Abstract:
An apparatus is provided for intended use in pumping a fluid under sterile conditions. In one embodiment, a first rigid container is internally pressurized to pump fluid through a first flexible vessel within the rigid container. In another embodiment, first and second containers are provided, each for receiving flexible vessels that create independent pumping chambers upon the selective or periodic internal pressurization of the containers. Related aspects and methods are also provided.

Description:
[0001]     This application claims the benefit of U.S. Provisional Patent App. Ser. No. 60/777,376, filed Feb. 28, 2006, the disclosure of which is incorporated herein by reference. 
     
    
     TECHNICAL FIELD  
       [0002]     The present invention relates generally to fluid pumping and, more particularly, to a disposable pumping apparatus.  
       BACKGROUND OF THE INVENTION  
       [0003]     A number of applications in the bioprocessing industry exist where process fluids must be pumped from one location or vessel to another in a sterile, non-invasive and measured fashion. Such pumping must occur in multiple upstream and downstream applications. Typical upstream pumping applications include: buffer preparation, media preparation, bioreactor media feed and supplement addition. Typical downstream applications include pumping the cell suspensions, protein solutions or buffers to or through purification devises such as centrifuges, filters, membranes, chromatography columns or formulation and fill vessels.  
         [0004]     It is advantageous to use disposable pumps in the above pumping applications in an effort to eliminate cross contamination risks between the batches, as well as to reduce cleaning and validation downtime and overall manufacturing cost for biopharmaceuticals. One popular disposable pumping technology in the bioprocess industry is a peristaltic pump. In one form, such as is shown in U.S. Pat. No. 3,737,251 (the disclosure of which is incorporated herein by reference to the extent not inconsistent with the present teachings), such a pump uses a flexible tube as a pumping chamber, as well as the pumping line to move the fluid from one location to another. Compressing the tube with a driving head produces the desired pumping action.  
         [0005]     Despite the number of advantages of the peristaltic pump which include simplicity, low cost and sterility, limitations restrict the usage of such a pump in a number of important bioprocessing steps. These include relatively low pressure, low flow rate and pulsations of the transported liquid. For these reasons, such pumps are rarely used in applications such as cross flow filtration or chromatography columns.  
         [0006]     Accordingly, a need is identified for a pumping apparatus that addresses and overcomes the foregoing limitations, while still being disposable and usable under sterile conditions.  
       SUMMARY OF THE INVENTION  
       [0007]     In accordance with a first aspect of the invention, an apparatus for intended use in pumping a fluid under sterile conditions is disclosed. The apparatus comprises a first rigid container having an interior capable of being pressurized (either positively or negatively). A first flexible vessel is positioned at least partially within the interior of the first rigid container, and includes an outlet for discharging the fluid. At least one pressure source, such as a gas cylinder, compressor, or even a vacuum pump, is provided for pressurizing the interior of the rigid container to cause the fluid to move through the outlet of the flexible vessel.  
         [0008]     In one embodiment, the apparatus further includes a feed vessel connected to an inlet of the first flexible vessel, as well as a pump for delivering the fluid from the feed vessel to an inlet of the first flexible vessel. A filter may also be provided for receiving fluid from the outlet of the first flexible vessel, along with a return line for delivering fluid from the filter to the feed vessel. Preferably, the pressure created in the interior of the first rigid container comprises hydrostatic pressure to create a substantially constant flow of fluid through the outlet of the first flexible vessel.  
         [0009]     In this or another embodiment, the apparatus may further comprise a second container having an interior capable of being pressurized by the pressure source, as well as a second flexible vessel for positioning at least partially within the second container. The second flexible vessel further includes an outlet for discharging the fluid to a line in common with the outlet of the first flexible vessel. Preferably, the pressure source alternately pressurizes the first and second containers, such as through the use of valves.  
         [0010]     In accordance with another aspect of the invention, an apparatus for intended use in pumping a fluid is provided. The apparatus comprises at least two containers, each having an interior capable being pressurized. A flexible vessel is positioned at least partially within the interior of each container and is capable of receiving and holding the fluid. Each flexible vessel further includes an outlet. At least one pressure source is provided for selectively pressurizing the interiors of the containers to cause the fluid to move through the outlets of the corresponding flexible vessels.  
         [0011]     Preferably, the pressure source alternatively pressurizes the containers. The apparatus may further include a common line connected to the outlets of the flexible vessels, or a feed vessel for feeding fluid to the inlets of the flexible vessels. In the latter case, a filter may receive fluid from the outlet of one or both of the flexible vessels, and a return line may be provided for returning fluid from the filter to the feed vessel. Alternatively, a chromatography column may be provided for receiving fluid from the outlets of the flexible vessels.  
         [0012]     In accordance with still another aspect of the invention, a method of pumping a fluid is disclosed. The method comprises providing the fluid in a first flexible vessel positioned at least partially within a first rigid container, and pressurizing an interior of the first rigid container to pump the fluid from the first flexible vessel. The method may further include the steps of at least partially relieving the pressure in the first rigid container, allowing fluid to enter the first flexible vessel through an inlet, and then pressurizing the interior of the first rigid container. Alternatively or additionally, the method may further include the steps of delivering the fluid to a second flexible vessel positioned at least partially within a second rigid container, and pressurizing an interior of the second rigid container to pump the fluid from the second flexible vessel.  
         [0013]     In accordance with yet a further aspect of the invention, a method of pumping a fluid is disclosed. The method comprises delivering the fluid to a first flexible vessel positioned at least partially within an interior of a first rigid container; pressurizing the interior of the first rigid container to move fluid through an outlet of the first flexible vessel; delivering the fluid to a second flexible vessel positioned at least partially within an interior of a second rigid container; and pressurizing the interior of the second rigid container to move fluid through an outlet of the second flexible vessel.  
         [0014]     Preferably, the step of delivering the fluid to the second flexible vessel is concurrent with the step of pressurizing the first rigid container. The delivering step may comprise delivering step comprises delivering fluid from a common feed vessel. The method may further include the step of delivering the fluid from the outlet of the first or second flexible vessel to a filter, and then delivering the fluid to a vessel for feeding either the first or second flexible vessel. Preferably, the pressurizing steps are performed to create a substantially constant flow of fluid along a common line associated with the outlets of the flexible vessels. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0015]      FIG. 1  is a schematic diagram of one pumping apparatus forming one aspect of the invention;  
         [0016]      FIG. 2  is a schematic diagram of a pumping apparatus forming another aspect of the invention;  
         [0017]      FIGS. 3a and 3b  are graphical illustrations of the flow rate versus time created from the use of a pumping apparatus of  FIG. 1  or  2 ;  
         [0018]      FIGS. 4, 5 , and  6  schematically illustrate various configurations usable with the disclosed pumping apparatus. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0019]     In accordance with one aspect of the invention, the general nature of the proposed pumping apparatus comprises a container capable of being pressurized, such as for example with a periodically oscillating internal pressure. The pressure is of a hydrostatic nature and maybe created by introducing gas or fluid media to the interior of the pressure container. A hermetically closed or scaled collapsible container, such as a flexible bag, is placed at least partially and preferably entirely inside the pressure container. When used in connection with pumping sterile fluids or fluids under sterile conditions, the outer surface of the flexible vessel is in contact with pressure transferring media and need not be sterile, but the inner surface of the flexible vessel may be in contact with the pumped sterile fluid so it must also be sterile.  
         [0020]     When the pressure container is periodically or selectively pressurized, the flexible vessel then works as a fluid pumping chamber The flexible vessel and the chamber have an inlet port and a discharge port. The pumped fluid is introduced into the flexible vessel by an inlet port connected to an inlet line (such as flexible tubing) via an inlet valve. The pumped fluid discharges from the flexible vessel via the discharge port connected to a discharge line by a discharge valve. These lines may penetrate into the pressure container, which may be hermetically sealed from the outside environment in the entire range of the pressure developed inside the container.  
         [0021]     To illustrate and describe a more specific and preferred implementation, and with reference to  FIG. 1 , one embodiment of the pumping apparatus  10  includes two flexible vessels  11 ,  12 , such as disposable plastic bags, that create pumping chambers. These flexible vessels  11 ,  12  are preferably hermetically sealed and at least partially (and most preferably) fully contained within separate rigid pressure containers  13 ,  14  capable of being pressurized (positively or negatively).  
         [0022]     Both pressure containers  13 ,  14  are preferably connected with an external pressure source P for delivering a media under pressure by lines with valves  21 ,  22 . The pressure source P can be a compressed gas cylinder, a gas compressor, a hydraulic press, or the like. The media producing hydrostatic pressure to the bag chambers is preferably air, but can be any suitable gas or liquid capable of creating the desired hydrostatic pressure.  
         [0023]     Preferably, valves  15 ,  16  open and close the outlets of the flexible vessels  11 ,  12 , while valves  17 ,  18  open and close the associated inlets. Vent valves  19 ,  20  open or close the lines connecting the internal volume or space of the rigid pressure containers  13 ,  14  with the atmosphere. A feeding vessel V may contain the fluid to be pumped, and a low pressure pump  23  may be used to fill the pumping chambers  11 ,  12  with fluid prior to high pressure pumping action. In one of the possible embodiments, this pump  21  may comprise a peristaltic pump.  
         [0024]     Operation of the pumping apparatus  10  described above may proceed as outlined in the following description. During the initial cycle, the pumping chamber formed by one of the flexible vessels  11  is filled with a fluid, such as a liquid, preferably to capacity. Pumping chamber formed by the other flexible vessel  12  may be initially empty. Fluid valves  16  and  17  are closed while valves  15  and  18  are open. The vent valve  20  is open, while vent valve  19  is closed.  
         [0025]     Initially, pressure valve  22  is open while valve  21  is closed. Accordingly, pressure developed in pressure container  13  results in the discharge of the fluid from the vessel  11  through the outlet line. Since the pressure in the container  13  remains constant, the flow rate of the fluid pumped is also constant until all the fluid from the vessel  11  is pumped out and it collapses. During this cycle, the other pressure chamber within vessel  12  maybe filled to capacity with fluid by the pump  23 .  
         [0026]     Once pumping chamber  12  is filled to capacity with the fluid and pumping chamber of vessel  11  is empty, fluid valves  16  and  17  are opened while valves  15  and  18  are closed. Furthermore, vent valve  20  is closed while valve  19  is opened, and pressure valve  22  is closed while valve  21  is open. The pressure developed in the rigid container  14  results in discharge of the fluid from the pressure chamber of vessel  12  through the outlet line. During this cycle, pressure chamber of vessel  11  is filled to capacity with fluid, such as by the pump  23 .  
         [0027]     Turning now to  FIG. 2 , this alternative embodiment of the pumping apparatus  10  is similar in many respects to the embodiment in  FIG. 1 . However, the low pressure pump  23  on the  FIG. 1  is replaced with vacuum pump  24  that creates negative pressure in the pressure containers  13 ,  14  during the filling steps. The vacuum line from the pump  24  is connected to the pressure containers  13 ,  14  and controlled by valves  25  and  26 . During pressurization, negative pressure within the containers  13 ,  14  thus forces the fluid to exit through the corresponding outlet(s) of the flexible vessels  11 ,  12  (provided, of course, the associated valves  15 ,  16  are selectively opened).  
         [0028]     The sequence of pumping actions in an arrangement of two flexible vessels  11 ,  12  in rigid containers  13 ,  14  that are periodically pressurized, such as is described above, is shown in the  FIG. 3a .  FIG. 3b  shows the resultant flow rate in the discharge line D of the pumping apparatus  10  (see also  FIG. 1 ). The resultant flow rate is constant as long as the spikes resulting from switching from one pumping chamber to another can be minimized by proper synchronization of the valves.  
         [0029]     Turning to  FIG. 4 , an illustration is provided of a pre-sterilized (by means of gamma radiation or other methods) disposable flexible bag assembly  40  consisting of the feed bag serving as the vessel V containing the fluid to be pumped and two pumping vessels  11 ,  12 . The two pumping vessels  11 ,  12  forming the pressure chambers of this assembly  40  maybe introduced into the two rigid pressure containers  13 ,  14  of the pumping apparatus  10  shown on  FIG. 1  or  FIG. 2  to pump the fluid from the feed bag.  
         [0030]      FIG. 5  shows a pre-sterilized (by means of gamma radiation or other methods) disposable bag assembly  50  consisting of a bag as the feed vessel V with the fluid to be pumped, two flexible pumping vessels  11 ,  12  forming the pressure chambers and a filter F, such as for example a tangential flow filter. In this embodiment, a re-circulating, disposable filtration loop is described. The two pumping vessels  11 ,  12  of the assembly  50  maybe introduced into the pressure containers  13 ,  14  of the pumping apparatus  10  shown in  FIG. 1  or  FIG. 2  for re-circulation of the fluid from the feed bag serving as the feed vessel V, through the filter F, and back again.  
         [0031]     Illustrated in FIGS.  6  is a disposable bag assembly  60  connected to a chromatography column C. As in  FIG. 5 , the bag serving as the feed vessel V contains the fluid to be processed. Flexible vessels  11 ,  12  maybe introduced in the pumping apparatus  10  shown in  FIG. 1  or  FIG. 2  to activate the pumping of the fluid through the chromatography column C. In one embodiment, the chromatography column C can be re-usable. In another embodiment, the bag assembly  60  and the column C are single use components.  
         [0032]     In the embodiments of  FIGS. 1 and 2 , the pumping apparatus  10  is based on two chambers created by separate flexible vessels  11 ,  12 . However, pumping with a single vessel having chamber is also possible. With one chamber pumping, greater pulsation of the flow through the outlet will result due to the pressurization of the rigid container, but would be acceptable for certain applications. Pumping using three or more chambers is also possible and would have the same principle of operation based on disposable flexible pumping bags placed inside the periodically pressurized containers where pressurization cycles are synchronized with valve operations.  
         [0033]     The foregoing descriptions of various embodiments of the present inventions have been presented for purposes of illustration and description. These descriptions are not intended to be exhaustive or to limit the invention to the precise forms disclosed. All the pumping apparatuses described above may have single-use fluid path components and thus eliminate cleaning sterilization and validation procedures. The embodiments described provide the best illustration of the principles of the invention and its practical applications to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated.