, or a membrane. The separation medium may be a depth filter, a single layer, or a composite of at least two fiber and/or membrane layers.

Brief Descri~tion of the Drawinas Figure 1 is an embodiment of a biological fluid processing system according to the invention.
Figure 2 is another embodiment of a biological fluid processing system according to the invention.
Figure 3 is an optional biological fluid processing assembly segment which includes a separation medium.
Figure 4 is an optional biological fluid processing assembly segment which includes a gas inlet and a gas outlet.
Figure 5 is a flow chart of an exemplary initial sequence according to the invention.
Figure 6 is a flow chart of an exemplary second sequence according to the invention.
Figure 7 is a flow chart of an exemplary third sequence according to the invention.
Figure 8 is a flow chart of an optional priming , ,~, . ;

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2 ~ 3 sequence.
Figure 9 is a flow chart of an exemplary sequence according to the invention.
Figure 10 is a flow chart of an optional venting S sequence according to the invention.

S~ecific Descri~tion of the Invention The present invention involves a biological fluid processing system comprising a pressure differential generator a biological fluid processing assembly including a collection container operatively associated with the pressure differential generator, a second container in fluid communication with the collection container, and a porous medium interposed between the collection container and the second container; and an automated control arrangement coupled to at least one of the pressure differential generator and the biological fluid processing assembly to control flow between the collection container and the second container. In a preferred embodiment, the biological fluid processing assembly includes a first porous medium, comprising at least one of a leukocyte depletion medium, a red cell barrier medium, and a combined leukocyte depletion red cell barrier medium;
and/or a second porous medium, which may be a leukocyte depletion medium which may, optionally, include a microaggregate filter element and/or a gel pre-filter element. As shown in more detail below, the assembly may also include additional containers, porous media, and conduits interconnecting the containers and porous media.
~ he invention also involves a method for collecting and processing blood comprising collecting a . .

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2 ~ L~ 3 biological fluid such as whole blood in a container;
separating, e.g., by centrifugation, the biological fluid into a supernatant layer and a sediment layer, passing the supernatant layer of the separated biological fluid through a first porous medium, the first porous medium comprising at least one of a leukocyte depletion medium, a red cell barrier medium, and a combined leukocyte depletion red cell barrier ; medium; and passing the sediment layer of the separated biological fluid through a second porous medium, the second porous medium comprising a leukocyte depletion medium.
The invention also may involve separating the biological fluid into three layers -- the supernatant and sediment layers as noted above, and an intermediate layer. In the embodiments of the invention in which an intermediate layer or zone is formed, the intermediate layer or zone, typically buffy coat, can be further processed into a second supernatant layer and a second sediment layer. The second supernatant layer may then be passed through a third porous medium comprising at least one of a leukocyte depletion medium, a red cell barrier medium, and a combined leukocyte depletion red cell barrier medium. The second sediment layer may be passed through a fourth porous medium comprising a leukocyte depletion medium.
The invention also involves a method for automatically processing a biological fluid comprising expressing a biological fluid from a first container to a first porous medium comprising a red cell barrier medium; and expressing a biological fluid from the first container to a second porous medium. As shown in more detail below, the method may also include , ~
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2~3~3 processing the fluid through additional containers, flow paths, and porous media, and the system may be designed to process more than one separate unit at the same time.
Exemplary automated biological fluid collection and processing systems are shown in Figures 1 and 2. A
system according to the invention may comprise a pressure differential generator 51, e.g., an expressor, or the like, which is suitable for inducing fluid flow from collection container 11 to other parts of the system, or inducing flow from other parts of the system to collection container 11. ~he pressure differential generator is operatively associated with a biological fluid processing assembly, an example of which is shown as 10 in Figure 1.
As noted in more detail below, the individual parts which constitute a biological fluid processing assembly 10 may vary according to an intended use. In the illustrated embodiments, the biological fluid processing assembly 10 may comprise a first container or collection bag 11; a needle or cannula 1 adapted to be inserted into or connected to the donor; an optional red cell barrier assembly 12; a first leukocyte depletion assembly 13, preferably suitable for removing ; 25 leukocytes from a platelet-containing solution or suspension, e.g., PRP; a second container (first satellite bag) 41 suitable for receiving and/or storing a platelet-containing solution or suspension; an optional fourth container (third satellite bag) 42 suitable for receiving and/or storing platelet concentrate; a second leukocyte depletion assembly 17, preferably suitable for removing leukocytes from a red cell containing solution or suspension, e.g., PRC; and _ g _ : ,. .
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a third container (second satellite bag) 18 suitable for receiving and/or storing a red cell containing solution.
Each of the assemblies or containers may be in fluid communication through conduits, preferably flexible tubing, 20, 21, 25, 26, 27 or 28. A seal, valve, clamp, pinch clamp, or transfer leg closure or cannula may also be positioned in or on the tubing or in the collection and/or satellite bags. A seal (or seals), or the like, may be opened in response to a pre-programmed command from the automated control arrangement. In accordance with the present invention, the assemblies, containers, and conduits may be previously connected in a closed, sterile manner, or segments of the system may be inserted into a closed system in a sterile manner.
In accordance with the present invention, ; processing a biological fluid through the system can be automated by coupling an automated control arrangement to the biological fluid processing assembly 10 or to the pressure differential generator 51. As noted in more detail below, the individual parts which constitute an automated control arrangement may vary ; according to an intended use. In the illustrated embodiment, the automated control arrangement may comprise a control unit 50, typically a microprocessor controller, coupled to at least one of the pressure differential generator 51 and the biological fluid processing assembly 10 to control flow between the collection container 11 and another container 41 and/or 18.
Each of the components of the assembly will now be described in more detail below.

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PRESSURE DIFFERENTIAL GENERATOR
Movement of the biological fluid through the system is effected by maintaining a pressure differential between the collection bag and the destination of the biological fluid (e.g., a container such as a satellite bag). Exemplary means of establishing this pressure differential may be by a mechanical member bearing directly against the collection container, mechanical expressor, gravity head, applying pressure to the collection bag by hand or with a pressure cuff, by placing the other container (e.g., satellite bag) in a chamber (e.g., a vacuum chamber) which establishes a pressure differential between the collection bag and the other container, or by an in-line pump.
In accordance with the invention, expressors which generate substantially equal pressure over the entire collection bag may be used. Also included are expressors which shake or agitate the biological fluid, and expressors which are capable of rotating on an axis, e.g., so that the upper discharge conduit becomes a lower discharge conduit. Alternatively, the collection container may be capable of rotating along its horizontal axis in order to change the relative 2S position of the discharge conduit.
An exemplary pressure differential generator may include an enclosed housing defining a chamber suitable for positioning a container therein. The housing or chamber may be in fluid communication with a pressure regulating mechanism suitable for varying the fluid pressure applied to the outside of the container positioned in the chamber. In a preferred embodiment, the pressure within the chamber may be increased or , - .

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decreased substantially evenly over the entire outside of the container.

BIOLOGICAL FLUID PROCESSING ASSEMBLY
Any number and combinations of assemblies, porous media, containers, and conduits are suitable. One skilled in the art will recognize that the invention as described here may be reconfigured into different combinations. ~xemplary biological fluid processing assemblies are disclosed in U.S. Patent 5,100,564 and International Publication No. W~ 92/07656.
In accordance with the invention, the tubes, assemblies, porous media, and containers which constitute a biological fluid processing assembly may be arranged to define different flow paths. For example, when whole blood is processed, the PRP may flow along a first flow path, e.g., through a red cell barrier assembly (if present), a PRP leukocyte depletion assembly, and into a satellite bag (e.g., a second container). Similarly, the PRC may flow along a second flow path, e.g., through the PRC leukocyte depletion assembly, and into a satellite bag (e.g., a third container). Since independent flow paths may be present, included within the scope of the present invention is the concurrent or sequential passage of separate biological fluids (e.g., PRP and PRC) through the biological fluid processing assembly.
The containers which are used in the biological fluid processing assembly may be constructed of any material compatible with a biological fluid, such as whole blood or a blood component, and capable of withstanding a centrifugation and sterilization environment. A wide variety of these containers are .
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2~$~3 already known in the art. For example, blood collection and satellite bags are typically made from plasticized polyvinyl chloride, e.g. PVC plasticized with dioctylphthalate, diethylhexylphthalate, or trioctyltrimellitate. The bags may also be formed from polyolefin, polyurethane, polyester, and polycarbonate.
It is intended that the present invention is not limited by the type of material used to construct the containers which connects the containers~
The conduit may be any tubing or means which provides fluid communication between the containers, and is typically made from the same flexible material as is used for the containers, preferably plasticized PVC. It is intended that the present invention is not limited by the type of material used to construct the conduit which connects the containers.
The conduit may extend into the interior of the container. There may be a number of tubes providing fluid communication to any individual container, and the tubes may be oriented in a number of ways. For example, there may be at least two tubes oriented at the top of the collection bag, or at the bottom of the bag, or a tube at each end of the bag, or a tube extending from an intermediate portion of the bag.
Included within the scope of the present invention are single discharge tube containers (upper and lower); two discharge tubes (upper, lower, and both); three tubes (upper, lower, and/or intermediate), and variations on any of these configurations. Also included within the scope of the present invention are containers having a clamp for mechanically separating a layer or zone within the container from another layer or zone.
A flow control device, such as a seal, valve, ~ 13 -:: :

2 ~ 3 clamp, pinch clamp, transfer leg closure, or the like is typically located in or on the tubing. In accordance with the invention, a flow control device may be positioned on or in any or all of the conduits in order to facilitate a desired function, i.e., establishing a desired flow path for biological fluid or gas. It is intended that the present invention should not be limited by the number, placement, or use of such flow control devices.
The porous media for removing leukocytes from a biological fluid may be any media which effectively removes leukocytes without having a deleterious effect on the biological fluid passing therethrough. In a preferred embodiment of the invention, a porous medium for use with a biological fluid such as a non-red cell containing layer (e.g., PRP) may comprise a medium disclosed in U.S. Patent 4,880,548. In a preferred embodiment of the invention, a porous medium for use with a biological fluid such as a red cell containing layer (e.g., PRC), may comprise the type of media disclosed in U.S. Patent 4,925,572 and U.S. Patent ; 4,923,620.

RED CELL BARRIER MEDIUM
A red cell barrier medium, in accordance with the present invention, are typically interposed between the blood collection bag and the PRP bag, and may comprise a porous medium that separates a non-red cell containing biological fluid, such as a suspension of platelets and plasma, from a red cell containing biological fluid. The red cell barrier medium may allow the non-red cell containing fluid to pass therethrough but stops the flow of the red cell ~ :. . : .
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~83~3 containing fluid without allowing red cells to pass through the porous medium. ~ypically, the red cell barrier medium allows a platelet-containing fluid to pass therethrough, abruptly stopping flow when red blood cells block or contact the medium. ~xemplary red cell barrier media are disclosed in U.S. Patent 5,100,564; U.S. Serial No. 07/609,574 (now allowed);
and International Publication No. wo 91/04088.
In a secondary aspect of the invention, the porous lo medium may slow the flow of the non-red cell containing fluid, which allows the operator to manually stop the flow prior to red cells passing through the porous , medium. This embodiment of the invention allows the operator more time to intervene and stop the flow. For example, a supernatant platelet-containing fluid may flow through the red cell barrier medium at an initial rate of about 15 ml/min, but the flow may decrease to about 5 ml/min as a sediment red cell containing fluid approaches the medium. The reduction in flow, e.g., a 33% reduction, may provide the operator sufficient time to stop the flow at the appropriate time. In some circumstances, for example, when platelet-containing fluid is expressed from a plurality of separate bags at approximately the same time, this reduction in flow allows the operator to process a greater number of containers more efficiently.
A principal function of the red cell barrier medium is to separate a red cell containing fraction of a biological fluid from a non-red cell containing fraction. The red cell barrier medium may act as an automatic "valve" by stopping the flow of a red cell-containing biological fluid without allowing red cells to pass through the porous medium. The automatic valve : - . .

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2~3~3 function may quickly or instantly stop the flow of the red cell-containing biological fluid, thereby obviating the need for the operator to monitor this step.
The valve-like action is not well understood, but it is believed that flow is quickly or instantly stopped or inhibited due to aggregation in or on the medium of one or more constituents in the biological fluid. For example, at the present time, it is believed that as the non-red cell containing biological fluid passes through the medium, leukocytes are depleted from this fluid. These leukocytes appear to accumulate in or on the medium, but the remainder of the non-red cell containing fluid typically flows through the medium. However, once red cells directly or indirectly contact the medium, i.e., directly contact the medium or contact the leukocytes which, in turn, may directly contact the medium, flow through the medium ceases. Without intending to be limited to any particular explanation for the mechanism of this valve-like action, it is presently believed that the stoppageof flow may reflect aggregation of the red cells alone and/or in combination with leukocytes, forming a barrier which prevents or blocks further flow through the porous medium. It may be that other factors, such as the zeta potential, the CWST, and/or other characteristics of the fibers or the porous medium may contribute to the valve-like action.
This theory for the proposed mechanism is supported by the existence of filters capable of highly efficient leukocyte depletion of human red cell suspensions and which have pore sizes as small as 0.5 microme~ers, through which red cells pass freely and completely with no clogging, with applied pressures of .

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the same magnitude as that used in the present invention. On the other hand, the filters of the present invention, which typically have pore diameters larger than about 0.5 micrometers, abruptly stop the flow of red cells when the porous medium is contacted or penetrated by the red cells.
In one embodiment of the invention, the leukocyte depletion efficiency of the red cell barrier medium is increased, and so the red cell barrier medium may also function as a leukocyte depletion medium.

In another exemplary configuration, the biological fluid processing assembly may include a separation assembly 81, preferably a non-centrifugal separation assembly, as shown in Figure 3.
This embodiment of the present invention involves the separation of one or more components from a biological fluid without subjecting the biological fluid to centrifugation. In accordance with the present invention, a biological fluid, particularly PRP, may be exposed to a separation medium suitable for passing at least one component of the biological fluid, particularly plasma, therethrough, but not other components of the biological fluid, particularly platelets and/or red cells. Clogging of the separation medium by these other components is minimized or prevented.
In the embodiment of the invention which includes a separation assembly, the supernatant layer (e.g., PRP) may be passed through a leukocyte depletion assembly, and then passed through a non-centrifugal separation device where it may be processed and . .
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separated into components, which may be separately collected in container 15 and container 16. In a preferred embodiment, if the supernatant fluid is PRP, it may be separated into plasma and platelet concentrate as the PRP passes through the non-centrifugal separation device. The sizes, nature, and configuration of the present inventive device can be adjusted to vary the capacity of the device to suit its intended environment, may be suitable for recirculating biological fluid through the separation medium, and multiple separation medium assemblies may be used.
Exemplary separation media are disclosed in International Publication Number W0 92/07656.

GAS INLFT/OUTLET
In accordance with the invention, it may be desirable to remove gas, such as air, from the system or to separate or move gas from one part of the system to another part. In accordance with the invention, it may be desirable that gas in the system be separated from the biological fluid to be processed. For example, gas ahead of a column of biological fluid may clog or impair the function of a leukocyte depletion filter used to treat the biological fluid. Also, gas in a receiving container may affect the processed biological fluid stored in that container.
In accordance with the present invention, any arrangement or method which effects removal or displacement of gas in the system may be used. For example, the system may include, but is not limited to, one or more gas inlets, one or more gas outlets, one or more gas collection and displacement loops, one or more gas displacement containers, one or more bypass I

r ~ ;3 conduits, one or more conduits which extend into the biological fluid in the container, or combinations of any of these.
In an exemplary configuration, the invention may comprise at least one gas inlet and/or at least one gas outlet. Under certain circumstances, it may be desirable to maximize the recovery of a biological f~uid retained or entrapped in various elements of the biological fluid processing system. For example, under typical conditions, using a typical device, the biological fluid will drain through the system until the flow is stopped, leaving some of the fluid in the system. In one embodiment of the invention, the retained fluid may be recovered by using at least one gas inlet and/or at least one gas outlet. In a preferred embodiment of the invention, either or both of the gas inlet and~the gas outlet may be selectively operable between an open and closed position.
In accordance with the invention, the processing system may be provided with a gas inlet to permit the introduction of gas into the system, and/or with a gas outlet to permit gases in the various elements of the system to be separated from the biological fluid to be processed. The gas inlet and the gas outlet may be used together in connection with at least one assembly, porous medium, or container in the system, or they may be used separately.
An exemplary gas inlet and gas outlet may be described by reference to Figures 3 and 4, both of which illustrate optional disposable flow paths which may be added to a biological fluid processing assembly 10. When such a flow path is inserted into an assembly, it may be desirable to remove gas from the :. . . : , 2 ~ 3 flow path. In Figure 3, this may be accomplished by activating or opening gas outlet 73. In Figure 4, gas outlet 75 may be opened or activated to remove air from the flow path, and gas inlet 74 may be opened or activated to allow additional recovery of fluid from the filter assembly 17. In a preferred embodiment, both gas outlet 73 and gas outlet 75 are automatic outlets, i.e., contact with fluid closes the outlet automatically. Other exemplary gas inlets and gas outlets are also disclosed in International Publication No. WO 91/17809.
As used herein, gas refers to any gaseous fluid, such as air, sterilized air, oxygen, carbon dioxide, and the like; it is intended that the invention is not to be limited to the type of gas used.
The gas inlet and gas outlet are chosen so that the sterility of the system is not compromised. The gas inlet and the gas outlet are particularly suited for use in closed systems~ or may be used later, for example, within about 24 hours of a system being opened.
The gas inlet and the gas outlet each comprise at least one porous medium designed to allow gas to pass therethrough. A variety of materials may be used, provided the requisite properties of the particular porous medium are achieved. These include the necessary strength to handle the differential pressures encountered in use and the ability to provide the desired permeability without the application of excessive pressure. In a sterile system, the porous medium should also preferably have a pore rating of about 0.2 micrometer or less to preclude bacteria passage.

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6~ 3 To that end, a gas inlet or gas outlet may be included in any of the various elements of the biological fluid processing system. By way of illustration, a gas inlet or gas outlet may be included in at least one of the conduits which connect the different containers, in a wall of the containers that receive the processed biological fluid, or in a port on or in one of those containers. The qas inlet or gas outlet may also be included on or in a combination of the elements mentioned above. Also, an assembly or porous medium may include one or more gas inlets or gas outlets. Generally, however, it is preferred to include a gas inlet or gas outlet in the conduits which connect the containers or in a filter assembly.
Included within the scope of the invention is the use of more than one gas inlet or gas outlet in any conduit, receiving container, assembly, or porous medium.
It will be apparent to one skilled in the art that the placement of a gas inlet or a gas outlet may be optimized to achieve a desired result. For example, it may be desirable to locate the gas inlet upstream of a porous medium and in or as close to the first container as is practical in order to maximize the recovery of biological fluid. Also, it may be desirable to locate the gas outlet downstream of the porous medium and as close to the receiving container as is possible in order to maximize the volume of gas that is removed from the system.
In an embodiment of the invention, air or gas may be stored in at least one gas container; upon opening of valve or clamp means in the conduits, gas can be fed through them to purge the conduits and assemblies, .

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2~3~3 thereby facilitating the recovery of biological fluid that may have been trapped during processing.
Preferably, the purge air or gas is fed to the conduits at a point as close as is reasonably possib~e to a source container to maximize the volume of biological fluid recovered. The air or gas container is preferably flexible so that the gas therein may be fed to the system merely by simple compression. Blood product that has become entrapped in these elements during processing may be recovered either by passing purge gas through the conduits and biomedical devices or by drawing at least a partial vacuum on the system so as to draw out the entrapped liquid and to permit it to drain into the appropriate receiving container. The purge gas may be provided from any of a number of sources. For example, the blood processing system may be provided with a storage container for the storage of the purge gas, the purge gas may be the gas that is removed from the system during the blood processing function, or the purge may be injected aseptically into the system from an outside source (e.g., through a syringe). For example, it may be desirable to use sterile purge gas that has been sterilized in a separate container apart from the blood processing system.
In accordance with the invention, recovery from the various elements of the biological fluid processing system may be maximized. For example, whole blood is subjected to a processing step, resulting in separate PRP and PRC layers. Then, the separate fractions of blood components are expressed to their respective receiving containers through the appropriate conduits and porous media, if any. Blood product that has .

~, ' - . ' ': :, ' æ ~ 3 become entrapped in these elements during processing may be recovered either by passing purge gas through the conduits and porous media, or by creating at least a partial vacuum in the system to draw out the retained blood product and to permit it to drain into the appropriate receiving container or assembly.
The purge gas may be from any of a number of sources. For example, the biological fluid processing system may be provided with a storage container for the storage of the purge gas, the purge gas may be the gas that was removed from the system during the processing function, or the purge gas may be injected aseptically into the system from an outside source (e.g., through a syringe). For example, it may be desirable to use sterile purge gas that has been sterilized in a separate container apart from the biological fluid processing system.
The gases separated by the gas outlet may be vented from the system, or they may be collected in a gas container (not shown) and returned to the system as a purge gas to facilitate the recovery of biological fluid that becomes trapped in the various components of the system.
In the present invention, means and methods are provided to displace air, oxygen, and other gases from the system in order to minimize the volume of gases that remain in, or in contact with, a blood product during storage. Means and methods are also provided for the recovery of valuable biological fluids that may become entrapped in the various elements of the system during blood processing and which would otherwise be lost.
In accordance with an embodiment of the present :` :

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C~3~3 invention, an air collection and displacement loop is in fluid com~unication with a selected conduit of the system 10. For example, one end of the loop may be in fluid communication with conduit 25 and the other end of the loop may be in fluid communication with conduit 26.
In accordance with the invention, the gas collection and displacement loop provides a flow path for separating gas from the biological fluid flow path, and, optionally, using that collected gas to recover additional biological fluid. The loop may also include a container interposed in the loop for collecting and storing the displaced gas, and for collecting and isolating contaminated (leukocyte-containing) biological fluid from non-contaminated biological fluid. In a more preferred embodiment, third container may be a flexible bag which can be squeezed in order to transfer gas. Included within the scope of the present invention are other structures which function as described above, such as a syringe, or the like, which could draw gas from the processing assembly into the loop, and could transfer the collected gas in the syringe into another container and/or conduit. It is intended that the gas collection and displacement loop functions so that leukocyte-laden fluid is barred from contacting leukocyte depleted fluid.

MISCELLANEOUS
A number of additional containers may be in communication with the biological fluid processing .
system, and can be utilized to define different flow paths. For example, an additional satellite bag containing physiological solution may be placed in ~ ' . .

2J~83~3 communication with the biological fluid processing system upstream of the leukocyte depletion assembly (e.g., through the gas inlet), and the solution may be passed through the leukocyte depletion assembly so that the biological fluid that was held up in the assembly can be collected.
Similarly, a satellite bag containing physiological solution may be placed in communication with the biological fluid processing system downstream of the leukocyte depletion assembly (e.g., through the gas outlet), and the solution may be passed through the leukocyte depletion assembly so that the biological fluid that was held up in the assembly can be later collected. It will be appreciated that when the biological fluid from the collection bag 11 is expressed toward one or more satellite bags, some of the biological fluid may be trapped in the conduits and/or a porous medium.

AUTOMATED CONTROL ARRANGEMENT
In accordance with the invention, an automated control arrangement, in response to predetermined conditions, sends and receives signals, and controls the overall sequence and flow of biological fluid from the collection container 11 to any of the receiving containers. For example, the automated control arrangement may include one or more devices, switches, and/or indicators or monitors to achieve a desired purposej including, but not limited to: a power ; switch; a start switch; a stop switch; a sequence selection switch; weight sensor devices, switches, and/or indicators; time sensor devices, switches, and/or indicators; optical sensor devices, switches, ., : ~ , . . - , . ' ,.

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and/or indicators; and fluid flow sensor devices, switches, and/or indicators; and at least one interface monitor for sensing the point of separation between the first portion of the biological fluid and a second portion. As used herein, monitoring the interface includes a monitor associated with a red cell barrier medium, for monitoring the flow rate of the first portion or the back pressure upstream of the red cell barrier medium; an optical se~sing device, for monitoring the transition between the first and second portions of the biological fluid; a weight sensing device or a total flow monitor, for sensing a predetermined weight or amount of biological fluid which defines the separation point between the first and second portions of the biological fluid; and any other mechanism for sensing the separation of one portion of the biological fluid from another portion.
It is intended that each of these sensors monitor a predetermined condition, and react or provide feedback according to a predetermined or pre-set array of variables. For example, as flow through the red cell barrier medium stops, a flow sensor may trigger a predetermined command in the au`omated control arrangement which stops sequence 1 and initiates sequence 2.
The automated control arrangement 50 may be co~mected to the various elements of the system, and .
may include one or more connections to a container, to a conduit, to a specific element in the biological fluid processing assembly or the pressure differential generator, to a valve, or the like.
The operation of an automated biological fluid processing system in accordance with the invention may ~ (~ g ~ 3 be illustrated by reference to the flow charts shown in Figures 5-7.
In step 1 (hereinafter, Sl, S2, S3, etc.~, the initial sequence is started. The initial sequence may include collecting the biological fluid directly into the collection bag 11, selecting the first sequence selection, placing the collection container 11 in differential pressure generator 51, and connecting the collection container to any satellite containers, if necessary. In a preferred embodiment of the invention, the collection container 11 contains a biological fluid, typically whole blood, which has been separated into a supernatant layer 31 and a sediment layer 32~
If whole blood is used, the supernatant layer may be primarily PRP, and the sediment layer may be primarily PRC. In an embodiment of the invention, the biolo~ical fluid can be separated under conditions in which a transition layer (typically buffy coat) spans the interface between the supernatant layer and the sediment layer. In another embodiment of the invention, the supernatant layer may be primarily PPP.
The biological fluid may be expressed from the collection bag as separate supernatant and sediment layers, respectively.
In S2, valves 61 and 62 are closed. In S3, a differential pressure may be generated between collection container 11 and satellite bag 41.
; In S4, valve or clamp 61 is opened, and the pressure differential between the collection container and first satellite bag 41 causes the supernatant layer to flow in the direction of satellite bag 41. As the supernatant layer passes from the collection bag to the ~;~ first satellite bag, it may pass through at least one ':

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21~3~3 porous medium, preferably a leukocyte-depletion medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medi~m.
In S5, the flow rate of the supernatant is 5 monitored. If the flow rate is too high or too low, a signal may be generated whereby the differential pressure is decreased or increased.
In S6 and S7, the flow is ~onitored until a predetermined value is reached, at which point, a 10 signal is produced to indicate that flow should cease.
In accordance with the invention, the nature of the signal will depend upon the type of monitor used to distinguish one layer of biological fluid from another.
For example, in a preferred embodiment of the 15 invention, a red cell barrier porous medium is used, and the monitor produces a signal when the flow rate nears or reaches zero. In an embodiment of the invention which includes a weighing device, the monitor may produce a signal when a predetermined amount of 20 supernatant has passed into the satellite bag. In an embodiment of the invention which includes a optical reader, the monitor may produce a signal when the fluid passing the optical reader reaches a predetermined density. It is intended that the invention should not 25 be limited by the type of flow detection and monitoring system employed. r In S8, the signal produced in S6 and S7 closes valve or clamp 61. In S9, the process may be stopped completely, or one or more additional sequences may be 30 selected. If Sequence 2 is selected, the process, typically the processing of the sediment layer, is started in S10.
In accordance with the invention, it may be ,. . -: , .
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~83~3 desirable to remove gas or air from the system or to separate or move gas/air from one part of the system to another part. In accordance with the present invention, any arrangement or method which effects removal or displacement of gas/air in the system may be used. In an embodiment of the invention, the process may include Sll in which the collection container is inverted, either by rotating the collection bag within the pressure differential generator, or by rotating the pressure differential generator. Inversion of the bag and/or container may be a desirable process step to achieve a variety of results, including but not limited to mixing a biological fluid with an additive solution, diluent, or the like, to orient the bag in a desired position, or to invert a bag which contains air/gas.
At the completion of the inversion step, conduit 62 may be oriented in a desired position, typically approximately 180- from its position at the beginning of Sll.
In S12, a positive pressure is generated, valve 62 is opened (S13), and sediment layer 32 in collection bag 11 may be passed through a leukocyte depletion assembly 17 and into a container 18, such as a satellite bag. S14 and S15 may correspond to S5 and S6, respectively, to assure that the desired flow rate ; is maintained. When the flow rate reaches or nears zero (S16), preferably when substantially all of the sediment layer has been expressed from the collection bag, valve 62 is closed (S17), a stop switch may be activated (S18), and the pressure differential is preferably reduced to zero (Sl9).
As noted in S9 above, the supernatant layer may be subjected to additional processing, if desired, ~: ~

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~35~3 preferably downstream of the leukocyte depletion medium, either connected to the system or after being separated from the system.
As exemplified for Sequence 3, the sequence is started when a desired amount of the supernatant fluid has been collected in first satellite bag 41. This fluid may in turn be separated into a second supernatant layer, typically plasma, and a second sediMent layer, typically a platelet-rich suspension such as PC.
In S22, valves or clamps 63 and 64 are closed, and a positive pressure differential is generated between satellite bag 41 and satellite bag 42. Once a desired pressure is reached, valve 64 may be opened (S23), allowing the second supernatant layer to flow through conduit 28 into satellite bag 42.
In S24 and S25, flow continues until a predetermined value or condition is reached, e.g., a sufficient amount of second supernatant has passed into satellite bag 42. In accordance with the invention, the amount of supernatant passing into satellite bag 41 ; may be predetermined, e.g., based on weight or density, but it is intended that the invention should not be r limited thereby.
In S26, after the predetermined amount of second supernatant has been collected, valve 64 closes, a stop switch may be activated (S27), and the pressure differential may be reduced to zero (S28).
In accordance with an additional embodiment of the invention, a method is provided whereby the recovery of various biological fluids trapped or retained in various elements of the system is maximized, either by causing a volume of gas behind the trapped or retained , . .

2~3~'~3 biological fluid to push the fluid through those elements and into the designated container, assembly, or porous medium, or by drawing the trapped or retained fluid into the designated container, assembly, or porous medium by pressure differential (e.g., gravity head, pressure cuff, suction, and the like). This provides for a more complete emptying of the container, assembly, or porous medium. Once the container is emptied completely, the flow may be stopped automatically.
Figure 9 illustrates an exemplary flow chart for an embodiment of the invention as shown in Figure 2.
In this exemplary embodiment, collection container 11, which includes biological fluid which has been separated into a supernatant layer 31 and a sediment layer 32, may be positioned in a differential pressure generator 51. In this exemplary embodiment, it is preferred that the differential pressure generator 51 is a combined pressure or vacuum expressor. Collection container 11 may be in fluid communication with a first satellite bag 41 suitable for receiving the supernatant layer 31, a second satellite bag 18 suitable for receiving a sediment layer 32, and a fourth satellite bag 71 suitable for storing physiologically acceptable solution, such as a nutrient solution or a preservative solution. The fluid flow path between the collection container 11 and the first satellite bag 41 preferably includes a combined leukocyte depletion red cell barrier porous medium 12, and the fluid flow path between the collection container 11 and the second satellite bag 18 preferably includes a leukocyte depletion assembly 17.
The three satellite bags may be positioned in a :~.

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flow monitor 72 suitable for monitoring flow by weighing the amount of fluid in the respective satellite bags. Flow monitor 72 may be connected to control unit 51, preferably a microprocessor controller. Control unit 51 may be connected to the pressure differential qenerator 51 through pump 73 and valve 74, preferably.a two-way valve, suitable for inducing pressure or a vacuum on collection container 11. In a preferred embodiment, pump 73 can create positive pressure on collection bag 11 through line 75 and can create a vacuum in collection bag 11 through line 76.
The operation of an automated biological fluid processing system in accordance with an embodiment of lS the invention illustrated in Figure 2 may be described by reference to the flow chart shown in Figure 9. As this se~uence is initiated, the flow paths leading from the collection bag 11 to all of the satellite bags are closed (S41). In S42, Sl through S8 in Figure 5 may be . 20 conducted, whereby a differential pressure between collection bag 11 and satellite bag 41 is established and the supernatant layer is expressed into satellite bag 41. Valve 61 may then be closed (S8) and valve 65 opened (S43).
~ 25 In S44, steps S31 through S34 are conducted, .~ whereby an anti-coagulant solution or the like in : fourth satellite bag 71 is passed from fourth satellite bag 71 into collection container 11. After valve 65 is closed (S45), sediment layer 32 may then be expressed into third satellite bag 18 (S46).
Figure 10 includes an exemplary flow chart for an embodiment of the invention which includes separating gas in the system from the biological fluid to be .. .
~''`' "' 2~3~3 processed. In a preferred embodiment, gas in the system may be displaced to a part of the system separate from the biological fluid; in a more preferred embodiment, gas in the system may be expelled from the system.
In an exemplary embodiment, in which a gas outlet and additive/priming fluid is used to prime a leukocyte depletion filter, a gas outlet 71 and a gas inlet 72 may be positioned as shown in Figure 1 and container 18 includes an additive/priming solution. In S50, clamp 62 is closed. In S51, gas outlet 71 is activated or opened, and a differential pressure is generated between container 18 and container 11 so that a column of additive solution flows through conduit 26, through filter 17, and into conduit 25. As the liquid advances, it pushes gas in the conduit ahead of it until the gas reaches gas outlet 71. Gas ahead of the column of additive solution passes through the outlet and out of the system.
In S52, before the fluid reaches a predetermined position upstream of the gas outlet, the column of additive solution triggers a monitor which closes a valve in the fluid flow path leading to the gas outlet, if the gas outlet is a non-automatic gas outlet.
Optionally, if the gas outlet is an automatic outlet, no monitor is required, or a monitor may signal the location of the additive solution. In S53, clamp 62 opens, and additive solution flows into container 11.
In S54, the flow of additive/priming solution is stopped or completed. The flow path between container 11 and contaîner 18 is now prepared for use in accordance with the invention, for example, by the initiation of Sequence 3.

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2~83~3 In order to recover the very valuable blood product retained in the system, ambient air or a sterile gas may enter the system through gas inlet 72.
If gas inlet 72 is a manual inlet, a closure is opened or a clamp released; if the gas inlet 72 is automatic, the pressure differential between the gas inlet and satellite bag 18 will cause the air or gas to flow through conduit 25, through filter 17, and toward satellite bag 18. In the process, retained blood or blood product that is trapped in those elements during processing are recovered from those components and collected in satellite bag 18.
In another embodiment of the invention, a gas displacement conduit may be provided, preferably in sealed communication with container 11 through valve or clamp means. In a preferred embodiment, the gas displacement conduit includes a gas reservoir, preferably a flexible gas reservoir.

While the invention has been described in some detail by way of illustration and example, it should be understood that the invention is susceptible to various modifications and alternative forms, and is not restricted to the specific embodiments set forth in the `~ 25 Examples. It should be understood that these specific embodiments are not intended to limit the invention but, on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

.

,

Claims (29)

1. An automated biological fluid processing system comprising:
a pressure differential generator;
a biological fluid processing assembly including:
a first container operatively associated with the pressure differential generator, a second container in fluid communication with the first container, and a porous medium interposed between the collection container and the second container; and an automated control arrangement coupled to at least one of the pressure differential generator and the biological fluid processing assembly to control flow between the first container and the second container.

2. The automated biological fluid processing assembly of claim 1 wherein the porous medium comprises at least one of a leukocyte depletion medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium.

3. The automated biological fluid processing assembly of claim 1 wherein the biological fluid processing assembly further comprises a third container in fluid communication with the first container.

4. The automated biological fluid processing assembly of claim 3 wherein a leukocyte depletion filter is interposed between the first container and the third container.

5. The automated biological fluid processing assembly of claim 3 wherein the automated control arrangement controls flow between the first container and the third container.

6. An automated biological fluid processing assembly comprising:
a pressure differential generator;
a first container suitable for containing a biological fluid, operatively associated with the pressure differential generator and with at least one second container and with at least one third container;
a porous medium interposed between the first container and the second container;
a valve arrangement for directing the flow of biological fluid from the first container;
at least one separation monitor for monitoring the interface between a first portion of the biological fluid and a second portion of the biological fluid;
a control unit coupled to the valve arrangement and to the separation monitor to control flow between the containers.

7. The automated biological fluid processing assembly of claim 6 further comprising a leukocyte depletion filter interposed between the first container and the third container.

8. The automated biological fluid processing assembly of claim 6 wherein the porous medium interposed between the first container and the second container is at least one of a leukocyte depletion medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium.

9. The automated biological fluid processing assembly of claim 1 further comprising at least one flow path downstream of the first container for separating gas from the biological fluid.

10. The automated biological fluid processing assembly of claim 9 wherein the flow path includes at least one of a gas inlet, a gas outlet, and a gas displacement loop.

11. A method for automatically processing a biological fluid comprising:
a) placing a container of biological fluid into an enclosed chamber of a differential pressure generator;
b) supplying a signal from an automated control arrangement to the differential pressure generator; and c) in response to the signal, varying pressure within the chamber to establish fluid flow into or out of the container.

12. The method of claim 11 further comprising passing a portion of the biological fluid through at least one of a leukocyte depletion porous medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium.

13. The method of claim 12 further comprising separating gas from the biological fluid.

14. The method of claim 12 wherein the biological fluid includes first and second portions and further comprising monitoring the interface between the first portion of the biological fluid and a second portion.

15. A method for automatically processing a biological fluid comprising:
a) establishing flow of a first portion of a biological fluid along a first fluid flow path to at least one of a leukocyte depletion porous medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium;
b) generating a signal indicative of the separation of the first portion of the biological fluid and a second portion, and supplying the signal to an automated control arrangement; and c) in response to the signal, terminating flow through the first fluid flow path.

16. The method of claim 15 wherein generating the signal indicative of the separation of the first portion of the biological fluid and the second portion includes generating a signal indicative of at least one of a predetermined position of the second portion, a predetermined back pressure in the first fluid flow path, and a predetermined flow rate through the first fluid flow path.

17. The method of claim 15 further comprising establishing flow of a second portion of the biological fluid through a second fluid flow path to a leukocyte depletion porous medium.

18. The method of claim 17 wherein flow of the second portion of the biological fluid through a second fluid flow path is established in response to the signal indicative of the separation of the first portion of the biological fluid and a second portion.

19. The method of claim 15 further comprising:
a) in response to a signal from the automated control arrangement, establishing flow of a physiologically acceptable fluid through a second fluid flow path;
b) generating a termination signal for terminating the flow of the physiologically acceptable fluid, and supplying the termination signal to the automated control arrangement; and c) establishing flow of a second portion of the biological fluid though the second fluid flow path in response to the termination signal.

20. The method of claim 19 wherein establishing flow of a physiologically acceptable fluid through a second fluid flow path includes passing the physiologically acceptable fluid through at least one of a leukocyte depletion porous medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium.

21. The method of claim 19 further comprising separating gas from the second fluid flow path.

22. A method for processing a biological fluid comprising separating a biological fluid into a supernatant portion and a sediment portion; and passing at least one of the supernatant portion and the sediment portion through at least one porous medium, wherein said passing includes initiating, monitoring, and terminating flow of the portions by an automated control arrangement.

23. An automated biological fluid processing system comprising:
a pressure differential generator;
a biological fluid processing assembly including:
a first container operatively associated with the pressure differential generator, a second container in fluid communication with the first container and suitable for containing a priming/additive solution and a biological fluid, and a porous medium interposed between the collection container and the second container; and an automated control arrangement coupled to at least one of the pressure differential generator and the biological fluid processing assembly to control flow between the first container and the second container.

24. The automated biological fluid processing system of claim 1 wherein the pressure differential generator is a mechanical member bearing directly against the first container.

25. The automated biological fluid processing system of claim 1 wherein the pressure differential generator includes an enclosed housing in fluid communication with a pressure regulating mechanism suitable for controlling the fluid pressure applied to the outside of a container positioned in the housing.

26. The automated biological fluid processing system of claim 1 further comprising at least one separation monitor for monitoring the interface between a first portion of the biological fluid and a second portion of the biological fluid.

27. The automated biological fluid processing assembly of claim 1 further comprising a third container in fluid communication with the second container.

28. The method of claim 15 further comprising establishing flow of the first portion of a biological fluid along a second fluid flow path from the leukocyte depletion porous medium, a red cell barrier medium, or a combined leukocyte depletion red cell barrier medium;
b) generating a signal indicative of the termination of flow through the second fluid flow path, and supplying the signal to an automated control arrangement; and c) in response to the signal, terminating flow through the second fluid flow path.

29. An automated biological fluid processing system comprising:
a pressure differential generator;
a biological fluid processing assembly including:
a first container operatively associated with the pressure differential generator, a second container in fluid communication with the first container, a third container in fluid communication with the first container, a fourth container in fluid communication with the second container, and a fifth container in fluid communication with the fourth container, and at least one porous medium interposed between at least one of the collection container and the second container, the collection container and the third container, the second container and the fourth container, and the fourth container and the fifth container; and an automated control arrangement coupled to at least one of the pressure differential generator and the biological fluid processing assembly to control flow between the containers.