Abstract:
A bioprocess container consists of a flexible container, placed inside a heat exchanger. By providing a disposable agitation device inside the sealed container, a filled container can be stirred without having to open the container. Possible agitation elements include traditional stirrers, rotating magnetic rods, bladder devices integral with the structure of the container, as well as different devices for manipulating the shape of the sealed container. Finally, a containment disk is used to ensure that the magnetic rod is maintained in the magnetic field.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    1. Field of the Invention  
           [0002]    The present invention relates to the field of mixing containers of fluids, most often at least one liquid. More specifically, the device and method of the invention concern disposable, sealed containers and various devices and processes for mixing the contents therein.  
           [0003]    2. Description of the Related Art  
           [0004]    The biopharmaceutical process industry has been moving toward technologies that use disposable manufacturing components versus stainless steel tanks and piping. One key component is bioprocessing containers (BPCs). Conventional manufacturing, mixing and/or stirring devices have been used in this type of industry for a considerable period of time. In one type of system, the various ingredients or components are introduced into a typical glass beaker.  
           [0005]    When a large scale production is required, the glass beaker may be replaced by a large metal vat or other conventional industrial vessel that also provides heating and cooling capacity. In either system, the components are sequentially or consecutively added to the vessel where the mixing and/or stirring is conducted. In such systems, a stirring device is generally inserted through the upper, open face of the container and powered from an external source. Additionally, reuse of the conventional system requires significant cleaning and sterilization processes to ensure the absence of undesirable materials.  
           [0006]    Improvements to the traditional beaker or industrial vat mixing systems include those described in U.S. Pat. Nos. 5,795,330, 5,941,635 6,076,457, and 6,190,913, each of which is herein incorporated by reference in its entirety.  
         SUMMARY OF THE INVENTION  
         [0007]    In order to overcome the problems associated with conventional BPC mixing devices, the present invention utilizes a new container-heat exchanger combination. Specifically, the BPC of the invention generally includes a flexible container, placed inside a rigid heat exchanger. In one embodiment, the flexible container is destroyed and replaced after use to eliminate the necessity of cleaning and sterilization. The shape of the heat exchanger is selected to correspond to the shape of the flexible container when the container is filled. Because the container is inserted into a cavity in the heat exchanger, by matching the shape of the heat exchanger (in particular, the cavity) to the shape of the container, the efficiency of the heating and/or cooling elements can be increased.  
           [0008]    The BPC of the invention is designed to be utilized with a mixing device. In a first embodiment, a shaft of conventional (optionally disposable) agitator passes through an opening in the container, with the stirring element disposed therein. A motor is provided at the other end of the shaft to rotate the stirring element.  
           [0009]    A second embodiment utilizes a magnetic agitator. A magnetic rod is placed inside the container and a magnetic field is generated by a magnetic drive device to rotate the rod. By locating a magnetic drive device external to the container, preferably outside the heat exchanger, the container need not have an opening and may be sealed, albeit with the rod and optional containment disk therein. The magnet rod may be disposed inside a containment disk.  
           [0010]    Alternatively, the container and/or heat exchanger may include mixing devices mounted thereto. In a third embodiment, the container has a series of discontinuous baffles, such that when the baffles are alternatively inflated and deflated, the contents of the container can be stirred. Similarly, the container may have a series of fluid-filled sleeves, such that the mixing is performed when the sleeves are squeezed. In a final embodiment, the container includes, on the outside thereof, a series of hinged plates, and the cavity of the heat exchanger includes corresponding mechanical plates. When the mechanical plates in the cavity apply pressure to the hinged plates on the outside of the container, the bag is compressed and the contents thereof mixed. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0011]    [0011]FIG. 1 is a partial is cut-away view of a first embodiment of the invention.  
         [0012]    [0012]FIG. 2 is a partial cut-away view of a second embodiment of the invention.  
         [0013]    [0013]FIG. 3 a  is an exploded view of a rod containment device of the invention.  
         [0014]    [0014]FIG. 3 b  is a side view of a containment disk of the invention.  
         [0015]    [0015]FIG. 4 is a partial cut-away view of a third embodiment of the invention.  
         [0016]    [0016]FIG. 5 a  is an isometric view of a fourth embodiment of the invention.  
         [0017]    [0017]FIG. 5 b  is an isometric view of a fifth embodiment of the invention.  
         [0018]    [0018]FIG. 5 c  is an isometric view of a sixth embodiment of the invention.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0019]    A bioprocess container (BPC) in accordance with the invention is shown in the various figures, each figure detailing an embodiment thereof. FIG. 1 shows a BPC  10 , comprising a flexible container  12  in conjunction with a rigid, jacket-type heat exchanger  14 . Specifically, heat exchanger  14  comprises a cavity  15 , defined by a bottom  16 , and side walls  18 . For simplicity, container  12  is shown as being seated in heat exchanger  14 , however, optionally, a small section may extend above side walls  18  heat exchanger  14 . Although container  12  and heat exchanger  14  are shown in the shape of cylinders, any three-dimensional shape may be used. Preferably, however, the shape of cavity  15  of heat exchanger  14  is selected as to correspond to the size and shape of container  12  when filled. When the sizes and shapes correspond, the exterior surfaces of container  12  contact the interior surface of cavity  15  to increase efficiency of heat transfer therebetween. In any event, although the shape of each of container  12  and cavity  15  may be any three dimensional shape, e.g., rectangular prism, cubic, substantially spherical, pyramidal, and conical, a cylindrical shape, having either squared or rounded-off comers, is preferred.  
         [0020]    Although the structure and size of container  12  is not particularly limited by the invention, preferably, container  12  is cylindrically shaped (approximately 36″ diameter by 30″ high) and made of polymeric materials, such as polyolefins, thermoplastic elastomers, polyamides, polyesters, polyimides, polysulphones, or barrier polymers (such as MX D  6  available from Mitsubishi Gas Chemical America, Inc. of N.Y., ethyl vinyl alcohol, polychlorotetrafluoroethylene, polyvinyl chloride). Most preferred however are polyolefins, thermoplastic elastomers and polyamides, alone or in combination. The polymeric materials may be processed in a multilayer laminate and/or film with a thickness from about 2 to about 12 mils, typically about 4 to about 8, and preferably from about 6 to about 8 mils.  
         [0021]    Preferably, side walls  18  of heat exchanger  14  contain liquid-transfer media in spirally arranged tubes. Thus, when heating of the contents of container  12  is desired, the liquid-transfer media can be either heated or cooled to add or remove heat from container  12 . During operation, the liquid transfer medium is pumped from an external location (where it is heated or cooled), through the tubes (transferring heat either to or from container  12 ), and back to the external location. In order to cool container  12 , the liquid transfer medium is first cooled before it is pumped into the tubes.  
         [0022]    In any event, the liquid-transfer media may be replaced by conventional heating or cooling coils, such as electric resistance or refrigerant-filled coils. Such heating and cooling coils may be provided independently or may both be incorporated into the same heat exchanger  14 . For example, heat exchanger  14  preferably comprises a series of circular heat exchanger plates in side walls  18 , providing a means for transferring heat out of the water by circulating a colder liquid through closed channels on the plate surface.  
         [0023]    [0023]FIG. 1 also depicts a BPC mixing device comprising BPC  10 . Specifically, the BPC mixing device comprises BPC  10  and an agitator  22 . Agitator  22 , in one embodiment, comprises a shaft  24 , extending through an aperture  25  in a first end  26  of container  12  as to maintain sealing of container  12 . It is considered within the scope of the invention for aperture  25  to be a one-way port, allowing introduction of agitator  22  without allowing exit of the contents of container  12 . One extreme of shaft  24  terminates in a stirring element  28 , inside container  12 . Additionally, a motor  30  is connected to the section of shaft  24  external to container  12 . Alternatively, however, shaft  24  may extend through a second end  32  of container  12  and optionally through bottom  16  of heat exchanger, such that motor  30  is disposed either integral with bottom  16  or below heat exchanger  14 . Although FIG. 1, shows motor  30  disposed at the extreme opposite end from stirring element, as long as motor  30  is located outside container  12 , any location is sufficient.  
         [0024]    It must be noted that as used herein, the terms “stir”, “mix” and “agitate” are considered equivalents and are interchangeable, as each simply means manipulating the contents of container  12  to, for example, to incorporate two substances (such as liquid into liquid or a solid into a liquid), or simply to disturb a single substance. Thus, no distinction should be inferred from the uses of these different terms.  
         [0025]    Similarly, while stirring element  28  is depicted as a substantially flat, horizontally aligned device (with respect to the long axis of shaft  24 ), having multiple arms extending from a center, stirring element  28  need not be so limited. For example, stirring element  28  may be in the shape of a paddle extending vertically with respect to the long axis of shaft  24 , or may have extensions extending in all three dimensions from shaft  24 .  
         [0026]    [0026]FIG. 2 illustrates a second BPC mixing device embodiment in accordance with the invention. Specifically, the agitator in this embodiment comprises a magnetic rod  40  and a magnetic drive mechanism  42  (not shown). Magnetic drive mechanism  42  can be any device capable of generating a rotating magnetic field, such as a second magnetic rod attached to a motor, located either integral with heat exchanger  14 , such as in bottom  16 , or somewhere external thereto. In order to increase the efficiency of stirring created by the rotation of magnetic rod  40 , the surface upon which magnetic rod  40  rotates, e.g., second end  32 , may be provided with a non-stick or non-abrasive, low-friction coating, such as a polyolefinic material, preferably polytetrafluoroethylene. Although rod  40  is described as a magnetic rod, rod  40  may also be a magnetizable material, such as ferrous metals or ferrous metal-containing materials.  
         [0027]    For example, in such an embodiment, 485 L of water can be cooled from 70.1° F. to 49.0° F. in 2.0 hours. The cooling liquid supply in the plates of heat exchanger  14  set-point is 38° F. with the closed system supply operating in a range from 38.5-46.9° F. Continuous motion of the contents of the disposable container  12 , formed from a modified polyethylene, is generated by rod  40 , having a tapered shape (e.g., diameter of 25 mm and 90 mm long), rotating at 650 rpm. By recording the water temperature at 8 locations, including 4 depths, 3 radial distances and 4 locating angles, the mixing of the contents of container  12  can be measured. The data shown in Table I indicates that when the invention is employed, even or uniform cooling can be achieved.  
                                                                   TABLE I                       Test   Location   Radial               Location   Angle   Distance   Depth   Temp.       No.   (degrees)   (inches)   (inches)   (° F.)                                1   0   18   24   60.5       2   90   18   18   60.4       3   180   18   12   60.6       4   180   9   6   60.7       5   180   9   24   60.8       6   180   0   6   61.3       7   180   0   24   61.2       8   270   9   18   61.3                Mean   60.8           Standard Deviation   0.366                      
 
         [0028]    In a second example, heat exchanger  14  heats the liquid in container  12 , formed from a modified polyethylene, by circulating a liquid having a temperature hotter than the container  12 . 446 L of water is heated from 41.9° F. to 77.6° F. in 1.3 liquid in heat exchanger  14  having a set point of 95° F., and the closed system operating in a range from 77.1-96.2° F.  
         [0029]    [0029]FIGS. 3 a  and  3   b  show a rod containment disk  100  of the invention. Conventional magnetic stirrers often become free from the magnetic field, and as a result, the mixing stops. Thus, the inventors have developed a containment disk, indicated at  100 , into which magnetic rod  40  is placed. Due to the design of containment disk  100 , rod  40  is prevented from exiting the magnetic field. In particular, containment disk  100  preferably has an upper ring  105  and a lower ring  108 , which when assembled with bolts  110  and spacers  115 , form the structure shown in FIG. 3 b . The exploded view in FIG. 3 a  shows that bolts  110  pass through holes  112  in upper ring  105  and into threaded recesses  118  of lower ring  108 . The length of bolts  110  and spacers  115  are preferably selected such that when constructed, the distance between upper ring  105  and lower ring  108  is large enough to allow rotation of rod  40  and permit substantially unobstructed fluid flow therein, while simultaneously preventing rod  40  from escaping containment disk  100 . While containment disk  100  is shown in FIGS. 3 a  and  3   b  as being a separate device, it is preferable to integrate at lower ring  108  onto a plate  120 . Typically plate  120  is adhered to or part of container  12  and serves as the surface upon which rod  40  rotates.  
         [0030]    Typically, each of upper plate  105 , lower plate  108 , bolts  110  and spacers  115  are constructed from the same types of materials as container  12 , preferably a polyolefin and more preferably low-density polyethylene. However, it is also considered within the scope of the invention to form any one of the components of containment disk of other materials, such as metal. In order to reduce friction, plate  120  is also preferably at least coated with a reduced-friction coating, such as polytetrafluoroethylene.  
         [0031]    Preferably, each of the components of containment disk  100  is injection molded and once assembled, the components are ultrasonically welded together with rod  40  placed inside. Additionally, while upper ring  105  is shown as having a central aperture  125 , in a preferred embodiment, this aperture  125  is not large enough for rod  40  to fit through without disassembling containment disk  100  and is merely present to increase fluid flow about rod  40 .  
         [0032]    Because conventional magnetic rods are often tapered at their ends, the space formed between upper ring  105  and lower ring  108  is preferably similarly tapered. Because the particular shape of the tapered surface can correspond to the shape of the particular shape of rod  40  to be enclosed therein, containment disk  100  can effectively allow rod  40  to rotate freely without risking it leaving the magnetic field.  
         [0033]    Although it is preferable to position containment disk  100  at the bottom of container  12  with magnetic drive mechanism  42  located below container  12 , it is also considered within the scope of the invention to mount containment disk  100  removed from the bottom of container  12 . This may be accomplished, for example, with one or more feet supporting containment disk  100 , or by attaching the outer circumferences of upper ring  105  and lower ring  108  to the inside wall of container  12  at the desired location. Finally, plate  120  may be eliminated and lower plate  108  be provided with an aperture when containment disk  100  is not positioned at the bottom of container  12  to allow for efficient fluid flow. In order to rotate rod  40 , magnetic drive means  42  may comprise, instead of a rotating magnetic field, a pulsating magnetic field, alternating polarities to drive rod  40  inside containment disk  100 .  
         [0034]    Containment disk  100  may also be equipped with a baffle element  110  attached to upper ring  105  (FIG. 3 b ). Preferably, baffle element  110  is included to hinder or otherwise prevent the contents of container  12  from forming a vortex during agitation. In conventional mixing devices using a magnetic rod, if any air is trapped inside the container, rotation of the magnetic rod causes the liquid to form a vortex, necessarily drawing air into the liquid. By including baffle element  110 , the rotation of the liquid can be disrupted enough to limit any vortex formation, while increasing mixing efficiency. Preferably, baffle element  110  is similar in structure to upper ring  105 , but may alternatively be of any shape or size capable of hindering the vortex-causing forces, for example, a rectangular prism, thin vertically-extending flange or pyramid. Additionally, a second set of spacers  130  maintain a space between baffle element I  10  and upper ring  105 . Although spacers  130  are show as being substantially similar in size to spacers  115 , the particular dimensions of spacers  130  are preferably selected as to position baffle element  110  in the location where the vortex-causing forces are greatest.  
         [0035]    In an additional set of embodiments, the contents of container  12  are stirred by physically changing the shape and/or dimensions of container  12 . By applying pressure to a particular area or location of container  12 , the contents are displaced and moved to another location inside container  12 . Thus, a shape manipulating means is utilized to stir the contents of container  12 .  
         [0036]    In a third embodiment, depicted in FIG. 4, container  12  comprises at least one bladder  60 , capable of being filled with a fluid disposed about the periphery of container  12 . In order to selectively inflate and/or deflate bladders  60 , an inflating apparatus  62  (not shown), such as an air or water pump is provided. Specifically, by forming an inflated bladder  60   a , and a deflated bladder  60   b , container  12  can be manipulated to create forces therein to mix the contents. While bladders  60  are preferably formed integral with the structure of container  12 , it is also considered within the scope of the invention to form bladders  60  in side walls  18  of heat exchanger  14  or as a separate inflatable/deflateable element between side walls  18  and container  12  (in which case bladders  60  may be affixed to side walls  18  and/or container  12  in a removable or permanent fashion). Bladders  60  may also be in fluid communication with conduits carrying the liquid-transfer media, such that by simply altering the volume or pressure of the liquid-transfer media, the shape of container  12  can be changed. Additionally, baffles  60  may be a single unit, or alternatively, multiple discontinuous units.  
         [0037]    In a third example, liquid syrup was mixed with water in a flexible container and single continuous bladder supported by a rigid outer structure. The flexible container was cylindrically shaped, having a diameter of 8 inches, and a circumferential bladder (4 inches in diameter and 440 cubic inches in volume) located at one end. Both the container and bladder were formed from a plastic film, processed into a multilayer laminate with a thickness between about 2 and about 12 mils. A cylindrical outer structure, having an 11 inch diameter was also provided. One milliliter of liquid syrup was introduced at the bottom of 1.7 gallons of water. After 29 cycles (each cycle including inflating the bladder completely with air and subsequently deflating the bladder) over 2 minutes, approximately 90% of the syrup had become mixed into the water. This mixing percentage can be determined by any sufficient means, for example, by measuring optical color change or opacity of the water.  
         [0038]    Furthermore, bladders  60  may be replaced by other devices designed to manipulate the shape of container  12  as to agitate the contents disposed therein. For example, FIG. 5 a  shows container  12 , wherein static fluid-filled sleeves  70  are attached to the exterior. Thus, in order to change the shape of container  12 , one or more sleeves  70  are squeezed by, for example, a clam-shell device, indicated at  71 , which may be motorized or actuated manually. In order to perform the agitating, clam-shell devices  71  simply clamp down on sleeves  70  to force the contents of sleeves  70  into the main body of the container. When more than one sleeve  70  is provided, the sleeves  70  may be squeezed simultaneously or independently.  
         [0039]    One or more arms  80  may be attached to container  12 , as shown in FIG. 5 b , such that when arms  80  are pushed, container  12  is deformed and fluid is forced from the area in proximity to arms  80 . Preferably, a stationary baffle  81  is provided near arms  80 , such that before entering the main section of container  12 , the fluid must first pass stationary baffle  81 . Additionally, arms  80  may be pulled to deform container  12  by stretching. Preferably, when arms  80  are utilized container  12  resembles a rectangular prism or a cube, with arms  80  positioned at the edges thereof. Most preferably, arms  80  are disposed at the edges, most preferably at each of the corners of container  12 .  
         [0040]    Finally, container  12  may be provided with a system comprising at least one hinged plate  90  (FIG. 5 c ), while heat exchanger  14  includes at least one mechanical plate  95  (not shown), corresponding to the location and number of the hinged plates, such that mechanical plates may be activated to create a pulsation in container  12 . Preferably, mechanical plates  95  in heat exchanger  14  correspond in number and position to hinged plates  90  in container  12 , such that each mechanical plate  95  impinges upon a separate hinged plate  90 . Thus, the manipulation of hinged plates  90  functions to massage container  12  to agitate the contents therein.  
         [0041]    Although the present invention has been described in terms of specific embodiments, it will be apparent to one skilled in the art that various modifications may be made according to those embodiments without departing from the scope of the applied claims and their equivalents. Accordingly, the present invention should not be construed to be limited to the specific embodiments disclosed herein.