HK1223884B - Bioreactors with multiple or adjustable-position agitator designs - Google Patents

Description

Bioreactors with multiple or adjustable position agitator designs

Cross-references to related applications

This application claims priority to U.S. Provisional Patent Application Serial No. 61/878,516, filed September 16, 2013, the entire contents of which are incorporated herein by reference.

Background Art

Bioreactors can be used to produce products such as drugs, vaccines, antibodies, etc. by culturing cells, tissues, cultures, etc. under a controlled environment. Disposable bioreactors are increasingly being used, which include a support structure and a disposable container configured to fit within the support structure. The use of these systems allows for simpler cleaning and disinfection of the bioreactor between processes. There are many designs for disposable bioreactors, and in some cases, a specific design may be desired - for example, for the production of a specific product, it may be desirable to use a disposable container made of a specific material or with a specific agitator system design. The disposable components in a disposable bioreactor are configured for use with a specific bioreactor system, and the arrangement of its ports and connectors is customized for that system.

Summary of the Invention

In some cases, the need to use different support structures with different disposable containers may be expensive and/or inefficient. Instead, it may be desirable to use a single support structure with multiple disposable container designs. Described herein is a bioreactor support structure configured to be used in conjunction with containers of different designs, as well as methods for making and using these bioreactors. The support structure described herein may include two or more agitator motors and a control system or an adjustable position agitator motor, a removable spacer and/or lid, multiple configurations for ports and detectors, and multiple exhaust filter heating blankets. Also described herein is a method for making a multi-agitator motor and/or adjustable position agitator motor bioreactor, as well as a method for converting an existing support structure into a container that was not originally designed to be used in conjunction with an existing support structure. Also described herein is a method for operating the bioreactor support structure described herein.

One specific embodiment includes a bioreactor comprising a support structure configured to hold a container and an agitator system including an impeller and an agitator motor, wherein the agitator system and the support structure are configured to position the agitator motor in a plurality of positions relative to the support structure. The support structure may include a top region and a bottom region, and the plurality of positions may include a top-mounted agitator motor position and a bottom-mounted agitator motor position. The plurality of positions may also include at least one intermediate position between the top-mounted agitator motor position and the bottom-mounted agitator motor position. The agitator motor may be mounted on an adjustable-length shaft. The agitator motor may be selectively mounted in a plurality of positions. The support structure may include a top region and a bottom region, and the impeller may be configured to selectively operate at a range of intermediate positions between the top and bottom regions of the support structure. The impeller may be mounted on the adjustable-length shaft. The bioreactor may also include a container configured to be positioned within the support structure and coupled to the agitator motor, wherein the container is a collapsible bag. The collapsible bag may be configured for use with the top-mounted agitator motor. The collapsible bag can be configured for use with a bottom-mounted agitator motor. The bioreactor can also include a spacer having a raised support surface configured to be removably positioned at the bottom of the support structure. The support structure can include a top opening and a removable lid configured to at least partially cover the top opening. The lid can be attached to the support structure when covering the top opening and when removed from the top opening. The support structure can be configured for use with both internal and external detectors.

A specific embodiment includes a support structure, a bottom-mounted agitator motor coupled to the support structure, and a bottom-mounted agitator motor coupled to the support structure, the support structure comprising sidewalls and a base, the support structure having a cavity formed therein, the cavity configured to hold a container, wherein the top and bottom agitator motors are configured to be selectively engaged based on the configuration of the container. The bioreactor may further include at least one connector configured to attach the container in at least one of the sidewalls or the base. The bioreactor may further include a container configured to be positioned within the cavity and coupled to the top-mounted or bottom-mounted agitator motor, wherein the container is a collapsible bag. The bioreactor may further include a spacer having a raised support surface configured to be removably positioned at the bottom of the support structure. The spacer may be configured to separate the container from the bottom-mounted agitator motor when the spacer is positioned at the bottom of the support structure. The bioreactor may further include a first control system configured to control the top-mounted agitator motor and a second control system configured to control the bottom-mounted agitator motor. The bioreactor may further include a selector for switching between the first and second control systems. The first and second control systems may be configured to be selectively engaged using a digital user interface. The first and second control systems may include a variable frequency drive. The support structure may include a top opening and a removable lid configured to at least partially cover the top opening. The lid may be attached to the support structure when covering the top opening and when removed from the top opening. The bioreactor may also include at least two exhaust filter heating blankets. The at least two exhaust filter heating blankets may have different sizes. The at least two exhaust filters may be configured to be selectively engaged based on the configuration of the vessel. The at least two exhaust filter heating blankets may be mounted on a rotatable element, and the at least two exhaust filter heating blankets may be configured to be selectively engaged by rotating the rotatable element. The support structure may also include one or more probe access/access/inspection ports. At least one of the probe access ports may be configured to accommodate an internal probe. The sidewall may include a body and a door, wherein the one or more probe access ports are located on the door of the sidewall. The sidewall may include a body and a door, wherein the top-mounted agitator motor is mounted on the door. The sidewall may include a body and a door, wherein the top-mounted agitator motor is mounted on the body.

One specific embodiment includes a method for modifying a bioreactor, the method comprising attaching a second agitator motor to a support structure comprising a first agitator motor and increasing an access area to the support structure. The first agitator motor may be a bottom-mounted agitator motor, and the second agitator motor may be a top-mounted agitator motor. The first agitator motor may be a top-mounted agitator motor, and the second agitator motor may be a bottom-mounted agitator motor. The support structure may include a sidewall body and a door, and increasing the access area may include adding an access panel to the door. The support structure may include a base, and the method may further include providing a preassembled removable spacer configured for placement above the base of the support structure. The support structure may include a top opening and a lid covering at least a portion of the top opening, and increasing the access area may include modifying the lid to enlarge an internal access area to the support structure. The method may further include attaching the lid to the support structure using a flexible member that remains attached to the lid when the lid is removed from the top opening of the support structure. Enlarging the access area may include adding one or more probe access ports to the bioreactor. The probe access ports may be configured to accommodate internal probes. The bioreactor may include an original exhaust filter heating blanket, and the method may further include adding an additional exhaust filter heating blanket to the bioreactor. The additional exhaust filter heating blanket may have a different size than the original exhaust filter heating blanket. The original and additional exhaust filter heating blankets may be configured to be selectively employed. Adding an additional exhaust filter heating blanket to the bioreactor may include mounting the additional exhaust filter heating blanket on a rotatable element connected to the support structure. The method may further include adding a control system configured to control a second agitator motor. The method may further include adding a selector for switching between the original and additional control systems. The original and additional control systems may be configured to be selectively employed using a digital user interface.

One particular embodiment includes a method of operating a bioreactor comprising a support structure and a multi-agitator motor system, the method comprising: selecting a bioreactor bag from the group consisting of a top-mounted agitator bag and a bottom-mounted agitator bag; selecting between a top-mounted agitator motor and a bottom-mounted agitator motor of the support structure; placing the selected bioreactor bag within the support structure; and coupling the selected bioreactor bag to the selected agitator motor. The method may further comprise confirming the presence of a spacer within the bioreactor. The method may further comprise placing the spacer within the bioreactor. The method may further comprise removing the spacer from the bioreactor. The method may further comprise attaching a bag connector to a support structure connector. The method may further comprise changing the vertical position of the top-mounted agitator motor.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1A shows a side view of one embodiment of a bioreactor with top-mounted and bottom-mounted agitator motors. Figures 1B-1C show perspective views of the support structure of the bioreactor of Figure 1A with its door open and closed, respectively.

Figure 2A shows a perspective view of a bag configured for use with a bottom mounted agitator motor. Figure 2B shows a perspective view of the rigid base of the bag of Figure 2A. Figure 2C shows a perspective view of a bag configured for use with a top mounted agitator motor.

3A-3B illustrate top and side perspective views, respectively, of the bottom portion of a bioreactor described herein, showing spacers.

Figures 4A-4C illustrate the top of one embodiment of a bioreactor described herein, showing a removable lid. Figures 4A-4B illustrate a top perspective view and a side view, respectively, of the bioreactor with the lid in a first position. Figure 4C illustrates a side view of the bioreactor with the lid in a second position.

Figure 5A shows a side perspective view of a bioreactor as described herein configured for use with a multiple probe configuration. Figure 5B is an enlarged view of the lower portion of the bioreactor of Figure 5A.

6 shows a perspective view of the top of one embodiment of a bioreactor described herein with a plurality of optionally usable exhaust filter heating blankets.

7A-7B illustrate perspective views of one embodiment of a bioreactor described herein having an adjustable position agitator motor shown in a first position in FIG. 7A and in a second position in FIG. 7B .

DETAILED DESCRIPTION

Disposable bioreactors typically include a container and a support structure configured to support the container, as well as other items coupled to the container. Typically, the support structure and container are designed to be used together, taking advantage of alternative container designs that incorporate the shortcomings of existing support structures. However, it may sometimes be desirable to utilize a single support structure to support containers of different designs. This article describes a bioreactor support structure configured for use with containers of different designs, as well as methods for using such a bioreactor. Bioreactors are typically categorized as having either a top-mounted or a bottom-mounted agitator motor, but the support structure described herein may include two or more agitator motors and control systems and/or adjustable position agitator motors, removable spacers and/or covers, multiple configurations for ports and probes, and multiple exhaust filter heating blankets. This article also describes methods for manufacturing a multi-agitator motor bioreactor and/or an adjustable position agitator motor bioreactor, as well as methods for modifying an existing support structure for use with a container that was not originally designed for use with an existing support structure, and methods for using such a bioreactor. These methods of modifying existing support structures can include some or all of the following: modifying an existing support structure to add one or more additional agitator motors or configuring the agitator motors to be adjustable, adding removable spacers, additional configurations for ports and probes, and exhaust filter heating blankets, and/or removing or modifying an existing lid. Also described herein are methods for operating the bioreactor support structures described herein and for operating the bioreactor support structures formed by the modification methods described herein. These bioreactors can be used in production processes with different disposable or single-use container configurations while still meeting mass transfer coefficient and culture performance standards with each container configuration.

FIG1A illustrates a side view of one embodiment of a bioreactor 100 described herein, configured for use with containers having various configurations. As shown, the bioreactor 100 may include a support structure 102 and a container 202. As shown, the support structure 102 may include a sidewall 104. Although shown in FIG1A-1C as being generally cylindrical and forming a bottom opening 116 and a top opening 118, the sidewall 104 may include any suitable shape configured to support a container, as described in greater detail below. The sidewall 104 may include an inwardly facing lip 120 at the top opening 118. The sidewall 104 may be comprised of any material or materials suitable for supporting a container, such as metal (e.g., stainless steel, aluminum, etc.), polymer (e.g., high-density polyethylene, polyacrylate, polycarbonate, polystyrene, nylon or other polyamide, polyester, or phenolic polymer), glass, fiberglass, etc. The bottom opening 116 of the sidewall 104 may be attached to a base 106, as shown in FIG1B , which may partially (or, in some variations, completely) cover the opening 116. In some variations, the base 106 may be integral with the sidewall 104. In conjunction with the sidewall 104, the base 106 may form a chamber 108, but as shown in FIG. 1B , the chamber 108 may not be completely covered at its bottom by the base 106. The base 106 may have a concave shape, such as a cone, or in other variations, the base 106 may have a flat or convex shape. In the variation shown in FIG. 1B , the base 106 may include an opening 140 configured to allow a bottom-mounted agitator motor 302 to interface with a container, as described in more detail below. The opening 140 may be circular, as shown, or it may have any suitable shape. The base 106 may additionally or alternatively include an opening 142, which may have any suitable shape configured to allow access through the base 106 to components such as ports, probes, and distributors, as described in more detail below. In the variation of FIG. 1B , the opening 142 may include a central region 148 and an outer region 150. The volume of chamber 108 may be any desired volume, such as, but not limited to, approximately 1 L, 3 L, 10 L, 20 L, 40 L, 100 L, 150 L, 200 L, 400 L, 600 L, 1000 L, 2000 L, 4000 L, or more.

In some variations, a portion of the sidewall 104 may include one or more doors 112. As shown in Figures 1A-1C, the door 112 may include a radial segment of the sidewall 104. The door 112 may be attached to the remainder of the sidewall 104 via a hinge. In variations having two adjacent doors 112a and 112b, the hinges may be located on opposite sides of the doors 112a and 112b, allowing the two doors 112 to open outward and away from each other. The door 112 may include a handle 146. When the door 112 is open, this may form an opening in the sidewall 104 that may make it easier to place a container within the support structure 102. Although the door 112 is shown in Figures 1A-1C as extending along the entire vertical length of the sidewall 104, it should be understood that in other variations, the door 112 may only extend along a portion of the vertical length of the sidewall 104. For example, the door 112 may extend from the top of the side wall 104 partially down the vertical length of the side wall 104, or in other variations, the door 112 may extend from an intermediate location along the length of the side wall 104 to the bottom of the side wall 104. The door 112 may optionally include a transparent or translucent window 138. It should also be understood that while the side wall 104 is shown in Figures 1A-1C as having a first door 112a and a second door 112b, in other variations, the side wall 104 may include only one door, or in still other variations, the side wall 104 may include no doors.

In some variations, support structure 102 may include a temperature regulation system for regulating temperature during the bioreactor process. The temperature regulation system may include an enclosure 136 that may allow for both heating and cooling. Enclosure 136 may be located within sidewall 104 between the inner and outer walls of sidewall 104. In other variations, the enclosure may be located within chamber 108 on the inside of sidewall 104. In some variations, the temperature regulation system may include an electrical heating element and/or a circulating fluid system. In variations where the temperature regulation system includes a circulating fluid system, there may be one or more fluid channels located within enclosure 136. The fluid channels may have one or more inlets and outlets that allow a fluid (e.g., propylene glycol, water, etc.) that can be heated or cooled by a temperature control unit to circulate through the channels to regulate the temperature of the bioreactor.

In some variations, bioreactor 100 may optionally include additional components as shown in FIG. 1A . For example, support structure 102 may optionally rest on support assembly 126 , which can elevate support structure 102 off the ground and allow it to be more easily moved. For example, support structure 102 may rest on cart 128 , which may be equipped with casters or wheels 132 . In other variations, support structure 102 may rest on the floor or another surface. Bioreactor 100 may additionally or alternatively include one or more control carts, which may hold components used in the production process, such as, but not limited to, temperature control units, pumps and mass flow controllers, media and buffer bags, and controllers, as described in more detail below. For example, in the variation shown in FIG. 1A , control cart 144 may hold temperature control unit 152 and controllers 306 and 308 , as described in more detail below, while a second cart (not shown) may hold a mass flow controller, also described in more detail below. It should be understood that in other variations with these elements, they may be held on two or more carts in different configurations, or they may be held by a single cart.

The support structure 102 can be configured to support, surround and/or accommodate a container 202, which can be configured to be placed in the chamber 108 of the support structure 102. The container 202 can define a reservoir 204 to keep the contents of the process for performing the bioreactor 100, such as, but not limited to, media, reactants, gases and other components. In some variations, the container 202 can be configured to be roughly sealed with the external environment, except for designated points such as ports and probe connectors (described below). Like this, the container 202 can keep the contents accommodated and not in contact with all or part of the support structure 102. This can allow the support structure 102 to be reused in multiple processes (e.g., by removing the container 202 from the support structure 102 and replacing it with a new container without the need for the same level of sterilization that would be required if the container 202 were not utilized, and the container 202 can be designed to be disposable or disposable.

In some variations, container 202 may include a bag 206. Bag 206 may be at least partially collapsible and/or at least partially comprised of a flexible material suitable for contact with the contents of reservoir 204 during the process performed in bioreactor 100, and may be water-impermeable. In some variations, bag 206 may comprise one or more materials, such as, but not limited to, polycarbonate, polyethylene, polypropylene, polyvinyl chloride, polyvinyl dichloride, polyvinylidene fluoride, ethylene vinyl acetate, polycarbonate, polymethacrylate, polyvinyl alcohol, nylon, and/or synthetic rubber or plastic, among others. Bag 206 may have any suitable thickness, such as, but not limited to, less than about 1 mm, about 1 to 3 mm, or about 3 to 5 mm, or more. In some variations, bag 206 may be single-layered, while in other variations, it may be multi-layered. In variations having more than one layer, each layer may have the same or different polymer orientation relative to other adjacent layers. The bag 206 can form the reservoir 204 in any number of ways; for example, in some variations, the bag may comprise two pieces of material joined at their edges to form the reservoir 204. In other variations, a single piece of material may be joined at its edges to form the reservoir 204. In still other variations, more than two pieces of material may be joined at their edges to form the reservoir 204, such as a single piece forming the cylindrical portion and two pieces forming the top and bottom panels. In some variations, a portion of the container may comprise a rigid material, such as a rigid base. In some variations, the bag 206 may be pre-sterilized and sealed. The bag 206 may also include one or more connectors for attaching the bag 206 to the support structure 102, as well as one or more inlet and/or outlet ports and one or more detector connectors as described in more detail below.

The reservoir 204 of the bag 206 can have any desired volume, such as, but not limited to, up to about 1 L, 3 L, 10 L, 20 L, 40 L, 100 L, 150 L, 200 L, 400 L, 600 L, 1000 L, 2000 L, 4000 L, or more. It should be understood that while disposable bioreactor support structures are typically used with vessels having approximately the same size and volume, such uniformity is not required, and in fact, the support structure 102 can be configured such that the support structure 102 can be used with a bag 206 having a different volume or size than the chamber 108 of the support structure 102. For example, in one variation, the chamber 108 of the support structure 102 can have a volume of approximately 200 L while being used with a bag having a volume of approximately 250 L. In another variation, chamber 108 may have a volume of approximately 200 to 250 L, while being used with a bag having a volume of approximately 100 L. In some variations, chamber 108 of support structure 102 may have a maximum diameter (or maximum distance transverse to the longitudinal axis) of approximately 20 to 22 inches, while being used with a bag having a diameter (or maximum distance transverse to the longitudinal axis) of approximately 23 to 25 inches. It should be understood that support structures having chambers having a range of volumes and sizes may be used with bags having a range of volumes and sizes, not limited to the examples provided herein. It should also be noted that in some cases, where the temperature regulation system of the support structure 102 includes a shell 136 located inside the side wall 104, or between the inner wall and the outer arm, if the diameter of the bag 206 (or the maximum distance transverse to the longitudinal axis) is smaller than the diameter of the support structure 102 (or the maximum distance transverse to the longitudinal axis) to an extent that affects the performance of the temperature regulation system, a member for transferring heat between the shell 136 and the bag 206, such as a spacer or other structure to assist in temperature regulation, may be added.

Typically, a disposable bioreactor includes an agitator system that facilitates mixing of the container's contents. The agitator may include an impeller and an agitator motor configured to rotate the impeller. The impeller may include blades or vanes for engaging the container's contents during rotation. The impeller may typically be located within the container, while the agitator motor is located outside the container, with the coupling between the agitator motor and the impeller configured to maintain the sterility of the container's environment. In some bioreactors, the coupling may be magnetic, for example, while in others, the coupling may be mechanical. Disposable bioreactors typically include a support structure with a top-mounted agitator motor or a bottom-mounted agitator motor, configured for use with either a top-mounted agitator container (i.e., a container having an impeller configured to be rotated by a top-mounted agitator motor) or a bottom-mounted agitator container (i.e., a container having an impeller configured to be rotated by a bottom-mounted agitator motor), respectively. However, as described above, it is desirable that a single support structure be capable of being used with containers of different designs, including both top-mounted and bottom-mounted agitator containers.

Thus, in one variation, the bioreactor 100 described herein may include an agitator system 300 that includes both a bottom-mounted agitator motor and a top-mounted agitator motor. Thus, the bioreactor 100 may be configured for use with containers having different designs, including containers configured for use with both bottom- and top-mounted agitator motors. As shown in FIG1B , the bioreactor 100 may include a bottom-mounted agitator motor 302. The bottom-mounted agitator motor 302 may be located below the base 106 of the support structure 102. The base 106 may include an opening 140 configured to allow for interfacing with a container as described in more detail below. The opening 140 may be circular as shown, or it may be any suitable shape.

As shown in Figures 1A-1C, the bioreactor 100 may also include a top-mounted agitator motor 304. The top-mounted agitator motor 304 may be mounted on the support structure 102. In the variation shown in Figures 1A-1C, the top-mounted agitator motor 304 may be mounted on the top 114 of the door 112 of the sidewall 104. In other variations, the top-mounted agitator motor 304 may be mounted on the lip 120 of the sidewall 104. For example, in some cases, it may be desirable to mount the top-mounted agitator motor 304 on a fixed member of the support structure 102. In some cases, it may be desirable to mount the top-mounted agitator motor 304 on a portion of the sidewall 104 above the enclosure 136, so that the top-mounted agitator motor 304 does not interface with the enclosure 136. However, in some variations, the top-mounted agitator motor 304 may be mounted on the portion of the sidewall 104 that contains the enclosure 136. In still other variations, the top-mounted agitator motor 304 can be mounted on a structure separate from the sidewall 104. For example, the top-mounted agitator motor 304 can be mounted on a rod that can be attached to the cart 144. Alternatively, the top-mounted agitator motor 304 can be mounted on a separate support structure. The top-mounted agitator motor 304 can be mounted via any suitable method, such as by welding the top-mounted agitator motor 304 in place or attaching it to the support structure 102 via a mounting bracket.

Although the agitator motor 304 is shown in Figures 1A-1C as having a fixed position, in other variations, the top-mounted agitator motor 304 may have an adjustable position. In some of these variations, the top-mounted agitator motor may be movable relative to the sidewall 104 of the support structure 102. For example, the top-mounted agitator motor may slide along a slide or track. In this case, the slide or track may allow the top-mounted agitator to be fixed at one or more discrete positions along the slide or track. For example, the slide or track may include openings for pins that allow the top-mounted agitator motor to be fixed at various positions along the slide or track corresponding to various vertical, horizontal, or radial positions relative to the sidewall of the support structure. In other variations, the slide or track may allow the top-mounted agitator to be fixed at any position along the slide or track. As another example, the top-mounted agitator motor may be removably fixed to one of a plurality of mounting brackets located at various positions relative to the sidewall of the support structure. The top mounted agitator motor can then be selectively secured to one of the mounting brackets (e.g., using removable pins) at a desired location. By having an adjustable position, for example, the top mounted agitator motor can be positioned and operated at a range of intermediate positions between the top and bottom regions of the support structure 102. A vertically movable top mounted agitator motor can have advantages, such as providing additional flexibility that allows the use of containers having a shorter height than the chamber of the support structure to be agitated by the top mounted agitator motor or allows the container to have a lower minimum working volume. Furthermore, an adjustable position agitator motor can allow the position of the agitator motor to be moved during a process cycle, for example, as the working volume increases.

In other variations, in order for a single support structure to be able to be used with containers of different designs, the bioreactor described herein may include only a single agitator motor with an adjustable position. Similar to multiple agitator motors with top-mounted agitator motors that have adjustable positions, in a single agitator motor design with an adjustable position agitator motor, the single agitator motor can move vertically, horizontally, and/or radially relative to the support structure, and/or can rotate relative to the support structure. By having adjustable positions, the agitator motor can be positioned and operated at a range of positions. In some variations, these positions may include a top-mounted agitator position and a bottom-mounted agitator position (that is, positions that allow the agitator motor to be used in conjunction with containers configured to be used with top-mounted and bottom-mounted agitators, respectively). In other variations, these positions may optionally additionally include one or more intermediate positions between the top position and the bottom position. An adjustable position agitator motor may have advantages such as, but not limited to, providing additional flexibility by allowing the motor to operate the impeller of a top-mounted or bottom-mounted agitator vessel, allowing the motor to rotate the impeller of a top-mounted agitator vessel having a shorter height than the chamber of the support structure, or allowing a vessel to have a lower minimum working volume. Additionally, an adjustable position agitator motor may allow the position of the agitator to be moved during a process cycle.

In one example of an adjustable position agitator motor, the agitator motor can slide along a slide or track in a manner similar to that described above for a top-mounted agitator motor. In some variations, the track can extend along the periphery of the support structure to allow the agitator motor to be adjusted horizontally around the periphery of the support structure. In other variations, the slide or track can extend vertically to allow the agitator motor to be adjusted vertically up and down relative to the support structure. In other variations, the track can be configured so that the agitator motor can be adjusted radially toward and away from the center of the support structure. In yet other variations, the angle of the agitator motor can be adjusted. In some variations, the track can be configured so that the agitator motor can be adjusted along two or more of these dimensions. The slide or track and the agitator motor can be configured so that the agitator motor can be selectively fixed at discrete locations along the slide or track, or they can be configured so that the agitator motor can be selectively fixed at any point along the slide or track. The blender motor may be secured using a mechanism such as, but not limited to, a removable pin, a rack and pinion arrangement, a clamp, or the like. For example, if the blender motor is secured to a rail or track using pins, the rail or track may include a series of openings configured to receive the pins. The blender motor may be slidably attached to the rail or track via a base and may be pushed or pulled along the rail or track until one or more openings in the base align with one or more openings in the rail or track. One or more pins may then be inserted into the one or more openings to secure the blender motor in the desired position. As another example, if the blender motor is secured to the rail or track using a clamp, the blender motor may slide along the rail or track when the clamp is in a released configuration. In some variations, the blender motor may be pushed or pulled along the rail or track, at which point the clamp may be placed in a tightened configuration to hold the blender motor in place. In other variations, the blender motor may be removable from the rail or track when the clamp is in a released configuration. The agitator motor can be placed in the desired position along the slide or track and fixed by placing the fixture in a tightening configuration. In some variations, the fixture and slide or track can be configured so that the agitator motor can be clamped at two or more angles relative to the slide or track, thereby allowing the agitator motor to be fixed at two or more angles relative to the supporting structure. In variations in which the agitator motor is pushed or pulled along the slide or track, the agitator motor can be directly pushed or pulled by the user, or it can be pushed or pulled indirectly, such as via a manual mechanism (e.g., a hand crank) or via an automated mechanism (e.g., a motor or user interface or a switch). In some variations, the slide or track can be fixed on the supporting structure of the bioreactor, and in other variations, the slide or track can be fixed on a separate structure alternatively. For example, the slide or track can be attached to a trolley (similar to the trolley 144 of FIG. 1A ) of other elements used during the bioreactor process, or can be fixed on a separate supporting structure or can be a part thereof.

As another example, the agitator motor can have an adjustable position by being fixed to a shaft that is, in turn, adjustable relative to the support structure. That is, the agitator motor can be fixedly attached to a shaft that is, in turn, adjustably attached to the support structure. As in the above variations, the shaft can be adjusted relative to the support structure to allow the agitator motor to move horizontally, vertically, and/or radially relative to the support structure, and/or to adjust the angle of the agitator motor relative to the support structure. The shaft can be adjusted relative to the support structure using any suitable mechanism, such as, but not limited to, a removable pin, a rack and pinion arrangement, a clamp, or the like. For example, the shaft can be adjusted relative to the support structure using a removable pin or clamp in a manner similar to that described above for agitator motors that can move along a slide or track. In other variations, the shaft can be attached to a structure separate from the bioreactor support structure, and the shaft can be adjusted relative to the separate structure, or the separate structure can be adjusted relative to the bioreactor support structure. As yet another example, the agitator motor can have an adjustable position by being fixed on a shaft having an adjustable length. In some variations, the shaft can have a telescopic section that allows for length adjustment. Additionally or alternatively, the shaft can have sections that can be added or removed to allow for length adjustment. As described above, the shaft can be mounted on a supporting structure for the bioreactor, or it can be mounted on a separate structure, such as a cart (such as cart 144 of FIG. 1A ) that holds other elements used in the bioreactor process, or a separate structure.

As another example, the agitator motor can have an adjustable position by being removably fixed on one of a plurality of mounting brackets located at various positions relative to the side wall of the support structure. The agitator motor can be selectively fixed on a mounting bracket in the mounting bracket (e.g., using a removable pin) at a desired position. In some variations, one or more mounting brackets in the mounting brackets can have a variety of configurations for attaching the agitator motor (e.g., the agitator motor can be fixed at a range of angles, and/or can be fixed at one of a plurality of positions on the mounting bracket). An example of a bioreactor in which the agitator motor is removably fixed on one of a plurality of mounting brackets is shown in Figures 7A-7B. In the bioreactor 800 shown therein, the adjustable position agitator motor 802 can be removably fixed on a first mounting bracket 804 or a second mounting bracket 806. When the adjustable-position agitator motor 802 is removably secured to the first mounting bracket 804 as shown in FIG7A , it can be positioned to allow the agitator motor 802 to be used with a container configured for use with a top-mounted agitator motor. The agitator motor 802 can be secured to the first mounting bracket 804 via a pin 808. When the adjustable-position agitator motor 802 is removably secured to the second mounting bracket 806 as shown in FIG7B , it can be positioned to allow the agitator motor 802 to be used with a container configured for use with a bottom-mounted agitator motor. It should be understood that the orientation of the agitator motor 802 can additionally or alternatively be adjusted; for example, the attachment portion for the container can be oriented generally downward when the agitator motor is secured to the first mounting bracket 804, while the attachment portion for the container can be oriented generally upward when the agitator motor is secured to the second mounting bracket 806. While the mounting bracket that optionally secures the agitator motor in Figures 7A-7B is attached to the support structure of the bioreactor 800, it will be appreciated that in other variations the mounting bracket may be located on a separate structure or cart.

Returning to FIG. 1A , in some variations, the bioreactor 100 may include a first control system 306 configured to control the bottom-mounted agitator motor 302 and a second control system 308 configured to control the top-mounted agitator motor 304. In some variations, the first control system 306 and/or the second control system 308 may include variable frequency drives. The first control system 306 and the second control system 308 may be selectively used to operate the bottom-mounted agitator motor 302 and the top-mounted agitator motor 304, respectively. In some variations, the bioreactor 100 may include one or more manual control switches that can be used to selectively turn the first control system 306 and/or the second control system 308 on and off, and/or a selector 310 for switching between using the first control system 306 and using the second control system 308. In other variations, the bioreactor 100 may additionally or alternatively include a user interface that can be used to selectively turn the first control system 306 and/or the second control system 308 on and off. In some variations, the user interface may be digital. In some variations, only one of the first control system 306 and the second control system 308 may be operational at a time, while in other variations, both the first control system 306 and the second control system 308 may be operational simultaneously. In addition to or in lieu of controlling the bottom-mounted agitator motor 302 and the top-mounted agitator motor 304 to turn on or off, respectively, the first control system 306 and the second control system 308 may also control the speed of the motors. Furthermore, in some variations, the first control system 306 and/or the second control system 308 may also control the temperature of a heating blanket for the exhaust filter to prevent filter clogging, and/or control other sensors.

In variations including both a bottom-mounted agitator motor 302 and a top-mounted agitator motor 304, which may be selectively employed by a separate control system in some variations, the bioreactor 100 can be used with containers configured for use with either a bottom-mounted or top-mounted agitator motor. Similarly, the bioreactor 800 described above, which has an adjustable position agitator motor, can also be used with containers configured for use with either a bottom-mounted or top-mounted agitator motor. For example, the bioreactor described herein can be used with a bag 208 configured for use with a bottom-mounted agitator motor, an example of which is shown in Figures 2A-2B. The bag 208 can include an agitator port 210 located in a lower portion 212 of the bag 208 that is configured to interface with either a bottom-mounted agitator motor or an adjustable agitator motor in a bottom-mounted position. In some variations, as shown in FIG2B , the agitator port 210 may be located in a rigid base 226 attached to the lower portion 212 of the bag 208. The rigid base 226 may comprise a rigid or semi-rigid material, such as, but not limited to, low-density or high-density polyethylene. In other variations, the agitator port 210 may be located on a flexible portion of the bag 208. In some variations, the interface, and therefore the agitator port 210, may be located offset from the center of the support structure 102 and/or bag 208. For example, the interface may be located approximately 10-20 degrees off-center, approximately 20-30 degrees off-center, approximately 30-40 degrees off-center, or more. The agitator port 210 may be configured to engage a bottom-mounted agitator motor or an adjustable agitator motor in a bottom-mounted position. In some variations, the base 1006 of the support structure 102 may optionally include a protrusion to help hold the agitator port 210 in place. The agitator port 210 can allow the agitator motor 302 mounted at the bottom to rotate the impeller 224. The agitator motor 302 mounted at the bottom can be configured to rotate the impeller 224 at any suitable speed or a range of speeds, such as, but not limited to, about 0 to 120 rpm, about 0 to 150 rpm, or about 0 to 360 rpm. The impeller 224 can have any suitable design. In some variations, the impeller 224 can include two, three, four, or more blades having a pitch angle of less than 10 degrees, about 10 to 20 degrees, about 20 to 30 degrees, about 30 to 40 degrees, about 40 to 50 degrees, or more. The impeller 224 can have any suitable diameter (or the maximum distance transverse to its longitudinal axis), such as less than 5 cm, 5 to 10 cm, 10 to 15 cm, or more. 2B , it will be appreciated that in other variations, the vertical position of the impeller 224 may be adjusted relative to the bag 208. For example, the impeller may interface with the agitator port via an agitator shaft having an adjustable length, the impeller may be adjustable along the agitator shaft, or the agitator shaft may be movable relative to the agitator port.

The bioreactor described herein can also be used with a bag 214 configured for use with a top-mounted agitator motor or an adjustable agitator motor in a top-mounted position, as shown in FIG2C . The bag 214 can include an agitator port 218 located in the top 216 of the bag 214. Within the bag 214, an agitator shaft 220 can be attached to the agitator port 218, which in turn can be attached to an impeller 222. The agitator motor can be configured to rotate the impeller 222 via the agitator shaft 220 at any suitable speed or range of speeds, such as, but not limited to, about 0 to 120 rpm, about 0 to 150 rpm, or about 0 to 360 rpm. The impeller 222 can have any suitable design. In some variations, the impeller 222 can include two, three, four, or more blades, each having a pitch angle of less than 10 degrees, about 10 to 20 degrees, about 20 to 30 degrees, about 30 to 40 degrees, about 40 to 50 degrees, or greater. Impeller 222 may have any suitable diameter (or maximum distance transverse to its longitudinal axis), such as less than 5 cm, 5 to 10 cm, 10 to 15 cm, or more.

In some variations, the vertical position of the impeller 222 can be adjusted relative to the bag 214. In these variations, the agitator shaft 220 can have an adjustable length, and/or the position of the impeller 222 can be moved relative to the agitator shaft 220. For example, the impeller 222 can be fixed on the agitator shaft 220, and the agitator shaft 220 can have one or more parts so that the length of the agitator shaft 220 can be adjusted. In some variations, the agitator shaft 220 can have a telescopic section that allows for length adjustment. Additionally or alternatively, the agitator shaft 220 can have sections that can be added or removed to allow for length adjustment. By adjusting the length of the agitator shaft 220 between the location where the impeller 222 is attached and the agitator port 218, the vertical position of the impeller 222 can be adjusted before or during the process. As another example, the vertical position of impeller 222 relative to bag 214 can be adjusted by being attached to agitator shaft 220 via one or more removable screws or pins that can secure impeller 222 in various vertical positions along agitator shaft 220. In one such example, impeller 222 can be mounted on a horizontal plate, which in turn can be attached to agitator shaft 220 via one or more removable screws or pins. This allows impeller 222 to be moved into a desired vertical position relative to agitator shaft 220 within the vessel before or during a process. As another example, the vertical position of impeller 222 can be adjusted relative to bag 214 by a support structure comprising a movable bottom plate that allows the bottom of the bag to move vertically relative to the impeller position. If the bottom plate is moved vertically upward relative to the support structure, it can push up on the bottom and the bag (which can cause the bag to collapse or compress), thereby moving the bottom of the bag toward the impeller. This can effectively reduce the volume of the bag. In some variations, the base plate may include a spacer 400, described in greater detail below, configured to couple to the inside of the inner wall of the support structure at variable vertical positions (e.g., via tabs or hooks). Making the vertical position of the impeller 222 adjustable relative to the bag 214 in one of the above-described ways or another may have certain advantages, such as, but not limited to, allowing the bag 214 to have a lower maximum working volume. Furthermore, a vertically adjustable impeller 222 may allow the position of the impeller 222 to shift during a process cycle, for example, as the working volume increases.

The container (e.g., bag 208 or bag 214) and/or the support structure may include one or more connectors for attaching the container to a bioreactor (e.g., bioreactor 100 or bioreactor 800) and/or for holding the container in a characteristic configuration (e.g., pulled into an expanded configuration). In some variations, at least one connector is located on a sidewall or base of the support structure for attachment to the container. For example, the container may include a bag connector (e.g., a hook) configured to attach to a support structure connector. In other variations, the container and support structure may not include connectors, and instead, the container may be held in place by attachment to the agitator motor described in more detail above.

In some variations, the bioreactors described herein may include a spacer 400 configured to fit adjacent the bottom opening 116 or base 106 of the support structure 102. More specifically, the spacer 400 may rest or be attached to the base 106 of the support structure 102 as shown in Figures 3A-3B. The spacer 400 may be configured to be placed in the support structure 102 when the bioreactor is used with a container configured for use with a top-mounted agitator motor (e.g., bag 214), and to be removed from the support structure 102 when the bioreactor is used with a container configured for use with a bottom-mounted agitator motor (e.g., bag 208). When the spacer 400 is positioned in the support structure, the top surface 402 of the spacer 400 can provide a raised support surface for the bottom of the container, form a smooth surface for the bottom of the container, and/or, in variations of bioreactors having a bottom-mounted agitator motor, prevent the bottom of the container from contacting the bottom-mounted agitator motor 302 and/or any structure (e.g., protrusions) associated with the bottom-mounted agitator motor 302. For example, the bag 208 can have a conical bottom, while the bag 214 can have a flat bottom, and thus the spacer 400 can be placed in the support structure 102 when the bag 214 is in use to form a flat bottom for the bag 214, while the spacer 400 can be removed from the support structure 104 when the bag 208 is in use to accommodate the conical bottom of the bag 208.

The spacer 400 may comprise any suitable material or materials. In some variations, the spacer 400 may comprise a low density material so that the spacer 400 can more easily move into and/or out of the support structure 102. For example, the spacer 400 may comprise a polymer, such as, but not limited to, polyoxymethylene or ultra-high molecular weight polyethylene. The spacer 400 may be sized and formed to fit within the support structure, and in some variations may have the same cross-sectional (e.g., transverse to the longitudinal axis) shape as the support structure and/or the base of the support structure. The spacer 400 may have any suitable thickness, such as, but not limited to, about 1 to 2 inches, about 2 to 4 inches, about 4 to 8 inches, or greater. In some variations, the spacer 400 may have a variable thickness.

In some variations, spacer 400 may optionally include other features. For example, spacer 400 may include a slot 404 extending from top surface 402 to bottom surface 406. In variations where spacer 400 is used with a container having a tube attached to the bottom of the container, slot 404 may allow the tube to pass through spacer 400. As shown in FIG3A , in some variations, slot 404 may include a generally circular region 408 and a generally rectangular region 410, which may be connected at a first end 412 of generally rectangular region 410. A second end 414 of generally rectangular region 410 may extend to an outer edge 416 of spacer 400. As another example, spacer 400 may include a notch 418 at outer edge 416 of spacer 400. Similar to slot 404, notch 418 may allow a tube exiting the container to pass through or around spacer 400. In some variations, notch 418 may be positioned generally diametrically opposite slot 404. Although shown as a portion of a cylinder in Figures 3A-3B, it should be understood that in other variations, the notch 418 may have other suitable shapes. It should also be understood that in other variations, the spacer may have any configuration that can be configured to include a slot, recess, or opening that allows a tube or other component to pass through or around the spacer, and that the spacer need not have the specific configuration shown in Figures 3A-3B. In other variations, the spacer may not include any slots, recesses, or openings. Spacer 400 may additionally or alternatively include two recesses 420. These recesses allow a handle to be attached to the spacer, thereby making it easier to remove it from the support structure. It should be understood that in other variations, the spacer may have other features to assist in its removal, such as tabs or an attached handle, or in yet other variations, the spacer need not have any features to assist in its removal. Although the spacer 400 is described above with respect to a bioreactor 100 having multiple agitator motors, it should be understood that the bioreactor 800 described herein having a single adjustable position agitator motor may also include a spacer having similar design and features.

As shown in Figures 4A-4C, in some variations, the bioreactor 100 can include a lid 500. This lid may be desirable when the bioreactor described herein is used with a container configured for use with a bottom-mounted agitator (e.g., bag 208), for purposes such as, but not limited to, assisting with the organization of tubing associated with the bioreactor and supporting one or more baffles. On the other hand, when the bioreactor is used with a container configured for use with a top-mounted agitator motor (e.g., bag 214), it may be desirable to have more headroom near the top opening of the support structure. Accordingly, the lid 500 can be moved between a first position and a second position, wherein the second position provides more headroom near the top opening of the support structure and/or expands the internal access to the support structure. Thus, the lid 500 can be generally in the first position when the bioreactor is used with a container configured for use with a bottom-mounted agitator motor (e.g., bag 208), while the lid 500 can be generally in the second position when the bioreactor is used with a container configured for use with a top-mounted agitator motor (e.g., bag 208).

In some variations, as shown with respect to bioreactor 100, in a first position, lid 500 can be attached or otherwise positioned adjacent to top opening 118 of sidewall 104, fully or partially covering top opening 118. As shown in Figures 4A-4B, in a first position, lid 500 can be attached to lip 120 of sidewall 104. This attachment can be via one or more bolts or screws 122 extending from lip 120, which can be configured to interface with one or more tabs 510 extending from lid 500. Bolts or screws 122 and tabs 510 can allow lid 500 to be secured in the first position. While the variation shown in Figures 4A-4C includes three bolts 122 and tabs 510, it should be understood that lid 500 and lip 120 can be connected at fewer or more points (e.g., one, two, four, five, six, or more). It should also be understood that lid 500 can be attached via another mechanism, such as a clip or slot.

In the second position, the lid 500 may not cover the top opening 118 of the sidewall 104. In some variations, the lid 500 may be completely removed from the bioreactor 100, such that in the second position, it is not attached to the bioreactor 100 and can be placed elsewhere. In other variations, such as the variation shown in FIG4C , the lid 500 may be attached to a portion of the bioreactor 100 when in the second position, so that the lid 500 cannot be misplaced. For example, the lid 500 may be attached to a flexible member or tether 518 (e.g., a chain or cord), which in turn may be attached to another portion of the bioreactor 100 (e.g., the lip 120 of the sidewall 104), such that the tether 518 prevents the lid 500 from being completely removed from the bioreactor 100. In some variations including a tether 518, the tether 518 can be configured such that the lid 500 can be in both a first position and a second position while the tether 518 remains attached to both the lid 500 and another portion of the bioreactor 100. The lid 500 can additionally or alternatively be configured to be attached directly to a portion of the bioreactor 100. For example, the sidewall 104 of the support structure 102 can include a bolt 124 configured to interface with one of the tabs 510 on the lid 500.

The lid 500 can have any suitable shape. In some variations, the shape of the lid can be configured to help hold the container, any baffles, and/or tubing extending from the container in place. In the variation of Figures 4A-4C, the lid can include a circular section 502 with two cutout areas 504 and 506, which can be rectangular as shown. The lid 500 can optionally include a handle 508, which can facilitate movement of the lid 500. Although the lid 500 is described above with respect to a bioreactor 100 having multiple agitator motors, it should be understood that the bioreactor 800 described herein, which has a single adjustable position agitator motor, can also include a lid having a similar design and features.

Typically, a bioreactor can include one or more inlet ports and one or more outlet ports that allow components (e.g., fluids or gases) to move into and out of a container. The inlet port can be connected to a pipeline for, for example, conveying components such as a medium and a cell culture. The inlet port can also include a distributor configured to convey gases required for the process implemented in the bioreactor, such as, but not limited to, oxygen, carbon dioxide, nitrogen, etc. The flow through these ports can be controlled by a mass flow controller. For example, in some variations, a bioreactor can include a group of mass flow controllers for air, oxygen, carbon dioxide, and nitrogen. These gases can have the flow rate required for the process to be implemented, such as, for example, approximately 20 slpm, approximately 20 slpm, approximately 5 slpm, and approximately 10 slpm, respectively. The outlet port can include a sample line. The bioreactor can also typically include a location for one or more detectors. The detector can be configured to measure temperature, pH value, dissolved oxygen, dissolved carbon dioxide, pressure, mixing speed, gas flow rate, etc. Just as disposable bioreactors typically have a support structure with an agitator system—where the configuration of the support structure (e.g., having a top-mounted or bottom-mounted agitator motor) typically limits the use of containers to those configured for use with that support structure—disposable bioreactors similarly typically have port and probe configurations such that only specific containers can be effectively used with specific support structures.

In contrast, the bioreactors described herein can include multiple configurations for ports and probes, allowing more than one container design to be used with the support structure. In some variations, the bioreactors described herein can be configured for use with containers having different configurations of inlet and outlet ports and distributors, as well as their associated tubing. For example, the spacer 400 described above can be placed within the support structure 102 or removed therefrom, as appropriate, to accommodate tubing or distributors at the bottom of the container; similarly, the lid 500 can be placed in a first or second position, as appropriate, to accommodate tubing at the bottom of the container. In some variations, the bioreactors described herein can be configured for use with containers configured for internal probes and with containers configured for external probes. For example, in the variation of Figures 5A-5B, the bioreactor 100 can include, in addition to a port 608 configured for use with an internal probe 612, an external sensor circuit 604 (shown in Figure 5A) configured for use with an external probe 606. The external sensor circuit 604 can be attached to the container 202 via a tube 616 and, in some variations, can include an external pH probe 606a and an external dissolved oxygen probe 606b. A port 608 configured for use with an internal probe 612 can include an opening 610 in the sidewall 104 of the support structure 102. In some variations, as shown in FIG. 5B , the opening 610 can be located on the door 112 (e.g., through the window 138). A probe support 614 can optionally be attached to the outside of the door 112 to support the internal probe 612 after insertion. In some variations, the openings 610 can include two top openings 610a and 610b configured for insertion of dual internal dissolved oxygen probes 612a and 612b and two bottom openings 610c and 610d configured for insertion of dual pH probes 612c and 612d. The openings 610 can also include an opening 610e configured for insertion of a temperature probe 612e. The door 112 may also include an opening 618 that can be used as a sampling port via a tube 620. It should be understood that in other variations, the opening may have different configurations and be configured for use with different types of probes, and in some variations, such as variations of the bioreactor 100 that do not include a door, the internal probe 612 may be configured to fit through other openings in the support structure 102, such as through an opening in the sidewall 104 or through an opening in the base 106. It should also be understood that the support structure 102 may include more than one set of openings for internal probes (e.g., the support structure 102 may include two, three, four, or more different sets of openings) to allow the support structure 102 to be used with containers having more than one different internal probe port configuration. Although the port and probe configurations are described above with respect to a bioreactor 100 having multiple agitator motors, it should be understood that the bioreactor 800 described herein having a single adjustable position agitator motor may also maintain a similar port and probe configuration.

Bioreactors may also typically include one or more exhaust filters. The exhaust filters can be connected to the containers via pipes and can allow gas to be discharged from the containers, which can prevent pressure accumulation in the containers. The exhaust filters are typically attached to the support structure of the bioreactor or supported by it in other ways, and the bioreactor can typically include a heating blanket that can prevent condensation in the filter or clogging of the filter. The heating blanket is typically sized to fit a specific exhaust filter, which can vary depending on the container. Therefore, the heating blanket usually needs to be compatible with the container used for the bioreactor support structure. Therefore, similar to the other characteristic structures mentioned above, the heating blanket design usually limits the use of the support structure to use with compatible containers. However, it is desirable to be able to use support structures with different containers, and therefore it is desirable for the bioreactor to include interchangeable or selectively employable heating blankets.

As shown in FIG6 , the bioreactor 100 can thus include at least one first heating blanket 702 having a first design and at least one second heating blanket 704 having a second design. The first heating blanket 702 and the second heating blanket 704 can be configured for use with containers configured to be used with different exhaust filter designs and can be selectively employed based on the exhaust filter that corresponds to the container configuration being used for a particular process. For example, the heating blanket 702 and the heating blanket 704 can have different sizes to accommodate exhaust filters that are sized in different ways. As shown in FIG6 , there can be two (or more, e.g., three, four, or more) heating blankets 704. Additionally or alternatively, there can be two (or more, e.g., three, four, or more) heating blankets 702. It should be understood that in other variations, the bioreactor 100 can include more than two different heating blanket designs (e.g., three, four, five, six, or more).

In some variations, the heating blanket 702 and/or the heating blanket 704 can be mounted so that they can be physically moved. This can allow a specifically designed heating blanket to be moved closer to the container. As shown in FIG6 , a rod 708 can extend vertically upward from the support structure 102. The heating blankets 702 and 704 can be attached to the rod 708. In some variations, the rod 708 can rotate about its longitudinal axis so that the positions of the heating blankets 702 and 704 relative to the support structure 102 can be adjusted. For example, as shown in FIG6 , the heating blankets 702 and 704 can be located on opposite sides of the rod 708 so that the rod 708 can rotate approximately 180 degrees to move the heating blanket 702 or the heating blanket 704 closer to the container. As shown, the rotation of the rod 708 to bring the heating blanket 704 closer to the container makes it easier to install the exhaust filter 710 within the heating blanket 704. In other variations, the heating blankets 702 and 704 may be spaced less than approximately 180 degrees apart, and thus the rod 708 may be rotated a smaller angle accordingly to bring the heating blanket 702 or 704 closer to the container. In still other variations, the rod 708 may have an adjustable length instead of or in addition to being rotatable. In these variations, the heating blankets 702 and 704 may be located at different vertical distances from the support structure 102 (on the same side of the rod 708, on opposite sides of the rod 708, or spaced at an intermediate radial distance), and the length of the rod 708 may be adjusted to bring the heating blanket 702 or 704 closer to the container. It should also be understood that in other variations, the heating blankets may be connected to the support structure via other mechanisms, or the heating blankets may be attached to an alternative structure rather than the support structure 102, such as a separate support post or cart. Although the heating blanket is described above with respect to a bioreactor 100 having multiple agitator motors, it should be understood that the bioreactor 800 described herein having a single adjustable position agitator motor may also include a heating blanket configuration having similar design and features.

Also described herein are methods for modifying an existing support structure for use with a container that was not originally configured for use with an existing support structure. In some variations, this can include modifying an existing single-agitator motor support structure into a multi-agitator motor support structure. For example, a support structure having the general configuration of support structure 102 described above, but having a single top-mounted or bottom-mounted agitator motor, can be modified to include a second agitator motor, such that the modified support structure has both top-mounted and bottom-mounted agitator motors. When the original support structure includes a bottom-mounted agitator motor (such as bottom-mounted agitator motor 302 described above), the modification can be implemented by installing a top-mounted agitator motor (such as top-mounted agitator motor 304 described above) in one of the configurations described above for installing top-mounted agitator motor 304 of bioreactor 100. Alternatively or additionally, the modification can be implemented by installing a top-mounted agitator in a manner that allows the top-mounted agitator to be vertically adjusted, as described above for top-mounted agitator motor 304 of bioreactor 100. In variations where the top-mounted agitator motor is mounted on a door of the support structure, the door hinges may be reinforced to support the additional weight of the top-mounted agitator motor. In variations where the top-mounted agitator motor is mounted on a portion of the side wall that contains a housing for temperature regulation, the housing may be modified to allow for installation of the motor. Alternatively, where the original support structure includes a top-mounted agitator motor, the modification may be implemented by mounting a bottom-mounted agitator motor adjacent a bottom opening in the side wall of the support structure. In some such methods that include installing a bottom-mounted agitator motor, it may be necessary to remove or otherwise modify all or a portion of the base of the support structure. When a second agitator motor is added to the support structure, the method may further include adding a control system to the bioreactor, such as control systems 306 and 308 described above, which control system may control the second agitator motor as described above.

In other variations, methods for modifying an existing support structure for use with a container not originally configured for use with the existing support structure may include modifying an existing single agitator motor support structure having a fixed agitator motor to provide an adjustable position of the agitator motor, thereby providing the features described above with respect to bioreactor 800. For example, the existing fixed agitator motor may be removed from the support structure and mounted in a manner that allows for vertical, horizontal, radial, and/or rotational adjustment, as described with respect to the adjustable agitator motor of the nitrogen agitator bioreactor described above. In some such methods, where the existing single agitator motor is a top-mounted agitator motor, all or a portion of the base of the support structure may not need to be removed or otherwise modified to allow the agitator motor to be selectively positioned at the bottom.

When the original support structure includes a bottom-mounted agitator motor, the modification may also include adding a spacer near the bottom of the support structure, such as the spacer 400 described in detail above. The spacer may provide support for a container configured for use with a top-mounted agitator motor and/or form a smooth surface for such a container and prevent it from contacting the bottom-mounted agitator motor or related structure, as described with respect to the spacer 400 discussed in detail above.

When the original support structure includes a bottom-mounted agitator motor, the modification may also include removing any existing cover on the support structure. This may provide more headroom near the top opening of the support structure and/or may enlarge the internal access to the support structure. In variations where the original support structure includes a cover integral with the sidewalls of the support structure, the cover may be cut away from the sidewalls to remove it. In some variations of this method, the cover may also be modified to allow the cover to be reattached to the support structure in a first position and, optionally, a second position, wherein the first and second positions are the positions described above with respect to cover 500.

The method may additionally or alternatively include modifying the original inlet port, outlet port, and/or detector configuration to allow the support structure to be used with a container configured to be used in conjunction with a bioreactor having a different configuration of one or more of these elements. In some variations, this may include modifying a mass flow controller or adding a mass flow controller to control the modified port, for example, to allow a higher mass flow rate. In variations in which the original support structure is configured to be used in conjunction with an external sensor circuit (such as the external sensor circuit 604 described above), the method may include forming a port in the support structure to accommodate an internal detector, which may be accomplished in one or more of the configurations described above for the port 608 for the internal detector 612. The method may additionally or alternatively include adding one or more exhaust filter heating blankets to the bioreactor, which may be accomplished in one of the configurations described above for the exhaust filter heating blankets 702 and 704.

Also described herein are methods for manufacturing a bioreactor with multiple agitator motors or an adjustable position agitator motor. In some embodiments, to manufacture such a bioreactor, a support structure configured to support, surround, and/or contain the vessel can be made of any suitable material or materials, such as metal (e.g., stainless steel, aluminum, etc.), polymer (e.g., high-density polyethylene, polyacrylate, polycarbonate, polystyrene, nylon or other polyamides, polyesters, phenolic polymers), glass, fiberglass, etc. The support structure can have the features described in detail above with respect to support structure 102. In some variations, the manufacturing method can include mounting a top-mounted agitator motor and a bottom-mounted agitator motor on the support structure. The top-mounted and bottom-mounted agitator motors can be mounted on the support structure in any of the configurations described in detail above with respect to support structure 102, and the top-mounted and bottom-mounted agitator motors can have the features described in detail above with respect to top-mounted agitator motor 304 and bottom-mounted agitator motor 302. The manufacturing method can also include installing a first and second control system to control the bottom-mounted and top-mounted agitator motors, respectively. The control system can have the features described in detail above with respect to control systems 306 and 308. In other variations, the manufacturing method can include attaching an adjustable position agitator motor to a support structure in any of the configurations described above. In some variations, the manufacturing method can include installing a temperature regulation system in the support structure. Installing the temperature regulation system can include installing an electric heating element and/or a circulating heating fluid system as described in more detail above with respect to the temperature regulation system of bioreactor 100.

The manufacturing method may optionally include providing or manufacturing additional elements accompanying the support structure, including but not limited to a support assembly and/or a control cart, such as the support assembly 126 and the control cart 144 described in more detail above. The method may also include forming one or more openings in the support structure to accommodate ports and probes, which may have one or more of the configurations described in detail above with respect to the support structure 102. In some variations, the manufacturing method may additionally or alternatively include mounting one or more exhaust filter heating blankets on the support structure. The exhaust filter heating blanket may have the features described in detail above with respect to the heating blankets 702 and 704 and may be mounted in one of the configurations described in detail above.

In some variations, the manufacturing method may include manufacturing a spacer configured to fit adjacent to the bottom opening of the support structure, and/or a cover configured to partially or completely cover the top opening of the support structure. The spacer may be made of any suitable material, such as, but not limited to, a polymer such as polyoxymethylene or ultra-high molecular weight polyethylene, and may have the features described in detail above with respect to spacer 400. The cover may also be made of any suitable material, such as one or more of the materials used to manufacture the sidewalls of the support structure, and may have the features described in detail above with respect to cover 500.

Also described herein are methods for operating the bioreactors described herein, and bioreactor support structures formed as a result of the modification methods described herein. The methods can include first deciding whether to use a top-mounted or bottom-mounted container, or deciding whether to use a top-mounted or bottom-mounted agitator motor. This decision can be based on various factors such as the specific process to be implemented - for example, the production of a particular product may preferably be carried out in bags of a particular material, which in turn are only available in a top-mounted or bottom-mounted configuration. As another example, the process may be preferably implemented using a bottom-mounted agitator motor due to the working volume during the process (and therefore, a bottom-mounted design can allow pre-production and production in the same bioreactor, thereby saving costs or improving efficiency), or may be preferably implemented using a top-mounted or bottom-mounted agitator motor or a specific bag design due to the mixing profile, sensitivity of the cells or protein being produced, or efficiency gains.

Therefore, the method may include selecting a container for use with the supporting structure (e.g., supporting structure 102) of a bioreactor. The container may be a container (e.g., bag 214 described in detail above) or a container (e.g., bag 208 described in detail above) installed at the top. When supporting structure had a multi-agitator motor design, the user could then select between the agitator motor installed at the top of supporting structure and the agitator motor installed at the bottom based on the configuration of selected container. Or, when supporting structure had a single agitator motor design with adjustable position, the user could adjust the position of the agitator motor to an appropriate position. In other variations of the method, the method may include selecting between the agitator motor installed at the top of supporting structure and the agitator motor installed at the bottom, or selecting the position of the agitator motor with adjustable position, then selecting between the container installed at the top and the container installed at the bottom based on selected agitator motor or position.

The user can then determine whether a spacer (e.g., spacer 400 described above) is present within the support structure. If the selected container is a top-mounted container, the user can confirm the presence of a spacer within the support structure or place a spacer within the support structure (if no spacer is present within the support structure). If the selected container is a bottom-mounted container, the user can confirm the absence of a spacer within the support structure or remove a spacer from the support structure (if no spacer is present within the support structure).

The container can then be placed in the support structure. In variations where the support structure includes one or more doors (e.g., door 112), the one or more doors can be opened to facilitate placement of the container. In variations where the container includes one or more connectors and/or the support structure includes one or more connectors, the container can be connected to the support structure via the connectors. In some variations, the container can be fully or partially inflated before being placed in the support structure. In variations where the container is a flexible bag, this can reduce the folding of the container during installation in the support structure. The container can be coupled to a selected agitator motor. In variations where the agitator port is included, the agitator port can be coupled to the agitator motor. In variations where the agitator motor has an adjustable position, the vertical position of the agitator motor can be changed. For example, if a top-mounted container with a height shorter than the support structure is selected, the top-mounted agitator motor with an adjustable position can be made movable, or the adjustable agitator motor can be moved to an appropriate position. In variations where the impeller is mounted on an adjustable-length shaft, the vertical position of the impeller can be changed. For example, if a top mounted vessel is selected and intended for use with a low working volume, the impeller may be moved downward.

As described above in more detail about bioreactor 100, the inlet port and/or outlet port of the container can be connected to appropriate piping. One or more detectors can also be connected to the bioreactor. If the selected container is configured to be used with an external sensor circuit (e.g., external sensor circuit 604), the external sensor circuit can be connected to the container. If the selected container is configured to be used with an internal detector, the detector can be inserted through the detector port. In the variation of the supporting structure with a detector port located in the side wall of the supporting structure (e.g., located on the door in the variation of the supporting structure with a door), the detector can be inserted through the side wall of the supporting structure. In the variation of the supporting structure with a detector support, the external detector can be placed in the detector support to keep them in place. Suitable exhaust filters can also be installed on the container via a pipe and placed in a heating blanket. In the variation in which the exhaust filter heating blanket is attached so that they can physically move relative to the container (e.g., by being installed on a rotatable rod such as rod 708), the position of the suitable heating blanket can be adjusted to make the exhaust filter closer to the container.

The user can also determine whether a removable lid (e.g., lid 500 described above) completely or partially covers the top opening of the support structure. If the selected container is a bottom-mounted container, the user can confirm that the lid partially or completely covers the top opening of the support structure, or place the lid over the top opening of the support structure (if the lid does not partially or completely cover the top opening of the support structure). If the selected container is a top-mounted container, the user can confirm that the lid does not cover the top opening of the support structure, or remove the lid from the top opening of the support structure (if the lid partially or completely covers the top opening of the support structure). In a variant of the support structure in which the lid remains attached to the support structure when removed from the top opening, if the user removes the lid, the user can then optionally attach the lid to a different part of the support structure (e.g., to the outside of the side wall in a variant with bolts or other elements for retaining the lid on the outside of the side wall).

Once the container is fully seated within the support structure and properly connected, the bioreactor can be used for the desired process. In this manner, an appropriate control system can be used to turn the agitator motor on and off, control the speed of the impeller, and/or control the temperature of any heating blankets used for the exhaust filter. In variations employing a multi-stirrer design with manual control switches for one or both agitator motors, the manual control switches can be used to select the appropriate agitator motor. In variations with a user interface (e.g., a digital user interface), the user interface can be used to control the selected motor.

Claims (12)

1. A bioreactor, comprising: Constructed to support the disposable container; A mixing system, comprising an impeller and a mixing motor, and A disposable container separate from the support structure, the disposable container being of a different design and configured to be located within the support structure and connected to the stirrer motor. The agitator system and the support structure are configured to position the same agitator motor relative to the support structure at one of a plurality of locations. The support structure includes a top region and a bottom region, and the plurality of locations include a top-mounted stirrer motor location and a bottom-mounted stirrer motor location. The same stirrer motor can be selectively installed at one of the selected locations from the plurality of locations. 2. The bioreactor of claim 1, wherein the plurality of positions further includes at least one intermediate position between the top-mounted agitator motor position and the bottom-mounted agitator motor position. 3. The bioreactor according to claim 1 or 2, wherein the same stirrer motor is mounted on an adjustable-length shaft. 4. The bioreactor of claim 1, wherein the support structure includes a top region and a bottom region, and wherein the impeller is configured to selectively operate at an intermediate position within a range between the top region and the bottom region of the support structure. 5. The bioreactor according to claim 1 or 2, wherein the impeller is mounted on a shaft of adjustable length. 6. The bioreactor according to any one of claims 1 to 5, wherein the disposable container is a collapsible bag. 7. The bioreactor of claim 6, wherein the collapsible bag is configured to be used in conjunction with a top-mounted agitator motor. 8. The bioreactor of claim 6, wherein the collapsible bag is configured to be used in conjunction with a bottom-mounted agitator motor. 9. The bioreactor according to any one of claims 1 to 8, further comprising a spacer having a raised support surface configured to be removably positioned at the bottom of the support structure. 10. The bioreactor according to any one of claims 1 to 9, wherein the support structure includes a top opening and a removable lid configured to at least partially cover the top opening. 11. The bioreactor of claim 10, wherein the lid is attached to the support structure when covering the top opening and when it is removed from the top opening. 12. The bioreactor according to any one of claims 1 to 11, wherein the support structure is configured to be used in conjunction with both an internal detector and an external detector.