Patent Application
20240367122
This application relates to bioprocessing containers, such as storage tanks, bioreactors, and other vessels. In particular, embodiments of the technologies disclosed herein relate to mixers useful in bioprocessing containers.
Biological fluids comprising cells and other viral vectors are manufactured within bioreactors and other vessels in the pharmaceutical and biopharmaceutical industries. Previous bioreactors were rigid stainless steel or glass having highly controlled processing parameters including pH, oxygen and carbon dioxide concentration, turbidity, and temperature, which were monitored and controlled by permanent sensors built into the rigid bioreactors. During bioprocessing, e.g., cell growth within the biological fluid in the bioreactor, uniform distribution of temperature, gases, and nutrients was maintained by mixing. A suitable mixing system provides three functions: the creation of a stable environment (nutrients, pH, temperature, etc.) in a homogeneous distribution, the dispersion of gases (i.e., supplying O2 and extracting CO2), and the optimization of the heat transfer. Many components are mixed into biological fluids, such as buffers, adjuvants, oxygen, cell culture media, and the like. Providing acceptable mixing, without imparting damaging shear effects, becomes more challenging as the scale of the bioreactor container increases. The inclusion of a well-designed impeller allows for better mixing efficiency without the risk of high shear associated with high impeller speeds.
Mixing systems typically comprise an impeller having a shaft, and blades projecting from the shaft, connected to a motor located outside the bioreactor. Multiple use stainless steel reactors require intensive cleaning and sterilization before re-use. The impeller, spargers, and sensors (e.g., gas, temperature and pH sensors) are also multi-use components, requiring sterilization after each batch process. More recent developments in bioprocessing introduced the advent of single-use bioreactors, which may provide greater flexibility in manufacturing and reduce the time needed to affect a valid regeneration or sterilization of the equipment. Processors have begun to utilize disposable sterilized containers such as bags that are used once and disposed, also using a shaft connected with a motor, typically top-loaded. Single-use bioreactors employ disposable bags comprised of thin, flexible polymeric films. Pre-sterilized, single-use bags, including components (e.g., single-use sensors and impellers), eliminate the need for cleaning, sterilization, and validation. Accordingly, their use results in substantial savings in manufacturing and maintenance costs. A bioprocessing challenge associated with single-use bags and components is the positioning of the components within a flexible bioreactor post-sterilization. Following sterilization, flexible bioreactors are stored and shipped. Unlike a rigid, stainless-steel vessel, a bioreactor bag has no structural rigidity and is subject to abrasion and tearing.
Generally, bioreactor components like impeller shafts, spargers, and sensors were attached inside the rigid vessel by threaded posts, bolts, clamps and/or other joining methods having seals and bearings. These methods were not suitable for flexible bioreactor bags as they would result in damage to the flexible bioreactor bags, leaking, contamination, and other failure modes both before and during processing.
Homogeneous mixing is important. However, thorough mixing may damage cells by introducing high amounts of shear. Many mixing operations are carried out in bioreactors having a mixing impeller mounted near a bottom of the vessel. A variety of impellers having differently sized and shaped impeller hubs, impeller blades, and shafts were necessary for mixing within many differently sized and shaped bioreactors. Past prior art bioprocessing included agitator tanks and systems to complete the mixing process. Such systems achieved mixing by using a mechanical stirrer that was lowered into the biological fluid through an opening in the top of the vessel and rotated by an external motor to create the desired mixing action. Such systems were also inefficient and required additional motors and components.
Attempts to solve these problems consist of systems for mixing biological fluids using a rotating magnetic impeller that was magnetically coupled with a shaft and conducting element. The magnetic impeller was placed in a vessel and positioned adjacent a conducting element. The vessel was sealed with the magnetic impeller therein, wherein the biological fluid was delivered after sealing. However, limitations remaining from this approach are that only magnetic interactions provide “support” of the magnetic impeller. These systems controlled vertical levitation of impellers but suffer from poor lateral control. Particularly at higher speeds, the levitating impellers wobble, which results in damage to the single-use bioreactors. External bearing rings were next used to laterally stabilize magnetic impellers, which did not work well, were heavy, and required a large amount of torque. Microprocessors utilizing feedback control are also necessary to stabilize the bearing ring-style impellers, which are expensive. Some past impellers attempted to solve these processing issues by providing a flow path through the shaft, which wobbled and also failed to withstand turbulence.
Providing an improved mixing system for single-use containers or bioreactors for biological fluid processing having a novel impeller that overcomes previous drawbacks to achieve homogeneous mixing necessary for optimal cell culture growth represents an advance in the art. Substantial gains in efficiency, shorter mixing times, lessened power usage and higher power delivered, lessened shear and impeller wobble, and ease of use are now realized and significantly expand the potential applications for which advanced mixing systems may be used. Also, the novel and inventive embodiments described herein are useful for vessels, containers, and/or bioreactors capable of holding fluid volumes greater than 10 liters. In some embodiments, the fluid volumes are from 10 L to 50 L. In some further embodiments, the fluid volumes are from 40 L to 200 L. In some even further embodiments, the fluid volumes are from 100 L to 500 L. In some additional embodiments, the fluid volumes are from 200 L to 1000 L. Moreover, in some embodiments, the fluid volumes are from 400 L to 2000 L. It is to be understood that a container or bioreactor capable of holding, for example, 50 L might sometimes process significantly less fluid, for example, 10 L.
Impellers are disclosed, which may include an impeller cap, an optional gasket, an impeller retainer, and a circular magnet, all of which may be at least partially housed within a hollow impeller housing. The hollow impeller housing may include an impeller bore and a hub. The circular magnet may include a bore, and may be placed within the impeller bore. The impeller cap may mate with an optional gasket or O-ring, and may be at least partially disposed within the impeller bore along with the impeller retainer. The impeller may further include plurality of impeller blades, wherein the plurality of impeller blades may project from the hub as shown in and/or described in connection with at least one of the figures. Novel and inventive features of the present disclosure, as well as details of exemplary embodiments thereof, will be more fully understood from the following description and drawings.
In at least one embodiment, a hollow shaft impeller includes a hollow impeller housing, a magnet, an impeller cap, an impeller retainer, and a plurality of impeller blades. The hollow impeller housing may have a hub that defines an interior volume and an impeller bore that provides access to the interior volume. The magnet may be sized to be disposed within the interior volume. In addition, the impeller cap may be removably coupled to the hollow impeller housing proximate to the impeller bore. The impeller retainer may be removably coupled to the magnet and may be sized such that it may be disposed within the interior volume. The plurality of impeller blades may project from the hub of the hollow impeller housing.
In some instances, the plurality of impeller blades include three, four, five, or more impeller blades. In some further instances, at least one fin may be disposed on each impeller blade of the plurality of impeller blades, where the at least one fin may be triangular shaped. In some even further instances, the at least one fin may be disposed on each impeller blade of the plurality of impeller blades between a top edge and a bottom edge of each impeller blade of the plurality of impeller blades. The at least one fin may be disposed on, and extend from, a blade face of each impeller blade of the plurality of impeller blades.
In yet some further instances, the hollow shaft impeller further includes a gasket coupled to the impeller cap. The gasket may be configured to seal, along with the impeller cap, the interior volume at the impeller bore. In some additional instances, the gasket may be an O-ring. In some even further instances, the gasket comprises an elastomeric material such as, but not limited to, a vinyl material, a polyethylene material, a polypropylene material, a nylon material, a silicon material, a polytetrafluoroethylene material, or a rubber material.
In some other instances, the impeller retainer may include a circular flange that has a top surface, an opposite bottom surface, a boss projecting from the top surface of the circular flange, and a cylinder descending from the bottom surface of the circular flange. When the impeller retainer is disposed within the interior volume, the boss may be configured to interact with the impeller cap. The cylinder of the impeller retainer may include a plurality of rails disposed about an exterior surface of the cylinder. In some further instances, the magnet may include a bore centrally disposed on the magnet and a plurality of slots disposed around a perimeter of the bore. The cylinder and the plurality of rails may be keyed to the bore and the plurality of slots of the magnet such that the bore and the plurality of slots of the magnet are configured to at least partially receive the cylinder and the plurality of rails of the impeller retainer. In some additional instances, when the cylinder and the plurality of rails of the impeller retainer are disposed within the bore and the plurality of slots of the magnet, the magnet may be coupled to the impeller retainer.
In even some further instances, the impeller cap may include cap beams and cap slots disposed about the impeller cap. In addition, the impeller bore of the hollow shaft impeller may include hub beams and hub slots disposed about the impeller bore. The cap beams may be configured to be disposed within the hub slots and the hub beams may be configured to be disposed within the cap slots when the impeller cap is coupled to the hollow impeller housing.
These advances and others embodied herein will become clear from the description, claims, and figures below. Various benefits, aspects, novel and inventive features of the present disclosure, as well as details of exemplary embodiments thereof, will be more fully understood from the following description and drawings. The manner in which the features disclosed herein can be understood in detail (i.e., more particular descriptions of the embodiments of the disclosure briefly summarized above) may be had by reference to the appended drawings. It is to be noted, however, that the appended drawings illustrate only typical embodiments of this disclosure and are therefore not to be considered limiting of its scope. The described embodiments may admit to other equally effective bags, biocontainers, films, and/or materials. It is also to be understood that elements and features of one embodiment may be found in other embodiments without further recitation and that, where possible, identical reference numerals have been used to indicate comparable elements that are common to the figures. As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which these embodiments pertain.
In this disclosure, reference is made to an integrated or unitary piece. For purposes herein, a unitary or integrated piece indicates a piece that cannot be disassembled without destroying the piece. For example, a hub having impeller arms that can be added or subtracted to the hub is not integral nor unitary. Conversely, a hub having impeller arms that cannot be added or subtracted to the hub is unitary and/or integrated. In some embodiments, an integrated or unitary piece is formed by a single manufacturing process, e.g., injection molding of the hub and impeller arms in a single injection molding cycle.
The apparatuses, systems, devices, and components presented herein may be better understood with reference to the following drawings and description. It should be understood that some elements in the figures may not necessarily be to scale and that emphasis has been placed upon illustrating the principles disclosed herein. In the figures, like-referenced numerals designate corresponding parts/steps throughout the different views.
Described herein are some embodiments of impellers, wherein the impellers can be used both with systems having direct connection with rotating drive shafts and magnetically-coupled, levitating hollow shaft impellers that comprise magnets. Embodiments of some impellers, according to the disclosure, comprise a hollow shaft. Embodiments of some impellers comprise a hollow shaft that further comprises a cap placed on the hollow shaft.
Embodiments of some impellers comprise a hollow shaft that further comprises a three-pitch blade or a four-pitch blade impeller. Embodiments of some impellers comprise a hollow shaft that further comprises a three-pitch blade or a four-pitch blade impeller having one or more fins on one or more blades. The hollow shaft may be sealed by a cap, which substantially prevents ingress of a liquid, wherein an air cavity equilibrates and/or stabilizes the impeller submerged in liquid without the additional weight of a solid shaft or the attendant wobble of a flow-through shaft. Also, additional weight requires additional torque, which leads to additional costs and unfavorably promotes impeller wobble. It is further believed that a hollow shaft(s) better distributes torque. In the case of a bottom mounted impeller, a hollow shaft designs reduce wobble and decrease mixing times. Moreover, the reduction of wobble helps protect a bag containing a hollow shaft impeller during processing. Many embodiments of hollow shaft impellers are contemplated within this disclosure.
For example, various sizes of blades on hollow shafts, various shapes of blades, various sizes of fins disposed on blades or on hollow shafts, and various locations of fins disposed on blades are disclosed herein. For example, embodiments of the disclosure comprise one or more fins on a shaft, one or more fins on top of a blade(s), one or more fins on a bottom of a blade(s), and/or one or more fins on a middle of a blade(s). Additional inventive features of some embodiments of the impeller(s) comprise a cap having a pin and hole design, and an internal cylinder in the hollow shaft for transfer of the torque, maintenance of stability, and keeping, for example, a motor magnet in place. Embodiments of hollow shafts disclosed herein are lighter in weight, have less material, have higher polar moments of inertia, have higher radii of gyration, and have higher torsional strength. Embodiments of the disclosure also exhibit shorter mixing times, higher power delivered, and significant decrease in wobble for an impeller used in 200 L to 2000 L and higher sized bioreactors. Embodiments of some hollow shaft impellers, wherein the impeller blades have fins that are located within approximately 10% of a center line of a width of the impeller blade exhibit little wobble and are not pushed down even at high revolutions per minute (RPM) (e.g., 100-120 RPM). A hollow shaft impeller having impeller blades that further comprise fins located within 10% of a center line of the width of the impeller blades exhibit so little wobble, even at high RPMs, that the impeller blades and/or fins do not hit a bottom of a bioreactor bag or biocontainer, as described more fully below.
The term biocontainer is defined as any reactor, container, or vessel capable of holding a fluid within an internal volume or region, and may be in the form of a two-dimensional, three-dimensional, and/or multi-faceted bag or bioreactor. In some embodiments, the biocontainer or bioreactor is flexible and has a baffle incorporated therein, wherein the baffle is capable of disrupting a vortex within a liquid formed when a mixer, such as an impeller, mixes the liquid. Also, some embodiments comprise a sparger for delivering and distributing gases into the bioreactor. The bioreactor or container may comprise a film. The term film within the meaning of this disclosure means any flexible material that is capable of being fused with another flexible film, including, but not limited to, polymeric sheet, composites, laminates, single-layer, and/or multi-layer polymeric materials. These films may further comprise substrates, which may comprise plastic netting, wovens, non-wovens, knits, and/or metallic foils and other flexible structures and materials. In some embodiments, the flexible films comprise a laminate film structure with a lower melting point material internal to an external higher melting point polymer. Also, in some embodiments, the flexible films comprise a laminate film structure with a lower melting point material surrounding a higher melting point woven, knit, or non-woven material. In some embodiments, any of the bottom film, middle film, or the top film comprise any of the films as described in WO2020101848A1, which is incorporated by reference in its entirety. In some embodiments, one or more of these films is/are substantially similar to a PUREFLEX®, PUREFLEX PLUS® or ULTIMUS® film as marketed by EMD Millipore Corporation, Burlington, MA, USA.
The hollow impeller housing 120 may further comprise a hub 130 that may define an interior volume 128 and an impeller bore that provides access to the interior volume 128. The impeller retainer 106 and the circular magnet 108 are sized and shaped to be disposed within the interior volume 128 such that the impeller retainer 106 and the circular magnet 108 are configured to be housed within a hollow impeller housing 120. The impeller cap 102 may be removably coupled to the hollow impeller housing 120 at the impeller bore, where the gasket 104 may be configured to form a seal proximate to the impeller bore to seal the interior volume 128.
In accordance with some embodiments disclosed herein, and as previously explained, the hollow impeller housing 120 may comprises a hub 130 that includes a top end, a bottom end, and at least first and second impeller arm slots 132 arranged substantially vertically and extending from the top end toward the bottom end. The impeller cap 102 may be placed on the top end of the hub 130 in order to seal an air cavity therein. Also, at least first and second impeller blades 134 extend from the hub 130 at the arm slots 132. As shown in the embodiment illustrated in
It is contemplated herein that the impeller blades 134 and the hub 130 can be a single unitary piece, i.e., a plastic piece made via an injection molding process, wherein the plastic piece could not be dissembled without destruction. The fins 140 could later be attached to the impeller blades 134. For example, the fins 140 may be attached using screws, bolts, rivets, adhesives, cantilever beams, snap fits, and/or other attachment means known to those in the art. Alternatively, an impeller blade 134 and a fin 140 may be molded as a single unitary piece, and subsequently attached to the hub 130. As explained previously, the impeller blades 134 having the fins 140 molded as a single unitary piece may be attached using screws, bolts, rivets, adhesives, cantilever beams, snap fits, and/or other attachment means known to those in the art. In some embodiments, screws, bolts, rivets, adhesives, cantilever beams, snap fits, and/or other attachment means known to those in the art can be used to attach the impeller blade 134 to the hub 130 and the fin 140 to the impeller blade 134. Moreover, while the illustrated embodiment includes four blades 134, the hollow shaft impeller 100 may include any number of blades 134, including, but not limited to, three blades 134, four blades 134, five blades 134, etc.
In some embodiments, the fins 140 may each be substantially triangular shaped and having edges 140a, 140b, and 140c, where edge 140a is attached to the impeller blade 134. The edges 140a, 140b, and 140c can be linear or, alternatively, form a curved or parabolic function. As shown, the edge 140b of the fin 140 begins at a distance from the hub 130 and ends at an outer edge 138 of the impeller blade 134. It is further contemplated that the fin 140 need not extend to the outer edge 138. Furthermore, the fin 140 may extend closer or right up to a surface of the hub 130. It is further contemplated that the fin 140 may form a right angle α with the impeller blade 134 or form an angle α that is greater or lesser than 90°. For example, in some embodiments, the angle α is approximately 50-80°. In some exemplary embodiments, the angle α is 76° with respect to a clockwise axis of rotation when viewing the outer edge 138 of the impeller blade 134 and toward the hub 130.
The impeller blade 134 has a thickness T. In general, the thickness T is scalable for different impellers, for example, the thickness T may be approximately 0.20 to 0.5 cm. The fin 140 has a thickness t, which is generally lesser than the thickness T of the impeller blade 134, such as 0.15 to 0.4 cm. The fin 140 has a length FL that, in some embodiments, is 50% a length BL of the impeller blade 134. In other embodiments, the length FL may be 90% of the length BL of the impeller blade 134. As shown in
All ranges for formulations recited herein include ranges therebetween and can be inclusive or exclusive of the endpoints. Optional included ranges are from integer values therebetween (or inclusive of one original endpoint), at the order of magnitude recited or the next smaller order of magnitude. For example, if the lower range value is 0.2, optional included endpoints can be 0.3, 0.4, . . . 1.1, 1.2, and the like, as well as 1, 2, 3 and the like, if the higher range is 8, optional included endpoints can be 7, 6, and the like, as well as 7.9, 7.8, and the like. One-sided boundaries, such as 3 or more, similarly include consistent boundaries (or ranges) starting at integer values at the recited order of magnitude or one lower. For example, 3 or more includes 4, or 3.1 or more.
Reference throughout this specification to “one embodiment,” “certain embodiments,” “one or more embodiments,” “some embodiments,” or “an embodiment” indicates that a feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Therefore, the appearances of the phrases such as “in one or more embodiments,” “in certain embodiments,” “in one embodiment,” “some embodiments,” or “in an embodiment” throughout this specification are not necessarily referring to the same embodiment.
Although some embodiments have been discussed above, other implementations and applications are also within the scope of the following claims. Although the specification describes, with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present disclosure. It is therefore to be further understood that numerous modifications may be made to the illustrative embodiments and that other arrangements and patterns may be devised without departing from the spirit and scope of the embodiments according to the disclosure. Furthermore, particular features, structures, materials, or characteristics may be combined in any suitable manner in any one or more of the embodiments.
Publications of patent applications and patents and other non-patent references, cited in this specification are herein incorporated by reference in their entirety in the entire portion cited as if each individual publication or reference were specifically and individually indicated to be incorporated by reference herein as being fully set forth. Any patent application to which this application claims priority is also incorporated by reference herein in the manner described above for publications and references.
This present application claims priority to U.S. Provisional Patent Application Ser. No. 63/292,445, entitled “HOLLOW SHAFT IMPELLER,” and filed on Dec. 22, 2021, the disclosure of which is incorporated herein by reference in its entirety for all purposes.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/079926 | 11/16/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63292445 | Dec 2021 | US |
