Patent Publication Number: US-2022213420-A1

Title: Bioprocessing system and consumable bag for a bioprocessing system

Description:
This application is a national stage of International Application No. PCT/EP2020/061862 filed on Apr. 29, 2020, which claims priority to U.S. Provisional Patent Application No. 62/841,888 filed on May 2, 2019, all of which are hereby incorporated by reference in their entireties. 
    
    
     BACKGROUND 
     Technical Field 
     Embodiments of the invention relate generally to bioprocessing systems and methods, and components, and, more particularly, to improvements in bioreactor systems. 
     Discussion of Art 
     A commonly used type of bioreactor for cultivating cells is provided on a rocker unit, e.g. the WAVE™ bioreactor (GE Healthcare). Mixing of the culture is accomplished by the wave-induced agitation which is performed by the rocker unit. The conditions in the cell culture can be regulated by different means, for example the temperature can be regulated by providing heat, pH can be regulated by adding acid or base and the amount of liquid/media added or removed can be controlled. One or more bioreactor bags are provided on the rocker unit and connected to various fluid flow lines for the addition or removal of fluids and gases. 
     While existing rocker-type bioreactor systems are generally suited for what is regarded as ordinary performance, there is a need for improvements in terms of ease and convenience of use, tubing management, filtering and the like. For example, tubing on existing bioreactor systems for air supply can become cumbersome and kinked. In addition, inlet and outlet ports are typically associated with non-integrated vent filters which are costly and provide a lot of variability from system to system. 
     Accordingly, there is a need for a rocker-type bioreactor system and disposable bag therefore that minimizes or addresses the drawbacks of existing systems and devices. 
     BRIEF DESCRIPTION 
     In one aspect, the invention discloses a bioreactor system including a base platform, a lid received atop the base platform and defining an interior space for receiving a bioprocessing bag/bioreactor bag, and a tubing management system supporting a tubing array a distance above the base platform and providing a means for quickly connector and/or disconnecting a fluid supply line. 
     In a second aspect, the present invention provides a vent filter with a superhydrophobic membrane to allow minimized stand-off separation from the bioreactor bag and reduce condensation and fouling. 
    
    
     
       DRAWINGS 
       The present invention will be better understood from reading the following description of non-limiting embodiments, with reference to the attached drawings, wherein below: 
         FIGS. 1-11  are various views of a bioreactor system according to an embodiment of the invention. 
         FIGS. 12 and 13  are perspective views of inlet and outlet vent filters of a bioprocessing bag of the bioreactor system of  FIGS. 1-11 . 
         FIGS. 14-24  are various views of additional vent filter designs, according to other embodiments of the invention. 
         FIG. 25  is a perspective view of a perfusion filter of a bioprocessing bag of the bioreactor system of  FIGS. 1-11 . 
         FIG. 26  is a tubing management device of the present invention. 
         FIGS. 27-30  depict a bioreactor-support plate of the present invention. 
     
    
    
     DETAILED DESCRIPTION 
     Reference will be made below in detail to exemplary embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference characters used throughout the drawings refer to the same or like parts. 
     Embodiments of the invention provide bioreactor or bioprocessing systems. In an embodiment, a bioreactor system includes a base platform, a lid received atop the base platform and defining an interior space for receiving a bioprocessing/bioreactor bag, and a tubing management system supporting a tubing array a distance above the base platform and providing a means for quickly connector and/or disconnecting a fluid supply line. 
     With reference to  FIG. 1 , a bioreactor system  10  according to an embodiment of the invention is illustrated. The bioreactor system  10  is generally configured similar to existing rocking-type bioreactor systems known in the art such as, for example, the WAVE™ line of bioreactor systems/platforms (GE Healthcare Life Sciences), and includes a generally rectangular platform or base  12  and a lid  14  received atop the base and defining an interior space therebetween. The lid  14  includes a front panel or door  16  that provides selective access to the interior space without entirely removing the lid  14 . In an embodiment, the lid  14  may be formed from a semi-transparent, UV-blocking material and/or may include a window made out of a semi-transparent, UV-blocking material that allows a user to see into the interior space. 
     The bioreactor system  10  also includes a tubing management system which will be hereinafter described. As shown in  FIGS. 1 and 2 , for example, tubing  18  is attached to the lid  14  adjacent to a top thereof using connect/disconnects  20 . As best shown in  FIG. 4 , inlets  22  on both sides of the bioreactor  10  allow for user setup of pumps and air supply on either side of the system  10 . As also shown therein, the tubing  18  interior of the system  10  hangs from the top of the system and has a connect/disconnect device  22  at the distal end thereof for selective coupling with a single-use bioprocessing/bioreactor bag  30 . Clamps  24  allow for a supply of air to be sent to one, both, or opposite bioprocessing/bioreactor bags  30  (the system shown in the figures is capable of accommodating two bioprocessing bags arranged side by side; one such bag  30  is shown in the figures). The clamps have an aperture and a slot that allows the clamps  24  to be moved between a position where fluid within the tubing is permitted to pass by the clamp, and a position where fluid is prevented from passing by the clamp. 
     With reference to  FIGS. 6 and 7 , in an embodiment, clips  26  are utilized to connect and hold the tubing  18  within the interior space/chamber to the underside of the lid  14 . The clips  26  are secured to the underside of the rear portion of the lid (i.e., rearward of the door  16 , which enables the door  16  to be selectively opened, as discussed below. 
     Turning now to  FIG. 8 , in one embodiment, scaffolding or a gantry-like structure  28  may be utilized to support the tubing  18  above the platform  12  (i.e., without the use of the lid  14  to support the tubing  18 ). This allows the lid to be removed entirely during bioprocessing, enabling more unobstructed access and viewing of the bioprocessing bag  30 . With reference to  FIG. 9 , the scaffolding  28  beneath the lid  14  allows for the door  16  to be opened (e.g., by rotating it rearward beneath the rearward portion of the lid  14 ). As shown in  FIGS. 10 and 11 , tubing  18  and T-connects  32  fit smoothly into the scaffolding  28  and can be removed/changed out, if needed. 
     With specific reference to  FIGS. 3-6 , the bioprocessing bag  30  may include a RFID chip or label  34  that may be passive or active. The RFID label can be read to provide information on the bag type, lot number, manufacture date, etc. The presence of the RFID device  34  facilitates real-time insight into the location of every consumable from manufacture to consumption, and can be used in better inventory management. 
     As also shown therein, the bioprocessing bag  30  includes a first vent filter  36  of the present invention. The present invention contemplates that the vent filter of the present invention is a stand-alone invention suitable for other bioprocessing applications and/or single-use bioreactors. The vent filters of the present invention can act as both inlets (for adding air, oxygen, etc.) and outlets (to vent waste) while retaining sterility in the bio reactor bag. Additional vent filters may be provided as back-ups in the event the vent filters vapor lock or foul. It is contemplated that the vent filter can include a check valve which may be integral to this assembly and would be desirable for proximity and cost reduction. 
     Vent filter  36  includes an integrated inlet port and check valve and a second vent filter  38  having an integrated outlet port and check valve. The bag  30  also includes a perfusion filter  40  positioned interior to the bag  30  and a tubing management apparatus  42  connected to the bag and extending upwardly from an upper surface of the bag. The vent filters  36 ,  38 , by being integrated with the bag  30 , itself, obviate the need for filter heaters and include a quick-connect means for attaching inlet or outlet tubing.  FIGS. 12 and 13  provide more detailed views of the vent filters  36 ,  38 , respectively. 
       FIGS. 14-23  illustrate other possible configurations for the integrated vent filters  36 ,  38 , according to yet other embodiments of the present invention. For example,  FIG. 14  illustrates possible check valves incorporating a collector feature  50  and one or more valve members  52  in a housing  54  with a hose barb connector  56  for gas entry.  FIG. 15  illustrates flush silicone check valves, having a filter membrane  58 , a housing  54 , and a silicone check valve membrane  52 .  FIG. 16  illustrates a vent filter having a membrane and a bored-in support area for reverse pressure control.  FIG. 17  illustrates different orders of bonding  60  between the housing  54 , filter membrane  58  and bag wall  30  to be used in the construction of the vent filter(s). As shown therein, a filter membrane  58  may be bonded to the inside of the bag  30 , and the valve housing  54  may be bonded to the outside of the bag  30 . In another embodiment, the filter membrane may be bonded to the inside of the bag, and the valve housing may have a flange  62  that is sandwiched between the inside of the bag and the membrane. In another embodiment, the valve may be bonded to the outside of the bag and the membrane may be positioned interior to, and attached to, the valve housing. 
     Referring to  FIG. 18 , in an embodiment the vent filters  36 ,  38  may have a skeletal structure  64  providing a base substrate for support, and a filter membrane  58  secured to the skeletal structure. 
       FIG. 19  is a perspective view illustrating the valve (i.e., vent filters  36 ,  38  with integrated check valve) bonded to the bioprocessing bag  30 . 
     In an embodiment, as illustrated in  FIG. 20 , a superhydrophobic filter membrane  58  may be attached directly to the consumable bag  30 . The filter membrane can also be supported by skeletal support structure  64 . 
     As shown in  FIG. 21 , in an embodiment, the inlet and outlet vent filters  36 ,  38  may be combined into a single housing  54 , and the housing may include a sliding cover  66  that can be selectively opened or closed to allow fluid communication with the interior of the bag through an outlet filet or an inlet filter.  FIG. 22  discloses a similar arrangement wherein the inlet  36  and the outlet  38  filters are integrated into a single housing  54 , with a mechanism  68  to selectively switch between the two. 
     With reference to  FIG. 23 , in an embodiment, a configuration is shown where a filter cover may be rotatable to expose either the inlet filter  36  or an outlet filter  38 . 
     Finally,  FIG. 24  illustrates multi-port filters (i.e., inlet and outlet) having a capping  70  option. 
     The filters described above present a number of cost saving opportunities, as well as containing fewer components than existing devices. 
     Turning now to  FIG. 25 , a more detailed view of the perfusion filter  40  within the bioprocessing bag  30  is shown. In contrast to existing bags which typically have a free-floating perfusion filter, the perfusion filter  40  of the bioprocessing bag  20  is secured or tethered to an inside surface of the bag  30 . The filter  40  is mounted on uprights  46  that space the surface of the filter  40  from the surface of the bag  30  to which it is attached. The filter  40  is therefore more robust than existing perfusion filters. 
     Turning to  FIG. 26 , a more detailed view of the tubing management device  42  is shown. The device  42  is configured for integration with the bioprocessing bag  30  and includes a plurality of ports  72  for selective connection to inlet/outlet tubing, and a plurality of clamps  74  for receiving, retaining and organizing such tubing. The tubing management device  26  combines a plurality of ports  72  at a single location, which provides for better usability. 
       FIGS. 27-30  depict a bioreactor support plate  75  of the present invention. The plate is to facilitate adding drains  76 , sensors  78  and such to bioreactor bags for a rocker like the WAVE product. Currently the trays don&#39;t have any good way to facilitate anything you want to come out the bottom like a drain or a sensor that needs to be on the bottom but has significant size. A drain or sensor sitting on the tray would be above the tray bottom surface that would make it difficult to drain or the sensor size would not be able to be at the bottom. Putting anything on the tray requires the bag to conform over it and could also cause damage to the bag as well as sticking too far up in the bag. If the sensor was inside the bag it would be well above the bottom and with low volume or rocking motion the sensor would be either above the liquid level and or end up above the liquid surface especially during rocking. Some sensors are preferred to operate below liquid level and a drain should be at the very bottom to facilitate draining completely and easily. This plate would support these items but also allow them to protrude well below the tray bottom surface, as currently only small drains/sensors are in or under the bag and on top of the tray. New sensors and drains are larger and this plate could accommodate these new and future components. The plate could have holes for drains or sensors and the plate would support those. If the sensors or drains and connectors below the bag are bigger than the sensor or drain port at the bag, the plate desirably includes a “U” shape channel in the plate which opens on a perimetrical edge of the plate. Such an open slot extending in from the perimetrical edge of the plate facilitates feeding the connector conduits through the opening in the tray while obviating the need to pass a connector or sensor through the opening in the plate. The slot design also allows the plate to still support the sensor and the bag once in place, both of which need support as the flexible bag with liquid in it would extrude through any significant opening. 
     This modular plate could be designed to support many different types of existing sensors, drains, etc. in the future. The present invention further contemplates sizing the plate to accommodate future devices that are added to the bottom of a bioreactor bag. Additionally, the plate need not be centrally-mounted about its pivot, but could be mounted off-center. Desirably, the plate is located so as to position the sensors in the center of the rocking motion to maximize the likelihood of always being under the liquid level during rocking. The end near the bottom would most likely would be used for the drain location. Alternatively, there could be more than one of these plates minimizing the area these require and better control the heating or cooling of the area the plate occupies. Existing trays have heat or cooling in a significant area of the tray to facilitate even and adequate temperature control. 
       FIG. 27  specifically shows a plate  75  of the invention with a drain port  76  attached to a bioreactor bag  30 . The plate has a recessed opening  80 , into which an insert  82  with one or more holes  84  is fitted, supported by the recessed edges (flange)  81  of opening  80 . The drain port  76  is welded to the bottom wall of bag  30  and placed in one of the holes such that the upper end  86  of the port is flush with or slightly below the bag support area  88  of the plate. The drain port may comprise a hose barb connection  90  to which a length of tubing  92  is attached. As an alternative to placing the drain port in a hole, the drain port may be integral with the insert  82 . 
       FIG. 28  shows the plate  75  of the invention with a sensor  78  attached to a bioreactor bag  30 . Insert  82  with one or more holes  84  is supported by the recessed edges (flange)  81  of opening  80  and sensor  78  is placed in one of the holes, e.g. such that the upper end  87  of the sensor is flush with or slightly below the bag support area  88  of the plate. As an alternative to placing the sensor in a hole, the sensor may be integral with the insert  82 . 
       FIG. 29  shows an overview of plate  75 , with recessed opening  80  and insert  82  placed in the opening. 
       FIG. 30  shows a top view of plate  75  with insert  82  and an axis  94 , around which the plate rocks. 
     In general terms, the insert  82  may comprise one or many of a load cell (for determining the weight of a bag), RFID module (e.g. for recognizing an RFID tag on a bag or for receiving a signal from an RFID sensor), temperature sensor, optical sensor (to be fitted adjacent to an optically transparent window on a bag), accelerometer, infrared sensor, dissolved air sensor, and components to enhance mixing (fins/blades, ultrasonics, etc). These devices may be integral with the insert or placed in holes of the insert. 
     As used herein, an element or step recited in the singular and proceeded with the word “a” or “an” should be understood as not excluding plural of said elements or steps, unless such exclusion is explicitly stated. Furthermore, references to “one embodiment” of the present invention are not intended to be interpreted as excluding the existence of additional embodiments that also incorporate the recited features. Moreover, unless explicitly stated to the contrary, embodiments “comprising,” “including,” or “having” an element or a plurality of elements having a particular property may include additional such elements not having that property. As used herein to describe the present invention, directional terms such as “up”, down”, “upwards”, “downwards”, “upper”, “lower”, “top”, “bottom”, “vertical”, “horizontal”, “above”, “below” as well as any other directional terms, refer to those directions in the appended drawings. 
     This written description uses examples to disclose several embodiments of the invention, including the best mode, and also to enable one of ordinary skill in the art to practice the embodiments of invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to one of ordinary skill in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.