Low-capacity magnetic mixing system

Abstract

A mixing system typically used within the vessel for mixing the contents includes a low volume magnetically driven mixer 30 mounted to the bottom of the process bottle 20. The mixer may have blades 32 and a lower groove 42, or may have no blades or grooves 42, 196 on both the top and bottom surfaces.

Description

Technical Field

[0001] [Notice Regarding Copyright and Trade Dress] Part of the disclosure of this patent document contains data that is subject to copyright protection. This patent document presents and / or may describe matters that are the owner's trade dress or may become trade dress. The owners of copyright and trade dress have no objection to a complete copy by any one of the patent disclosures as seen in a patent application or registration with the United States Patent and Trademark Office, but otherwise reserve all copyright and trade dress rights.

[0002] [Cross - Reference to Related Applications] This application claims priority to U.S. Provisional Patent Application No. 63 / 244,704, filed on September 15, 2021, entitled "LOW VOLUME MAGNETIC MIXING SYSTEM", the entire content of which is incorporated herein by reference.

[0003] The present invention relates to a mixing system, particularly to a magnetic mixing system having both a low - shear (blade or impeller - type) mixer and a high - shear (pack or disk) mixer or an impeller.

Background Art

[0004] In the preparation of liquid components for biotechnology and pharmaceutical processes, it is important to perform mixing in a sealed environment. Some magnetic stirrers are used in sterile containers for cell culture.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

[0006] A long time ago, at least as early as 1917, the magnetic stirrer was proposed by Stringham in Patent Document 1. It was later improved in 1942 by Rosinger in Patent Document 2. The stirring element consists of a rod-shaped magnet inside, surrounded by a neutral shell. The stirring rod is simply dropped into the container, placed at the bottom, and rotated by an external rotating electromagnet. Modern bioreactor processes, such as cell culture, often require specific mixing capabilities, such as low shear force and high torque, making simple stirring rods or bars unsuitable. [Means for solving the problem]

[0007] The mixing system of the present invention can be useful in many applications, including cell culture, buffer preparation, powder mixing, vaccine mixing using aluminum phosphate (AIPO4), and aseptic process vessels for other uses.

[0008] This application discloses a mixing system for typical use in a container for mixing contents, the mixing system comprising a low-shear or high-shear magnetic mixer mounted at the bottom of a process container. The mixer may have vanes and a bottom groove, or it may not have vanes or grooves on both the top and bottom surfaces.

[0009] One embodiment described herein is a sterile mixing system for a sterile process vessel having a volume and an upper opening having an upper diameter. The mixing system comprises a solid mixer positioned at the bottom of the process vessel to rotate about a central axis. The mixer has a disk-shaped body that is generally circular in plan view, having at least one vertical plane of symmetry passing through the central axis, and to which at least one magnet is attached to enable coupling with a magnetic-drive located outside the process vessel. The mixer has an overall outer diameter smaller than the upper opening of the process vessel and a plurality of lower grooves formed on the lower surface of the disk-shaped body.

[0010] The mixer in the aseptic mixing system may have a plurality of blades rising from a disc-shaped body and arranged at equal intervals in the circumferential direction. The blades may extend radially outward from the disc-shaped body. There may be four blades, and four lower grooves arranged at equal intervals in the circumferential direction around a central axis, with the four lower grooves offset circumferentially from the four blades.

[0011] The mixer may not have blades rising from a disc-shaped body and may be puck-shaped. The puck-shaped mixer may further have a plurality of upper grooves formed on the upper surface of the disc-shaped body. Six lower grooves may be provided at equal intervals in the circumferential direction around a central axis. The six lower grooves may be offset in the circumferential direction from the six upper grooves which are arranged at equal intervals in the circumferential direction around a central axis.

[0012] The sterile mixing system may further include a bearing assembly mounted through a hole in the floor of a process vessel configured to support the mixer for rotation about a central axis. The bearing assembly may have a bearing member that defines a central through-hole and is adapted to seal to the floor of the process vessel around the hole. A lower retaining nut having an upright internally threaded vertical column sized to pass through the central through-hole has a lower flange positioned to be fixed to the underside of the floor of the process vessel, and the bearing assembly further has a thread that passes downward through the central through-hole of a disc-shaped body and engages with the internally threaded vertical column, fixing the mixer on the floor while allowing its rotation. The bearing member may have a base flange that defines a downward groove, and the bearing assembly includes an O-ring positioned in the groove to seal to the floor of the process vessel around the hole.

[0013] The sterile mixing system preferably has two magnets mounted within a disc-shaped body to enable coupling with a magnetic drive unit located outside the process vessel, the magnets being positioned in two diametrically opposed cavities opening on the lower surface of the disc-shaped body. The two diametrically opposed cavities may be offset from the lower groove. [Brief explanation of the drawing]

[0014] [Figure 1] Figure 1 is a perspective view showing exemplary bottles that form part of the mixing system described herein. [Figure 2A] Figure 2A is a cross-sectional view of an exemplary bottle, showing an internal mixer with six blades pivotally supported to rotate around its lower base. [Figure 2B] Figure 2B is a magnified view of an exemplary bottle, schematically showing the external magnetic drive unit located beneath the bottle that is used to rotate the mixer. [Figure 3] Figure 3 is a top exploded perspective view of an exemplary mixer assembly including a first exemplary bearing and two magnets held within a six-blade mixer. [Figure 4]Figure 4 is a bottom exploded perspective view of the mixer assembly of Figure 3. [Figure 5A] Figure 5A is an elevation view of the six - blade mixer of Figure 3. [Figure 5B] Figure 5B is a plan view of the six - blade mixer of Figure 3. [Figure 5C] Figure 5C is a vertical cross - sectional view of the six - blade mixer of Figure 3. [Figure 6A] Figure 6A is a cross - sectional view of an exemplary bottle, showing an internal mixer having four blades pivotally supported to rotate about its lower floor. [Figure 6B] Figure 6B is an enlarged view of the lower part of the bottle, schematically showing an external magnetic drive under the bottle used to rotate the mixer. [Figure 6C] Figure 6C is a detailed view of the four - blade mixer and a second exemplary bearing assembly sealed through a hole in the floor of the bottle. [Figure 7] Figure 7 is an upper exploded perspective view of an exemplary mixer assembly including a second exemplary bearing assembly and two magnets held within the four - blade mixer. [Figure 8] Figure 8 is a bottom exploded perspective view of the mixer assembly of Figure 7. [Figure 9A] Figure 9A is an elevation view of the four - blade mixer of Figure 7. [Figure 9B] Figure 9B is a plan view of the four - blade mixer of Figure 7. [Figure 9C] Figure 9C is a vertical cross - sectional view of the four - blade mixer of Figure 7. [Figure 10A] Figure 10A is a cross - sectional view of an exemplary bottle, showing a pack - shaped internal mixer pivotally supported to rotate about its lower floor. [Figure 10B] Figure 10B is an enlarged view of an exemplary bottle, schematically showing an external magnetic drive under the bottle used to rotate the mixer. [Figure 10C] Figure 10C is an enlarged view of another arrangement where the pack - shaped mixer rotates within the bottle without bearing support. [Figure 11]Figure 11 is a top exploded perspective view of an exemplary mixer assembly, including a first exemplary bearing assembly and two magnets, held within a pack-type mixer. [Figure 12] Figure 12 is a bottom exploded perspective view of the mixer assembly shown in Figure 11. [Figure 13A] Figure 13A is an elevation view of the pack-type mixer shown in Figure 11. [Figure 13B] Figure 13B is a plan view of the pack-type mixer shown in Figure 11. [Figure 13C] Figure 13C is a vertical cross-sectional view of the pack-type mixer shown in Figure 11. [Figure 14] Figure 14 is a top exploded perspective view of an exemplary mixer assembly, including a second exemplary bearing assembly and two magnets, held within a modified pack-type mixer. [Figure 15A] Figure 15A is a top perspective view of a modified example of a pack-type mixer. [Figure 15B] Figure 15B is a plan view of a modified example of a pack-type mixer. [Modes for carrying out the invention]

[0015] Explanation of the diagram Figure 1 is a perspective view showing an exemplary flask or bottle 20 that forms part of a mixing system described herein. The bottle 20 includes vertical side walls 22 which may be reinforced with ribs or other reinforcing features as shown, and recesses 24 that function as handles may be incorporated into the opposing sides. The top wall 26 leads to an upper opening 28, to which a cap (not shown) for sealing the contents of the bottle may be fixed. In some processes, the cap may include a port and tube extending downward to introduce or remove fluid from inside the bottle 20, as described in Shor et al. Patent Document 3. Alternatively, the port and tube may pass through a through-hole formed in the side wall 22 or the top wall 26. The upper opening 28 defines an inner diameter DB which varies depending on the size of the bottle. Bottles 20 are supplied by various manufacturers as sterile process containers for cell culture, buffer preparation, powder mixing, vaccine mixing with aluminum phosphate (AIPO4), and other applications.

[0016] Bottles 20 have capacities ranging from 500 ml to 50 liters and are made of PET or polycarbonate. If made of polycarbonate, it is often preferred due to its inert properties, and a seal is provided for the bottle's access hole. While bottles 20 are shown, other containers may be used, and it should be understood that the term process container encompasses bottles, flasks, buckets, etc., of various sizes and shapes suitable for specific processes and holding fluids. When using bottles 20, the inner diameter DB of the top opening 28 varies depending on the bottle size, with larger bottles having a larger diameter DB. Common bottles supplied for processing have three top opening diameter DBs for three size classes: a small bottle (500 ml to 2 liters) with an opening diameter DB of 48 mm, a medium bottle (2 liters to 50 liters) with an opening diameter DB of 70 mm, and a large bottle (50 liters) with an opening diameter DB of 150 mm. Of course, this ratio of the top opening diameter DB to the bottle size may vary depending on the manufacturer.

[0017] Figure 2A is a cross-sectional view of an exemplary bottle 20, showing an internal mixer 30 having six blades 32 pivotally supported to rotate about a vertical axis on its lower floor surface 29. Figure 2B is an enlarged view of the mixer 30, schematically showing an external magnetic drive unit 46 (sometimes called a stirring plate) below the bottle 20 used to rotate the mixer. For example, the mixer 30 may incorporate two diametrically opposed rare-earth or ceramic magnets 48 facing the floor surface 29, and the magnetic drive unit 46 may have a rotating electromagnet or rotating rare-earth magnet (not shown). The magnetic drive unit 46 is in close proximity to the mixer 30 so that it can rotate the mixer.

[0018] One of the beneficial aspects of the mixing system of the present invention is that the mixer 30 can be lowered from the upper opening 28 of the bottle 20. Conventional agitators used in process mixing bottles are slim and linearly elongated, making them easy to insert through small bottle openings. Three-dimensional, or generally disc-shaped, mixers 30 with blades 32 have a more difficult problem in that they can be inserted through a relatively narrow opening while maintaining a width suitable for adequately agitating the fluid contents in the bottle. As a result, "micro-sized" three-dimensional, or generally disc-shaped, mixers are used. The mixer 30, like all mixers described herein, is generally rounded in plan view and has a central axis through which a plane of vertical symmetry can be drawn. For example, Figure 2B shows a cross-sectional view of the mixer 30 drawn radially through two opposing blades 32, defining a plane of symmetry that bisects the mixer. Numerous planes of symmetry can be drawn through the mixer 30, ignoring the presence of the magnet 48 and its associated mounting cavity. Each mixer described herein is generally circular in plan view and has at least one plane of vertical symmetry passing through its central axis.

[0019] Figures 3 and 4 are top and bottom exploded perspective views of an exemplary mixer assembly 50, including a bearing 52 and two magnets 48, along with a mixer 30 having blades 32, respectively. See also the elevation, plan, and vertical section views in Figures 5A to 5C.

[0020] The mixer 30 comprises a flat, generally cylindrical or disc-shaped body 33 from which blades 32 extend vertically upward and radially outward. The blades 32 are oriented vertically and have a generally triangular upper part 34 above the body 33 and a flange-shaped outer part 35 extending radially outward from the body. As shown in Figure 4, it is preferable that the blades 32 have the same outer extension as the lower surface 36 of the body 33. Preferably, there are six blades 32 spaced equally in the circumferential direction at 60° intervals, but there may be zero or twelve blades depending on the process requirements.

[0021] The central through-hole 38 opens in the upper part of the body 33 and extends downward through the lower surface 36. The through-hole 38 widens and is continuous with the lower end cavity 40 that receives the cylindrical bearing 52, as will be described later. Figure 4 shows four radially extending horizontal grooves 42 that extend outward from the lower end cavity 40 and intersect the outer wall of the body 33 between the blades 32. The grooves 42 are preferably arranged at 90° angles to each other and form a cross passing through the center of the disc-shaped body 33. The grooves 42 are slightly offset from the nearest blade 32 so as not to interfere with the mixing effect of each blade. The grooves 42 help to agitate the contents in the bottle 20, and in particular help to break up any sediment that has accumulated at the bottom of the mixer 30. Finally, the mixer 30 has two dead-end cavities 44 opening in its lower surface 36, each of which receives one of the magnets 48 that are held inside using adhesive or the like.

[0022] Referring again to Figure 2B, the mixer assembly 50 is attached to the bottom surface 29 of the bottle 20 via a pair of screws and a bearing 52. More specifically, the bearing 52 has internally threaded central vertical through holes 54 at both ends. The lower screw 56 (Figure 3) protrudes upward into the screw hole 54 through the central hole in the bottom surface 29. When the screw 56 is tightened onto the bearing 52 across the bottom surface 29, an elastic O-ring 58 is sandwiched between the bearing and the bottom surface, creating a seal to prevent leakage from the bottom surface. In this regard, the bearing 52 has a stepped lower circumference 59 (see Figure 4) which helps to hold the O-ring 58 and reinforces the formed seal.

[0023] The upper end of the bearing 52 fits into the lower end cavity 40 of the mixer body 33, and the upper thread 60 passes through the through hole 38 and engages from above with the threaded hole 54 of the bearing 52. The upper thread 60 includes a head 62, a shaft 64, and a distal end 66 of the thread. As seen in Figure 2B, the length of the shaft 64 is longer than the thickness of the mixer body 33 between its upper surface and the lower end cavity 40. As a result, the upper thread 60 is tightened into the bearing 52, but the mixer 30 remains loosely restrained between the upper thread and the bearing due to the gap G between the mixer and the thread head 62. Both the bearing 52 and the upper thread 60 are preferably made of a lubricating material such as polyetheretherketone (PEEK, a semi-crystalline thermoplastic) or polyphenylsulfone (PPSU, such as Raedel®) for low-friction rotation of the mixer 30. The mixer 30 can be made of a variety of materials, such as stainless steel or a non-reactive polymer.

[0024] The mixer assembly 50 is configured such that the lower surface 36 of the main body 33 is slightly elevated from the bottom surface 29 of the bottle 20. As previously mentioned, the rotation of the mixer 30 is generated by the rotation of a magnetic element in the magnetic drive unit 46, which attracts the magnet 48 and, consequently, the mixer 30, generating rotational torque. The blades 32 are tapered inward toward the upper part 34 to help reduce shear of the fluid in the bottle 20. The radially outer flange 35 assists in agitation of the fluid without generating much shear. Finally, radial grooves 42 on the lower surface of the mixer body 33 gently agitate any sediment or liquid in the sediment that may accumulate below the mixer 30. The grooves 42 have a concave cross-section, which minimizes sharp surfaces and facilitates agitation without shearing.

[0025] Exemplary dimensions of the mixer 30 are shown in Figures 5A-5C. Specifically, the mixer 30 has a total height H and a total diameter D, and a cylindrical body 33 with height h and diameter d. That is, the blades 32 protrude upward from the body 33 by a dimension Hh and extend radially outward from the body 33 by a dimension Dd. In a particular embodiment, the mixer 30 has a total height H of approximately 26.32 mm (1.43 inches) and a total diameter D of approximately 50.8 mm (2 inches), and the cylindrical body 33 has a height h of approximately 12.7 mm (0.5 inches) and a diameter d of approximately 44.45 mm (1.75 inches). Furthermore, the depth of the radial grooves 42 on the underside of the mixer body 33 is approximately 4.75 mm (0.187 inches), which is approximately 30-50% of the body height h. Of course, these dimensions are suitable for a particular size of mixer 30 used with a particular size of bottle 20. These relative dimensions may be increased or decreased depending on the application and bottle size.

[0026] As mentioned above, one of the beneficial aspects of the mixing system of the present invention is that the mixer 30 can be lowered from the top opening 28 of the bottle 20. To enable this, the overall diameter D of the mixer 30 is smaller than the opening diameter DB of a particular bottle. Thus, in the case of a medium-sized bottle as shown in Figure 1, the diameter DB of the top opening 28 is 70 mm, and the overall diameter D of the mixer 30 is 50.8 mm. In the case of a small bottle 28 with a top opening diameter DB of 48 mm, the overall diameter D of the mixer 30 is less than 48 mm, preferably less than 40 mm. In the case of a large bottle 28 with a top opening diameter DB of 150 mm, the overall diameter D of the mixer 30 is less than 150 mm, preferably less than 120 mm. Of course, these dimensions may vary depending on the size of the bottle opening and the design of the mixer.

[0027] The mixer assembly 50 is particularly suitable for small-volume bottom-mounted mixing. Specifically, the mixer 30 is configured to mix very efficiently when returning highly viscous powders that may settle at the bottom of the bottle 20 back into a larger suspension or colloidal mixture. In particular, the bottom groove 42 and outer flange 35 are designed to agitate settled powders and precipitates without causing excessive shear to the fluid mixture, which could be detrimental to the overall process. Furthermore, the mixer 30 is formed such that the torque required to rotate the mixer is relatively small, even with relatively thick fluids or fluids containing precipitates. That is, the magnetic drive unit or the stirring plate 46 and magnet 48 do not need to be extremely powerful to allow them to connect across the gap between them and rotate the mixer 30.

[0028] Figure 6A is a cross-sectional view of an exemplary bottle 20, showing an internal "micro-size" mixer 80 having four blades 82 pivotally supported to rotate about a vertical axis on its lower base surface 29. The bottle 20 includes vertical side walls 22 which may be reinforced with ribs or other reinforcing features as shown, and may incorporate recesses 24 on opposing sides that function as handles. The top wall 26 leads to an upper opening 28, to which a cap (not shown) for sealing the contents of the bottle may be fixed.

[0029] Figure 6B is an enlarged view of the bottom of the bottle 20, schematically showing an external magnetic drive unit 84 located beneath the bottle that is used to rotate the mixer 80. For example, the mixer 80 may incorporate two diametrically opposed rare-earth or ceramic magnets 86 facing the floor surface 29, and the magnetic drive unit 84 may have a rotating electromagnet or rotating rare-earth magnet (not shown). Because it is in close proximity to the mixer 80, the magnetic drive unit 84 can rotate the mixer.

[0030] Figure 6C is a detail view of the mixer 80 having four blades and a second exemplary bearing assembly 88, sealed through a hole in the bottom surface 29 of the bottle. Figures 7 and 8 show the top and bottom exploded perspective views of the exemplary mixer 80, along with the bearing assembly 88 and two magnets 86, respectively. See also the elevation, plan, and vertical section views in Figures 9A–9C.

[0031] The mixer 80 comprises a flat, generally cylindrical or disc-shaped body 90 from which blades 82 extend vertically upward and radially outward. The blades 82 are oriented vertically and have a generally triangular upper part 92 above the body 90, and a flange-like outer part 94 extending radially outward from the body. As shown in Figure 8, the blades 82 preferably have the same extension as the lower surface 96 of the body 90. Preferably, there are four blades 82 spaced equally in the circumferential direction at 90° intervals, but there may be zero or twelve depending on the process requirements. Four blades 82 are considered more suitable for gently mixing fluids in a bioreactor. This is because spacing them at 90° intervals at a certain desired speed reduces "drafting" where one blade follows the others during rotation, thereby improving fluid agitation.

[0032] The central through-hole 98 opens in the upper part of the body 90 and extends downward through the lower surface 96. The through-hole 98 widens and is continuous with the lower end cavity 100, which will receive a portion of the cylindrical bearing member 102 as described later. Figure 8 shows four radially extending horizontal grooves 104 that extend outward from the lower end cavity 100 and intersect the outer wall of the body 90 between the blades 82. The grooves 104 are preferably arranged at 90° angles to each other and form a cross passing through the center of the disc-shaped body 90. The grooves 104 are slightly offset from the nearest blade 82 so as not to interfere with the mixing effect of each blade. The grooves 104 help to agitate the contents in the bottle 20, and in particular help to break up any sediment that accumulates at the bottom of the mixer 80. Finally, the mixer 80 has two dead-end cavities 106 opening in its lower surface 96, each of which receives one of the magnets 86 held inside using adhesive or the like. To prevent dead space within the cavity 106, a thin rear end cap 108 can be attached so that its outer end is flush with the lower surface 96 of the main body 90.

[0033] As described above, the mixer 80 has a "micro-sized" three-dimensional shape, or generally disc-shaped, to effectively provide mixing in a bottle with a relatively small opening 28. The sizes of the mixer 80 for the three classes of bottles 28 (small, medium, and large) are as described above with respect to the 6-blade mixer 30. The mixer 80 is generally rounded in plan view and has a central axis from which a plane of vertical symmetry is drawn.

[0034] Referring to Figures 6B, 7, and 8, the mixer 80 is attached to the bottom surface 29 of the bottle 20 via an upper thread 112 that passes through the bearing member 102 and engages with a lower retaining nut 114, as described. The upper thread 112 includes a head 116, a shaft 118, and a threaded distal end 120. The retaining nut 114 has a central vertical column 122 with an internally threaded dead-end hole 124 that projects upward from a stepped base defined by a lower flange 126 and a small-diameter cylindrical shoulder 128. The bearing member 102 has a broad base flange 130 that extends outward at the lower end of a generally tubular post 132 having an upper end through-hole 134. The base flange 130 defines a circular channel 136 on its lower surface, in which an elastic O-ring 138 is positioned.

[0035] As shown in Figures 6B and 6C, the vertical column 122 of the retaining nut 114 fits tightly into an internal cavity defined within the tubular support 132 of the bearing member 102, and the tubular support 132 fits tightly into the lower end cavity 100 of the mixer body 90. The threaded hole 124 of the retaining nut 114 is aligned with and positioned just below the upper end through hole 134 of the bearing member 102 and the through hole 98 of the mixer body 90. Thus, the upper thread 112 can pass downward through the through holes 98 and 134 and engage with the threaded hole 124 of the retaining nut 114 from above. In this way, the base flange 130 is pressed down so that the elastic O-ring 138 provides a fluid seal against the bottle floor 29. The cylindrical shoulder 128 of the retaining nut 114 fits tightly into a hole formed in the bottle floor 29, and the lower flange 126 can be bonded or otherwise joined to the underside of the floor. This seal configuration ensures that the reaction solution inside the bottle does not reach the adhesive between the lower flange 126 and the bottle base 29. Exposure of the reaction solution to the adhesive can cause the adhesive to degrade over time.

[0036] As shown in Figure 6C, the length of the screw shaft 118 is longer than the thickness of the mixer body 90 between its top surface and the bottom end cavity 100. As a result, the upper screw 112 is tightened against the bearing member 102, but the mixer 80 remains loosely constrained between the upper screw 112 and the bearing member 102 due to the gap G between the mixer body 90 and the screw head 116. Both the bearing member 102 and the upper screw 112 are preferably formed from a lubricating material such as polyetheretherketone (PEEK, a semi-crystalline thermoplastic) or polyphenylsulfone (PPSU, such as Raedel®) for low-friction rotation of the mixer 80. The mixer 80 can be formed from a variety of materials, such as stainless steel or a non-reactive polymer.

[0037] The mixer 80 is configured such that the underside 96 of the main body 90 is slightly elevated from the bottom surface 29 of the bottle 20. As previously mentioned, the rotation of the mixer 80 is generated by the rotation of a magnetic element in the magnetic drive unit 84, which attracts the magnet 86 and, consequently, the mixer 80, generating rotational torque. The blades 82 are tapered inward toward the top 92 to help reduce shear of the fluid in the bottle 20. The radially outer flange 94 helps to agitate the fluid without generating much shear. Finally, radial grooves 104 on the underside of the mixer body 90 gently agitate any sediment or liquid in the sediment that may accumulate below the mixer 80. The grooves 104 have a concave cross-section, minimizing sharp surfaces and facilitating agitation without shear.

[0038] The exemplary dimensions of the mixer 80 are as described above for the 6-blade mixer 30 (see Figure 5A). Specifically, the mixer 80 has a total height H and a total diameter D, and a cylindrical body 90 with height h and diameter d. That is, the blades 82 protrude upward from the body 90 by a dimension Hh and extend radially outward from the body 90 by a dimension Dd. In a particular embodiment, the mixer 80 has a total height H of approximately 26.32 mm (1.43 inches) and a total diameter D of approximately 50.8 mm (2 inches), and the cylindrical body 90 has a height h of approximately 12.7 mm (0.5 inches) and a diameter d of approximately 44.45 mm (1.75 inches). Furthermore, the depth of the radial grooves 104 on the underside of the mixer body 90 is approximately 4.75 mm (0.187 inches), which is about 30-50% of the body height h. Of course, these dimensions are suitable for a particular size of mixer 80 to be used with a particular size of bottle 20. These relative dimensions may be increased or decreased depending on the application and bottle size.

[0039] The micro-sized mixer 80 is particularly well-suited for small-volume, bottom-mounted mixers. Specifically, the mixer 80 is configured to very efficiently mix highly viscous powders that may settle at the bottom of the bottle 20 back into a larger suspension or colloidal mixture. In particular, the bottom groove 104 and outer flange 94 are designed to agitate settled powders and precipitates without causing excessive shear to the fluid mixture, which could be detrimental to the overall process. Furthermore, the mixer 80 is formed so that relatively little torque is required to rotate the mixer even with relatively thick fluids or fluids containing precipitates. That is, the magnetic drive unit or the stirring plate 84 and magnet 86 do not need to be extremely powerful to allow them to connect across the gap between them and rotate the mixer 80.

[0040] Figure 10A is a cross-sectional view of an exemplary bottle 20, showing an alternative “micro-sized” disc-shaped or pack-shaped mixer 180 pivoted to rotate about a vertical axis directly above the lower floor surface 29 of the bottle. Figure 10B is an enlarged view of the mixer 180, schematically showing an external magnetic drive unit 146 beneath the bottle 20 used to rotate the mixer. For example, the mixer 180 may incorporate two opposite rare-earth or ceramic magnets 182 facing the floor surface 29, and the magnetic drive unit 146 may have a rotating electromagnet or rotating rare-earth magnet (not shown).

[0041] Figure 10C is an enlarged view of another configuration (arrangement) in which the pack-shaped mixer 180 rotates within the bottle 20 without bearing support. That is, in the case of the small bottle and mixer combination, the pack-shaped mixer 180 is stable enough to rotate around the center without requiring bearings, like conventional agitators in the art. The rotating magnetic field generated by the external magnetic drive unit 146 located below the bottle 20 attracts magnets mounted inside the mixer 180, holding the mixer in place.

[0042] Figures 11 and 12 are top and bottom exploded perspective views of an exemplary mixer assembly 190, including the bearing 192 and magnet 182 along with the "micro-size" mixer 180, respectively. See also the elevation, plan, and vertical section views in Figures 13A–13C.

[0043] The mixer 180 has no blades but comprises a flat, generally cylindrical or pack-shaped body 194 having radial grooves on its upper and lower surfaces. In particular, the body 194 has a series of radial grooves 196 formed on its upper surface 198 and a series of radial grooves 200 formed on its lower surface 202. Preferably, each upper and lower surface has six grooves 196, 200 spaced equally in the circumferential direction at 60° intervals, but depending on the process requirements, there may be two or twelve.

[0044] The grooves 196 and 200 have a generally semicircular radial cross-section and extend along most of the radial dimensions of the pack-shaped body 194. Each of the grooves 196 and 200 opens onto the cylindrical outer surface of the body 194 and terminates at a generally spherical radial inner end. The grooves 196 and 200 help to agitate the contents inside the bottle 20, and in particular help to break up any sediment that has accumulated below the mixer 180.

[0045] The central through-hole 210 opens in the upper part of the main body 194 and extends downward through the lower surface 202. The through-hole 210 widens and is continuous with the lower end cavity 212 which receives the cylindrical bearing 192 as described later. Finally, the mixer 180 defines two dead-end cavities 214 opening in its lower surface 202, each of which receives one of the magnets 182 held inside using adhesive or the like.

[0046] Referring again to Figure 10B, the mixer assembly 180 is attached to the bottom surface 29 of the bottle 20 via a pair of screws and a bearing 192. More specifically, the bearing 192 has internally threaded central vertical through holes 216 at both ends. The lower screw 218 (Figure 3) protrudes upward into the screw hole 216 through the central hole in the bottom surface 29. When the screw 218 is tightened across the bottom surface 29 into the bearing 192, an elastic O-ring 220 is sandwiched between the bearing and the bottom surface, creating a seal to prevent leakage from the bottom surface. In this regard, the bearing 192 has a stepped lower circumference 222 (see Figure 4) which helps to hold the O-ring 220 and reinforces the seal thus formed.

[0047] The upper end of the bearing 192 fits into the lower end cavity 212 of the mixer body 194, and the upper thread 224 passes downward through the through hole 210 and engages from above with the threaded hole 216 of the bearing 192. It should be noted that the upper thread 224 includes a head 226, a shaft 228, and a distal end 230 of the thread. As seen in Figure 10B, the length of the shaft 228 is longer than the thickness of the mixer body 194 between its upper surface and the lower end cavity 212. As a result, the upper thread 224 is tightened into the bearing 192, but the mixer 180 remains loosely constrained between the upper thread and the bearing due to the gap G between the mixer and the thread head 226. Both the bearing 192 and the upper thread 224 are preferably formed of a lubricating material such as polyetheretherketone (PEEK, a semi-crystalline thermoplastic) or polyphenylsulfone (PPSU, such as Raedel®) for low-friction rotation of the mixer 180. Mixer 180 can be made from a variety of materials, such as stainless steel or non-reactive polymers.

[0048] Exemplary dimensions of the mixer 180 are shown in Figures 13A-13C. Specifically, the mixer 180 has a total height H and an overall diameter D. In a particular embodiment, the mixer 180 has a total height H of approximately 12.7 mm (0.5 inches) and an overall diameter D of approximately 50.8 mm (2 inches). Of course, these dimensions are suitable for a particular size of mixer 180 used with a particular size of bottle 20. These relative dimensions may be increased or decreased depending on the application and bottle size. The grooves 196, 200 may have a depth of 20% to 50% of the total height H of the mixer 180, for example, about 25% to 33%. In one embodiment, the upper groove 196 is rotationally offset from the lower groove 200 so that there is no area of ​​extremely thin material between them, and the depth of both grooves is 2.54 mm to 6.35 mm (0.1 inches to 0.25 inches).

[0049] As described above, the mixer 180 has a "micro-sized" three-dimensional shape, or generally disc-shaped, to effectively provide mixing in a bottle with a relatively small opening 28. The sizes of the mixer 180 for the three classes of bottles 28 (small, medium, and large) are as described above with respect to the 6-blade mixer 30. The mixer 180 is generally rounded in plan view and has a central axis from which a plane of vertical symmetry is drawn.

[0050] Mixer assembly 190 is particularly suitable for small-volume bottom-mounted mixers. Specifically, mixer 180 is configured to mix very efficiently when returning highly viscous powders that may settle at the bottom of bottle 20 back into a larger suspension or colloidal mixture. In particular, grooves 196, 200 are designed to agitate settled powders and precipitates without causing excessive shear to the fluid mixture, which could be detrimental to the overall process. Furthermore, mixer 180 is formed so that relatively little torque is required to rotate the mixer even with relatively thick fluids or fluids containing precipitates. That is, the magnetic drive unit or agitation plate 146 and magnet 182 do not need to be extremely powerful to allow them to connect across the gap between them and rotate mixer 180.

[0051] One process for which the pack-type mixer 180 is specifically designed is the mixing of aluminum phosphate (AIPO4), which is commonly used in vaccine manufacturing. Conventional mixing vessels for such applications have used mixers with agitators that are poorly designed to agitate solidified AIPO4 precipitates using indirect magnetic drive mechanisms. As a result, in a typical process, the mixing vessel is first lifted and shaken or smashed to break up the precipitate layer. Such processes clearly pose a certain risk, such as actual injury to technicians or simply wasting expensive products. The streamlined shape of the pack-type mixer 180 is specially designed to begin rotating even when surrounded by heavy precipitates, and the grooves 196, 200 impart sufficient turbulence to the fluid to break up the precipitate with relatively low drive torque.

[0052] Figure 14 is a top exploded perspective view of an exemplary mixer assembly, including a second exemplary bearing assembly 88 and two magnets 86, held within a modified pack-type mixer 280. The second exemplary bearing assembly 88 is as described above, and therefore similar reference numerals are used. As described above, the assembly includes an upper thread 112 that passes through the bearing member 102 and engages with a lower retaining nut 114. It should be noted that the upper thread 112 includes a head 116, a shaft 118, and a threaded distal end 120. The retaining nut 114 has a central vertical column 122 with an internally threaded dead-end hole 124 projecting upward from a stepped base defined by a lower flange 126 and a small-diameter cylindrical shoulder 128. The bearing member 102 has a broad base flange 130 extending outward at the lower end of a generally tubular support 132 having an upper end through hole 134.

[0053] See also Figures 15A and 15B, the mixer 280 comprises a generally cylindrical or pack-shaped body 294, which has no blades but has radial grooves on its top and bottom surfaces. In particular, the body 294 has a series of radial grooves 296 formed on its top surface 298 and a series of radial grooves 300 formed on its bottom surface 302. The grooves 296, 300, which are arranged at equal intervals in the circumferential direction, are preferably six in number, but may be two or twelve depending on the process requirements. The grooves 296, 300 have a generally semicircular radial cross-section and extend along most of the radial dimensions of the pack-shaped body 294. Each of the grooves 296, 300 opens onto the cylindrical outer surface of the body 294 and terminates at a generally spherical radial inner end. The grooves 296, 300 help to agitate the contents in the bottle 20, and in particular help to break up any sediment that accumulates at the bottom of the mixer 280.

[0054] The central through-hole 310 opens at the top of the main body 294 and extends downward through the bottom surface 302. The through-hole 310 widens and is continuous with a lower end cavity (not shown) that receives the tubular support 132 of the bearing member 102, as will be described later. Finally, the mixer 280 defines two dead-end cavities (not shown) that open at its bottom surface 302, each of which receives one of the magnets 86 held inside using a rear end cap 108 or the like.

[0055] In contrast to the pack-type mixer 180, the mixer 280 has gradually tapered upper and lower surfaces 300 and 302. That is, surfaces 300 and 302 each have a slight taper from the inner horizontal land 312 to the outer periphery, and both surfaces are frustoconical. The angle of the taper varies, but is preferably between approximately 5° and 30°. This may help prevent the accumulation or caking of material, particularly aluminum phosphate (AIPO4), between the mixer 280 and the bottom surface of the reaction bottle. Except for the tapered surfaces 300 and 302, the dimensions of the mixer 280 may be the same as those described above for the mixer 180.

[0056] As described above, the mixer 280 has a "micro-sized" three-dimensional shape, or generally disc-shaped, to effectively provide mixing in a bottle with a relatively small opening 28. The sizes of the mixer 280 for the three classes of bottles 28 (small, medium, and large) are as described above with respect to the 6-blade mixer 30. The mixer 280 is generally rounded in plan view and has a central axis from which a plane of vertical symmetry is drawn.

[0057] While the present invention has been described using specific terms, apparatus, and / or methods, such descriptions are intended to illustrate preferred embodiments. Those skilled in the art will be able to modify preferred embodiments without departing from the scope of the invention as described in the following claims. In addition, it will be understood that aspects of preferred embodiments may generally be replaced in whole or in part.

Claims

1. A sterile mixing system, A process container (20) having a floor surface (29), a vertical side wall (22), and an upper wall (26) extending inward from the vertical side wall (22) toward an upper opening (28) having an upper diameter, wherein the floor surface (29) of the process container has a hole located on a vertical central axis passing through the center below the upper opening, A solid mixer (30, 80, 180, 280) is positioned at the bottom of the process vessel (20) so as to rotate about a central axis, wherein the mixer (30, 80, 180, 280) is generally circular in plan view and has a generally cylindrical disc-shaped body (33, 90, 194, 294) to which at least one magnet (48, 86, 182, 282) is attached to enable coupling with a magnetic drive unit located outside the process vessel (20), and the mixer is positioned in front of the process vessel (20). A solid mixer (30, 80, 180, 280) having an overall outer diameter smaller than the upper diameter and a plurality of lower grooves (42, 104, 200, 300) formed on the lower surface (36, 96, 202, 302) of the disc-shaped body, wherein the mixer has a plurality of blades extending vertically upward into the container and radially outward from the disc-shaped body, and the blades are tapered inward toward the upper part of the blades in order to reduce liquid shear and gently mix the liquid in the container, A bearing assembly is provided which is configured to support the mixer for rotation about the central axis and is mounted through the hole in the floor surface (29) of the process vessel (20), Aseptic mixing system.

2. The aseptic mixing system according to claim 1, wherein the mixer (30, 80) has a plurality of blades (34, 82) that rise from the disc-shaped body (33, 90) and are arranged at equal intervals in the circumferential direction.

3. The sterile mixing system according to claim 2, wherein the blades extend radially outward from the disc-shaped body (33, 90).

4. The sterile mixing system according to claim 2, wherein four of the aforementioned blades are provided.

5. The sterile mixing system according to claim 4, wherein four of the aforementioned lower grooves are provided at equal intervals in the circumferential direction around the central axis.

6. The sterile mixing system according to claim 5, wherein the four lower grooves are offset circumferentially from the four vanes.

7. The sterile mixing system according to claim 1, wherein six of the lower grooves are provided at equal intervals in the circumferential direction around the central axis.

8. The sterile mixing system according to claim 7, wherein the six lower grooves are offset in the circumferential direction from the six upper grooves which are arranged at equal intervals in the circumferential direction around the central axis.

9. The aseptic mixing system according to claim 1, wherein the mixer (280) has frustum-shaped surfaces (300, 302) formed on the upper and lower surfaces of the disc-shaped body.

10. The aseptic mixing system according to any one of claims 1 to 9, wherein the bearing assembly is sealed on the floor surface (29) of the process vessel (20) around the hole and has bearing members (52, 102, 192) defining a central through hole (134, 216).

11. The bearing assembly has a lower retaining nut (114) having an upright internally threaded vertical column (122) sized to pass through the central through hole (134), and the lower retaining nut (114) has a lower flange (126) fixed to the lower surface of the floor (29) of the process vessel (20). The aseptic mixing system according to claim 10, wherein the bearing assembly further has a screw (112) that passes downward through the central through hole (98) of the disc-shaped body and is sized to engage with the upright internally threaded vertical column (122), thereby fixing the mixer on the floor surface (29) while allowing it to rotate.

12. The bearing member (102) has a base flange (130) that defines a downward groove (136), The sterile mixing system according to claim 11, wherein the bearing assembly includes an O-ring (138) positioned in the groove (136) that seals against the floor surface of the process vessel around the hole.

13. The sterile mixing system according to claim 10, wherein the central through hole (54, 216) of the bearing member (52, 192) is a threaded hole having internal threads at both ends, and a lower thread (56, 218) protrudes upward into the threaded hole (54, 216) through the central hole in the floor surface (29) to fasten the bearing member (52, 192) to the floor surface (29), and the bearing assembly includes an O-ring (58, 220) that seals the bearing member (52, 192) to the floor surface (29) of the process vessel (20) around the hole.

14. The sterile mixing system according to any one of claims 1 to 9, comprising two magnets (48, 86, 182, 282) mounted inside the disc-shaped body to enable coupling with the magnetic drive unit located outside the process vessel (20), wherein the magnets are respectively arranged in two diametrically opposed cavities (44, 106, 214) opening on the lower surface of the disc-shaped body.

15. The sterile mixing system according to claim 14, wherein the two diametrically opposed cavities are offset from the lower groove.

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