Abstract:
A bubble trap assembly for critical bioprocess applications. The assembly includes a disposable liner for placing in a fluid stream of a critical bioprocess application. The liner includes at least one gas port disposed on a top of the liner, and at least two fluid ports disposed substantially on the bottom of the liner. The fluid ports are adapted to be coupled in-line to the critical bioprocess application. A rigid vessel is included for housing the liner. The liner being sized to substantially conform to a shape of the inside of the vessel. The vessel includes at least one upper aperture for aligning with the at least one gas port and a bottom opening opposed to the at least one upper aperture. A bottom cap is included, removeably secured to the vessel and closing the bottom opening. The bottom cap together with the vessel substantially enclosing the liner. The bottom cap includes at least one lower aperture for aligning with the fluid ports. The bottom cap being formed by at least two cap portions for facilitating installation of the liner in the assembly. The at least two cap portions capable of being separated from one another.

Description:
CROSS-REFERENCE TO RELATED APPLICATION 
       [0001]    The present application claims priority, in part, to provisional patent Application Ser. No. 60/995,951, filed Sep. 29, 2007. This earlier filed provisional application is incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    In certain processes like a liquid chromatography process used in biopharmaceutical production, it is desirable to remove bubbles or gases held up in a fluid flowing through the process path. Often, such gases get entrained in a fluid stream and should be removed to prevent them from being pumped into a chromatography column. The bubble trap also aids in removal of air initially present in the fluid path. Undesirable gases in the column can disrupt flow patterns, prevent process consistency and effectiveness and cause other problems. A bubble trap is commonly used to systematically remove such gases. 
         [0003]    Due to the stringent quality and purity requirements in many biopharmaceutical processes, contemporary bubble traps must be cleaned and/or thoroughly sanitized before they can be reused. Also, due to the high pressures involved in many chromatography processes, the bubble trap vessels must be durable and well constructed, and therefore relatively expensive. It is thus not cost effective to dispose of such expensive vessels after a single or very limited uses. 
         [0004]    When a piece of equipment is used for manufacture or development of products and limited equipment downtime is desired, there would be advantages to eliminate the necessity of a cleaning process for the bubble-trap. One way to do this is by having a disposable liner that can meet the requirements of the process. This includes being able to perform at pressure of 8 bar or higher. 
         [0005]    It is therefore desirable to provide a bubble trap assembly that can be quickly and easily ready for reuse, while ensuring a clean, sterile or uncontaminated process between uses. Also, such an assembly must also be able to perform under pressures at least as high as 8 bars. 
       SUMMARY OF THE INVENTION 
       [0006]    One aspect of the invention relates to a bubble trap assembly for critical bioprocess applications. The assembly includes a disposable liner for placing in a fluid stream of a critical bioprocess application. The liner includes at least one gas port disposed on a top of the liner, and at least two fluid ports disposed substantially on the bottom of the liner. The fluid ports are adapted to be coupled in-line to the critical bioprocess application. A rigid vessel is included for housing the liner. The liner being sized to substantially conform to a shape of the inside of the vessel. The vessel includes at least one upper aperture for aligning with the at least one gas port and a bottom opening opposed to the at least one upper aperture. A bottom cap is included, removeably secured to the vessel and closing the bottom opening. The bottom cap together with the vessel substantially enclosing the liner. The bottom cap includes at least one lower aperture for aligning with the fluid ports. The bottom cap being formed by at least two cap portions for facilitating installation of the liner in the assembly. The at least two cap portions capable of being separated from one another. 
         [0007]    Additionally, the at least one lower aperture can include an inner recess facing the vessel for aligning the fluid ports. The at least one lower aperture can include an outer recess opposed from the inner recess. The at least two cap portions can include mating elements for mutual alignment when assembled. Wherein, at least one of the fluid ports can include a nozzle extending from the bottom of the liner toward the top of the liner. The nozzle can extend toward the top at least beyond a central portion of the liner. The rigid vessel can be formed by at least two separatable portions. Also, the at least two separatable portions can be pivotally hinged to one another. The liner upon installation in the assembly can be capable of withstanding high pressure. 
     
    
     
         [0008]    These and other embodiments, features, and advantages of this invention will become apparent from the following detailed description of illustrative embodiments thereof, which is to be read in connection with the accompanying drawings. 
         BRIEF DESCRIPTION OF THE DRAWINGS  
         [0009]      FIG. 1  is a side view of a bubble trap liner in accordance with an embodiment of the subject invention. 
           [0010]      FIG. 2   a  is a top view of an end cap for a bubble trap assembly in accordance with an embodiment of the subject invention. 
           [0011]      FIG. 2   b  is a cross-sectional view of the end cap of  FIG. 2   a.    
           [0012]      FIG. 3  is a side view of a bubble trap assembly in accordance with an embodiment of the subject invention. 
           [0013]      FIG. 4  is a side view of a bubble trap assembly in accordance with another embodiment of the subject invention. 
           [0014]      FIG. 5  is a perspective view of a split design vessel in accordance with an embodiment of the subject invention. 
       
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0015]    In accordance with an embodiment of the subject invention, a bubble trap assembly is provided that includes a rigid vessel, a removable bottom cap and a disposable inner liner. The assembly is adapted to have the inner liner quickly and easily replaced with a new one for reusing the remaining bubble trap assembly. 
         [0016]    In accordance with an embodiment of the invention, a bubble-trap assembly is provided with a disposable liner along with an easy method of installation and removal of the liner from the vessel that forms the bubble trap housing. It should be understood that “disposable” as used throughout this disclosure is intended to mean for a single or limited use. 
         [0017]    As shown in  FIG. 1 , the liner  10 ,  10 ′ is preferably similar to a sealed bag with at least one fluid port  18  that acts as a fluid or liquid inlet, one fluid port  16  that acts as a fluid or liquid outlet and at least one gas port  12  that acts as an outlet for air and other gases. The fluid inlet  18  and outlet  16  are on the bottom and the gas outlet  12  on the top. The liner  10 ,  10 ′ is preferably made of a flexible material the can be made in the shape of a container or expand, preferably without stretching, to take the shape of the container. The liner  10 ,  10 ′ can be formed from a single ply or multi-ply, using suitable materials as listed in AAMI TIR17: 1997. The liner  10 ,  10 ′ can be formed as a pillow style bag, having port plates on a face of the liner  10 ,  10 ′, as opposed to a seam. Alternatively the liner  10 ,  10 ′ can be formed as a cylinder or almost any desired shape. Preferably the shape of the liner is adapted to conform to that of the vessel  30 ,  30 ′. 
         [0018]    It should be understood that the term “fluid” as referred to herein includes any flowing or readily moving substance having no fixed shape and yielding its collective form to external pressure. Fluids are not substantially solid or rigid, and include liquids, gases, a combination of liquids and gases, as well as liquids, gases and combinations thereof that include solid particulates or dissolved/disassociated solids. The term “liquid” as referred to herein consists of substances or a combination of substances which flow and take a shape determined by its container while occupying the same volume, rather than dispersing like a gaseous substance. The term “gas” as referred to herein consists of one or more fluids that can change volume indefinitely, such as but not limited to air. 
         [0019]    As shown in  FIGS. 3 and 4 , in preferred embodiments, the liner is placed into a rigid vessel  30 ,  30 ′ with a removeably secured bottom cap  20 . The vessel  30 ,  30 ′ is preferably a cylindrical member, although other suitable shapes and sizes are contemplated. Preferably, the liner  10 ,  10 ′ is sized to conform to the shape and size of the vessel  30 ,  30 ′ either by design or upon expansion with pressure. Alternatively, the top of the vessel could also be removeably secured to the assembly, in the form of a top cap  39  (as shown in  FIG. 4 ). The removable bottom cap  20  allows the liner  10 ,  10 ′ to be inserted through a bottom opening  32  of the bottom of the vessel  30 ,  30 ′. The liner is guided into the vessel  30 ,  30 ′ towards the top so that the gas outlet  12  aligns with an upper vessel aperture  34  for venting purposes. 
         [0020]    When the bubble trap assembly  100 ,  100 ′ (particularly the liner  10 ,  10 ′) is being filled with fluid, during a process, gas venting is required to let more fluid enter the inner chamber  110 . During installation/assembly, the gas outlet port  12  can be used to add gas, such as air, to inflate the liner  10 . Also, pressure can be maintained through the port  12  during process operations, if desirable, but such pressure should be maintained at or below the minimum process pressure. 
         [0021]    In a preferred embodiment, ports  12 ,  16 ,  18  are formed by an annular port plate that is sealingly secured to the liner  10 ,  10 ′. Preferably, a hose barb fitting  19   a ,  19   b  or other fitting is integrally formed with the port plate as one molded piece. Thus, a hose or tubing  42 ,  44 ,  46  can be secured to the hose barb  19   a ,  19   b . It should be understood, a different hose or tubing connection could be provided in place of the hose barb shown. Also, rather than having a tubing coupling like a hose barb, the tubing could be integrally formed or otherwise permanently fixed to the port plate. Additionally, the gas port  12  can include a bacterial retentive air filter or other type of filter (not shown) to assist in isolating the liner/bubble trap from ambient air. Also, the gas port  12  can be coupled to a valve and/or gauge  50 ,  50 ′. The tubing/hose  46  coming off the fitting  19   a  could be inserted into the valve, like a tubing pinch valve. A valve can vent/release gas from the bubble trap to enable removal of more entrained gas. A pressure gauge could be used to measure pressure in the vent line (after the valve), if positive pressure is being applied via a self relieving style regulator that will relieve gas pressure coming from the bubble trap vent, but it is not necessary to measure the pressure in the bubble trap because in theory it should be the same as the pressure in the fluid path which is either measured at other stages of the fluid flow path within the process or is assumed to be proportional to the pressure generated by any pump within the process (pump pressure less pressure drop due to flow through the process fluid path). Further, such a valve could be a pinch valve that is able to remain closed to keep the tubing closed under the pressure in the system. The valve can be opened manually or by a control system. 
         [0022]    In a preferred embodiment, the vessel  30 ,  30 ′ is made of transparent materials and the liner  10 ,  10 ′ is also made of transparent materials. In this way, automatic level sensors  60 , such as capacitance, ultrasonic or other level sensors, can read liquid level through the vessel  30 ,  30 ′ and liner  10 ,  10 ′ to monitor bubble-trap performance and even automatically control a valve for regulating or maintaining volume within the liner while allowing fluids to continue to flow through the assembly. Transparent materials also enable viewing for observation of operation. While the vessel  30 ,  30 ′, as shown in the drawings is generally cylindrical, it should be understood that the vessel could have another shape or form as desired. The vessel  30 ,  30 ′ can be made of materials such as glass, plastic, metal or a combination of materials. Additionally, the vessel  30 ,  30 ′ can include a sight glass or limited portions that are transparaent, as desired. Also, the vessel  30 ,  30 ′ can have at least one removable end cap  20  to insert the liner or open along a lengthwise parting line. These designs are beneficial because if the liner ports  12 ,  16 ,  18  have external tubing or hoses connected to or extending from them, the liner  10 ,  10 ′ can be inserted in the vessel  30 ,  30 ′ while maintaining a continuous liquid flow path between the inlet  18  and outlet  16 . 
         [0023]    The vessel  30 ,  30 ′ and liner  10 ,  10 ′ are sized to give the proper residence time based on the process pressure, flow rate and other factors. The volume of the vessel must accommodate enough volume of fluid so that the fluid flowing through the inlet  18  and out of outlet  16  has residence time to allow entrained gases to release into the top of the vessel  30 ,  30 ′. The volume of the vessel  30 ,  30 ′ must also consider the operation pressure because gas initially in the liner at or near atmospheric pressure will be compressed when pressure builds up in the vessel  30 ,  30 ′ or when the gas expands from process pressure being relieved. 
         [0024]    Alternatively as shown in  FIG. 5 , the vessel  30 ″ can be formed to open length-wise (from top to bottom), using clamps or seals (not shown) to maintain the vessel  30 ″ closed and still able to withstand significant pressure levels, such as those above approximately 0.5 bars. Hinges can be provided between the two portions  35   a ,  35   b  of the vessel  30 ″ for opening in a clam-shell design. Also, a closure mechanism (not shown) opposed from such hinges could further be provided. However, the two portions  35   a ,  35   b  of the vessel  30 ″ need not be permanently attached to one another. Preferably, a split vessel  30 ″ design includes aligning notches or tongue and groove mating elements in the two separate portions  35   a ,  35   b  for locating the inlets and outlets in the parting line of the vessel  30 ,  30 ′. Such a design can facilitate insertion and alignment of the liner  10 ,  10 ′ in the vessel  30 ,  30 ′. 
         [0025]    Additionally, the split vessel  30 ″ can have the bottom cap integrally formed therein. Accordingly, smaller apertures  51   a ,  51   b ,  52   a ,  52   b  are provided to accommodate the fluid ports  16 ,  18 . Also, at least one upper aperture  34 ′ a ,  34 ′ b  can be provided to accommodate port  12  in the liner. 
         [0026]    The liner  10 ,  10 ′ can be formed such that when under pressure and not being contained by the vessel  30 ,  30 ′, it will normally expand and possibly burst. The liner  10 ,  10 ′ is sized relative to the vessel  30 ,  30 ′, such that the vessel  30 ,  30 ′ does not allow the liner  10 ,  10 ′ to expand to the point rupture or compromising the integrity of the liner  10 ,  10 ′. Accordingly, the liner  10 ,  10 ′ is preferably slightly larger than the vessel  30 ,  30 ′. Preferably, the combination of the vessel  30 ,  30 ′ and liner  10 ,  10 ′ can withstand relatively high pressure, such as those above approximately 0.5 bars, but preferably at least  8  bars or more. 
         [0027]      FIGS. 2   a  and  2   b  show the removable bottom cap  20 . The bottom cap  20  is preferably designed to provide optimal drainage of liquid from the assembly  100 . Once the liner  10 ,  10 ′ is inserted in the vessel  30 ,  30 ′, the bottom cap  20  is secured to the vessel  30 ,  30 ′. Preferably, the liner ports  16 ,  18  align with at least one aperture  22 ,  24  in the bottom cap  20 . Thus, the lower liner ports  16 ,  18  are quickly and easily secured in place by the bottom cap  20 . 
         [0028]    The bottom cap  20  is preferably formed by two or more parts  20   a ,  20   b  that when joined together, along with the vessel  30 ,  30 ′, enclose the liner  10 ,  10 ′ inside the assembly  100 . Preferably, the bottom cap  20  has notches cut along the parting line of at least one of the end cap pieces that form part of the apertures  22 ,  24  to allow the tubing to pass. Also, it can have indentations  21  that will allow the inlet  18  and outlet  16  ports (or single port with inlet/outlets) on the liner  10 ,  10 ′ to seat properly. Preferably, the bottom cap  20  inner surface aperture  22 ,  24  diameter is formed as small as possible to maintain alignment of the liner  10 ,  10 ′ and any fittings secured thereto. Additionally, the bottom cap parts  20   a ,  20   b  can include mating elements  25 , such as mating dowels/recesses, to keep the parts  20   a ,  20   b  aligned and stable when assembled on to the end of the vessel  30 ,  30 ′. Also, the bottom cap  20  can have cut-outs  29  on the outer surface to allow space for hose clamps or the like that hold hoses on a barb fitting incorporated into the liner ports  12 ,  16 ,  18 . The bottom cap  20  can be secured to rigid vessel  30 ,  30 ′ with known methods, such as a clamp/gasket, nuts, bolts, screws or large threaded screws/nuts in order to remain secure at process pressures. The notches  22 ,  24  in the bottom cap  20  that guide the ports  16 ,  18  or tubing  42 ,  44  integral to the liner  10 ,  10 ′ are sized such that when the assembly  100 , and particularly the liner  10 ,  10 ′, is pressurized they will prevent the ports  16 ,  18  or integral tubing  42 ,  44  from bulging past the notches  22 ,  24 . 
         [0029]    The ports  12 ,  16 ,  18  can be made of materials such as low density polyethylene (LDPE) or high density polyethylene (HDPE) or other desired materials such as those listed in AAMI TIR17: 1997. In a preferred embodiment of the ports  12 ,  16 ,  18  have a hose barb  19   a  external to the liner  10 ,  10 ′ where tubing or hose  42 ,  44  can be secured and also can be part of a tubing/manifold assembly designed for single or limited use. Additionally, the fluid inlet  18  can include a further hose barb  19   b  on the inside of the liner  10 ,  10 ′ to help direct liquid up and away from the liquid outlet and give the trapped gas time to separate from the liquid. This barb  19   b  can include an extension  15 , extending substantially into the liner. As described above with regard to alternative designs for the ports  12 ,  16 ,  18 , extension  15  can either be integrally formed with port  18  or a tube or hose could be added, as shown in  FIG. 3 . Such an extension  15  could potentially extend across the entire length of the liner  10 ,  10 ′ or even extend to the top of the liner and then bend back toward the bottom of the liner  10 ,  10 ′. The liner  10 ,  10 ′ itself and the ports  12 ,  16 ,  18  are preferably optimally designed to prevent dead liquid zones (zones of poor circulation) and promote flow through the ports  12 ,  16 ,  18 . 
         [0030]    While various embodiments of the present invention are specifically illustrated and/or described herein, it will be appreciated that modifications and variations of the present invention may be effected by those skilled in the art without departing from the spirit and intended scope of the invention.