Mixing system comprising a fillable 3D flexible bag for biopharmaceutical fluids and method for improving mixing in single-use bioreactors

Abstract

The invention relates to a mixing system comprising a fillable 3D flexible bag for biopharmaceutical fluids and a method for improving mixing in single-use bioreactors. Initially heterogeneous biopharmaceutical ingredients are mixed in a bag (2) designed as a mixed bioreactor with a capacity of at least 1500 liters using an apparatus (1) comprising a tank, a flexible collapsible bag received in the tank and a stirring device. The device (3) comprises an impeller (13) driven from below for stirring starting near the tank base (5). Once the bag is stretched under liquid pressure, it becomes a parallelepiped with a bottom wall, a top wall and a tubular side wall (2c). The bag in abutment contact with the four side panels of the tank has a rectangular cross section comprising four rounded corners each spaced apart from the tank side wall (15) with the following relationship being fulfilled: 0.1 < 4r / p < 0.45, where p is the inner circumference at the base and r is the radius of curvature d at the four rounded corners.

Description

Technical Field

[0001] This invention relates to container systems for mixing and storing fluid components used in the biopharmaceutical field. The invention also relates to a method for mixing biopharmaceutical components in a disposable bioreactor, wherein a stirrer is driven from below.

[0002] "Biopharmaceutical ingredient" means a product derived from biotechnology, culture environment, cell culture, buffer solution, artificial nutrient solution, blood product and blood product derivatives, or a pharmaceutical product, or more broadly, a product intended for use in the medical field. Such a product / ingredient, when mixed, is in the form of a liquid or paste. This invention also applies to filling flexible pouches with other products, but similar requirements apply to their packaging. Background Technology

[0003] Mixing and / or suspending solutions are common in many technologies. For example, biotechnology companies use large quantities of culture media, buffer solutions, and reagents. These materials are initially in powder form and must be hydrated with purified water before use. The hydration process typically involves combining precise amounts of powdered material and purified water in a closed reservoir. As disclosed, for example, in US 7153021 B2, the reservoir is typically a bag of flexible plastic material that is a single-use / disposable three-dimensional (3D) fillable bag. The bag, which may have a polygonal cross-section, is placed within a rigid container of a cylindrical shape. These components are then mixed into the desired solution using a special mixer. A stirring member is positioned inside the bag and driven from below. As disclosed in US2011 / 0158037, the bag can be removably placed within a rigid container having the same transverse rectangular cross-section as the bag's sidewalls, thus allowing the stirring member to be centered. In use, this parallelepiped-shaped bag is provided with a jetting and dispersing device on the upper wall of the rectangular cross-section bag.

[0004] Using a collapsible bag with side panels allows for storage in a folded state before use. The bag is prone to collapse during discharge. The commercially available Sartorius Stedim Flexsafe® Pro Mixer bag is designed to fit inside a rigid container and is suitable for holding various quantities of products to be mixed due to the mixing mechanism being located on the bottom wall of the bag.

[0005] In this type of disposable, three-dimensional (3-D) bag constructed to contain biopharmaceutical products, the volume is typically defined by a lower end wall, an upper end wall, and flexible side walls, which can be in two extreme states—folded-flat and expanded-unfolded. The 3-D bag can deform to transition from any of these states or be in any intermediate state. The bag walls are composed of a single or multiple layers of film made of a plastic material such as polyethylene or a composite containing polyethylene, defining an internal space that has a minimum volume in the folded state and a maximum volume in the expanded-unfolded state. Such biocompatible, disposable, flexible bags can have a large volume (e.g., 1000 liters). Therefore, such bags offer considerable capacity while being easily stored. Patent US10232331 B2 discloses a rigid container for receiving such a bag, which is provided with a movable drive unit to drive a stirring device from below.

[0006] In large-scale operations, the use of flexible bags supported by external stainless steel support containers allows for single-use operations. The rectangular cross-section of the support container is likely preferred for controlling folding and unfolding operations. However, at such large scales, mixing efficiency becomes an issue, thus requiring large-scale single-use systems with improved mixing capabilities. Document US 10857510 B2 discloses a bioprocess mixer that provides two bottom-driven magnetic impellers, making the system relatively complex. Such bioprocess mixers, designed to overcome the problem of rapid mixing of large volumes, require relatively complex drive solutions.

[0007] Therefore, there is still room for improving mixing by using convenient bags (e.g., a collapsible bag that is easy to transport in its initial folded state), where a mixing device is included in the internal volume of a single-use bag. Summary of the Invention

[0008] Embodiments of the present invention provide an apparatus capable of mixing biopharmaceutical components comprising liquids, comprising: - A bag made of a flexible plastic material, the bag having a bottom wall, a top wall and tubular sidewalls (the tubular sidewalls typically extend from the bottom wall to the top wall, so that the bag defines an internal volume). - A can having a rectangular base, the can including rigid sidewalls and having four panels extending upward from the base to define a receiving compartment; - A stirring device located in the internal volume and adapted to be driven from below on the side opposite the top wall; The bags are arranged in the receiving compartment above the base and between the four panels. In the case of liquid inside the bag, the bag has a parallelepiped structure in its unfolded configuration. Once the bag is placed inside the can and unfolds according to the unfolding structure, the bag: - Extending approximately vertically parallel to the central axis of the can, which intersects the upper opening of the can. - It has a roughly rectangular cross-section including four rounded corners, each rounded corner spaced apart from the sidewall of the tank, and this rectangular cross-section corresponds to the rectangular distribution of the four panels, and - Satisfies the following two relations: 0.1 < 4r / p < 0.45 V2 ≥ 1500 liters Where p is the inner perimeter of the base used to define the receiving compartment, r is the radius of curvature measured at any of the four rounded corners, and V2 is the capacity of the bag.

[0009] Due to this arrangement, the stirring device can operate more effectively to generate eddies at the upper layer of the liquid present in the internal volume, although the significant height may exceed 900 mm, preferably exceeding 1600 mm. A distinct rounding is formed at the bag corners RC1, RC2, RC3, RC4, because bag 2 no longer contacts the tank wall at the corners, and because the contact area with the tank panel is sufficiently reduced. When the bag circumference p is in the range of [3000 – 4200] mm at / along the base boundary, the radius of curvature can be greater than 160 mm. It should be understood that in some options, the ratio r / p can be greater than 0.05 and less than 0.10. When the circumference p corresponding to the internal cross-section of the tank is approximately 4000 mm, the radius of curvature r can therefore be much greater than 100 mm and may be less than 400 mm.

[0010] The bag can withstand liquid pressure through a multilayer membrane thickness much greater than 100 or 200 micrometers (e.g., greater than 380 micrometers but less than 700 micrometers). Therefore, the membrane material of bag 2 can remain flexible (easy to fold / unfold), facilitating folding when bag 2 is filled and promoting a collapse effect when the product is discharged. The wide center face of the bag can stretch under liquid pressure to contact the can wall, while the corners stretch less, creating a larger radius at each corner.

[0011] For large volumes (including those greater than 2000 L), mixing will occur after the lower impeller or any suitable mixing part of the agitator starts rotating, without waiting for much time (usually about two minutes or less).

[0012] In some options, the mixing bag is lifted and unfolded before any mixing to ensure that the top wall of the bag is initially at least 1500 mm or 2000 mm higher than the bottom wall. This helps prevent unwanted folds in the bag's sidewalls.

[0013] In practice, it is desirable for flexible bags to expand without undesirable folding, which limits the actual folded volume. Due to the expansion defect, instead of manual monitoring, the lifting system can be secured to the tank to lift the top of the bag before any unfolding occurs on the sidewalls due to liquid pressure.

[0014] Alternatively, the bag is a gusseted bag with two opposing gusset plates.

[0015] Two gussets can interconnect two outer sheets with a larger surface area than the gussets. Each gusset is defined between a pair of longitudinal seams, such that the bag includes four longitudinal seams, a portion of which can extend vertically in the parallelepiped construction of the bag, forming corner seams, as seen in any cross-section.

[0016] Typically, as seen in any cross-section, with this arrangement, each of the longitudinal seams forming the corner joint can be maintained at a certain distance from the rigid wall of the outer container. The seams can have high strength compared to the strength of the bag's plastic material. In this case, the bag-like structure bears the weight of the contents and maintains a generally rectangular cross-section due to the very strong seams. Preferably, the overlap width at the welded areas forming the longitudinal seams is greater than or equal to 6 mm or 7 mm, for example, between 7 mm or 8 mm and 15 mm or 20 mm.

[0017] The central face of the bag stretches under the pressure of the flowable contents (such as water pressure) to contact the wall of the outer container, while the corners stretch much less, thus creating a larger radius at each corner.

[0018] Using a bag that can be stretched to selectively contact the inner surface of the can in areas away from the edge (with a noticeable rounding at the corners of the bag's cross-section) helps to generate the appropriate vortex for quickly (usually less than two minutes) mixing multiple liquids or liquid and solid (e.g., powder materials).

[0019] The option of having a high-strength, vertical seam that is stronger than the bag wall may be of interest, because the cross-sectional area of ​​the bag changes little or not at all in the liquid-filled portion of the bag.

[0020] In some embodiments, the bag contacts each of the four vertical panels. Contact between the bag and each of the four vertical panels can be achieved in four corresponding rectangular contact areas, each extending upwards from the base. Typically, a rectangular contact area is obtained along a given panel, wherein the contact width is greater than 50% of the panel width of the given panel, preferably at least 60%.

[0021] In various embodiments of the invention, one or more of the following arrangements may be used individually or in combination: - The bag is a flexible bag-like object specifically designed to contain biopharmaceutical fluids, preferably without any metal in the membrane material layer of the bag.

[0022] - The bag is provided with at least one port, which is located on the top or bottom wall.

[0023] - Two gusset plates are stretched to contact the two opposite panels of the tank.

[0024] - In the unfolded parallelepiped structure, each of the two gussets includes a first gusset portion and two second gusset portions, the first gusset portion belonging to a given panel portion of the bag sidewall, and the two second gusset portions belonging to two other wall portions of the bag adjacent to the given panel portion.

[0025] - According to one option, in the unfolded parallelepiped structure, a pair of portions of the second gusset plate portion distributed in the two gusset plates are triangular or trapezoidal portions facing the tank base (preferably in contact with the tank base).

[0026] - According to another option, in the unfolded parallelepiped structure, the two second gusset portions belong to the bag sidewalls, and each of the two gusset portions further includes a third gusset portion, which is an elongated gusset edge that contacts the base of the can.

[0027] - Each of the two gusset plates has a lower edge portion that extends along the base in the unfolded configuration.

[0028] - The tank is provided with a lower space, which can be used for a drive unit to drive the stirring device.

[0029] - The impeller is constructed in a parallelepiped shape and extends at the midpoint between the gusset plates.

[0030] - The stirring device consists of only a single impeller, which is preferably a turbine blade driven by a shaft or by magnetic force.

[0031] - The clearance between the impeller and the top wall ranges from 2000 mm to 3400 mm.

[0032] - In the unfolded configuration, the bag has a height measured between the bottom wall and the top wall that exceeds 900 mm, preferably exceeds 1600 mm.

[0033] - The height of the unfolded bag can be less than or equal to 4000 mm, preferably between 2000 mm and 3400 mm.

[0034] - The bag has a longitudinal extension and includes four plastic sheets and four longitudinal seams, such that two of the four plastic sheets are gusseted panels.

[0035] - Each of the four longitudinal seams includes the edges of two longitudinal sheets distributed in two adjacent plastic sheets that are part of the bag.

[0036] - The two gusset plates are made of the same sheet material, preferably made of multi-layered plastic film.

[0037] - The bag is made of only four identical / equal sheets of plastic material.

[0038] - The bag has a height measured between the bottom and top walls in its unfolded configuration. The bag includes two end seals that are spaced apart by an initial distance above the aforementioned height when the bag is folded.

[0039] - The two parallel end seals are each connected to two of the four longitudinal seams at the first joint and to the other two of the four longitudinal seams at the second joint.

[0040] - In the unfolded state, each of the two gusset plates defines a bag panel, which is typically perpendicular to the two end seals.

[0041] - The inner perimeter at the base is the same as the inner perimeter defined by the four panels.

[0042] - The bag in the unfolded structure remains upright, with no contact between the four longitudinal seams and the four panels (side panels).

[0043] - The tubular sidewalls have a given height in the parallelepiped construction, wherein each seam has an elongated seam portion that extends vertically and protrudes outward from the tubular sidewalls of the bag.

[0044] - The four longitudinal seams (slender welds) can typically be wider than 5 mm and can optionally serve as supports and reinforce the square or rectangular base / cross section (the contact area with the can panel can each be wide): by allowing rounding, there is not much radial clearance between the corner areas of the bag and the can, which can be considered advantageous for bag filling.

[0045] - The contact between the bag and each of the four vertical panels is achieved at four corresponding rectangular contact areas, each extending upward from the base.

[0046] - The device includes a support and a connecting element attached to the support for unfolding the bag by lifting displacement of the top of the bag (the support is part of the lifting system) and holding the top of the bag.

[0047] - The linking element is configured to engage with the bag at or through the reinforcing portion at the top.

[0048] - The bag may be provided with a reinforcing portion at the top, which has through holes arranged in and / or surrounded by the reinforcing portion.

[0049] - The linking element is configured to use a bracket and the linking element through / inserted into the through hole in the bag's retaining structure.

[0050] - Provide fastening elements to selectively hold the central region of the bottom wall in a predetermined position relative to the tank base (forming the bottom of the receiving compartment), wherein the sidewall unfolds in response to a lifting action applied to the top of the bag by the lifting system.

[0051] - The lifting system extends above and / or rests on the annular frame surrounding the upper opening of the tank.

[0052] - The annular frame protrudes radially outward relative to the outer surface of the rectangular cross-section tank.

[0053] - The can is provided with spacers covering the vertical edges, which are preferably made of a material that is as rigid as or less rigid than the can. Preferably, the spacers do not deform under pressure applied by the vertical corner areas of the bag when the bag is filled.

[0054] - The spacer is expandable or extendable, and can be controlled to unfold or expand only after the bag filling has begun.

[0055] In some embodiments, the bag has opposing end seals. The two end seals are each distributed in the bottom wall and the top wall, wherein the agitator includes an impeller that moves laterally relative to the end seals provided in the bottom wall, or the two end seals are provided in a tubular sidewall, the agitator including an impeller preferably centrally arranged relative to the bottom wall.

[0056] Optionally, the bag includes: - A first opening in the bottom wall, the stirring device having a shaft, guide protrusion, or any suitable equivalent insert extending along a vertical virtual axis and passing through the first opening; and - A second opening in the top wall, which is adapted to introduce powder into the internal volume from above.

[0057] Two corresponding ports can be provided at these openings.

[0058] The first opening is provided in one of the four sheets. The receiving cup is made of a rigid material, or a material more rigid than the plastic in the four sheets, and can tightly cover the first opening. The stirring device can be partially inserted into the recess defined by the receiving cup and is magnetically driven from below the base.

[0059] A method for using a bag for mixing in a disposable bioreactor is also provided, the bag being specifically designed to contain a biopharmaceutical component comprising liquid, wherein the bag, made of a flexible plastic material, is adapted to be a three-dimensional bag having a parallelepiped structure, such that the bag provides a bottom wall, a top wall, and tubular sidewalls extending from the bottom wall to the top wall, the method comprising unfolding the bag due to the liquid pressure of the liquid, wherein the corners formed at any cross-section below the upper level of the liquid have no contact with the side panel of the tank containing the bag, wherein the liquid contents of the bag are mixed by a stirring device extending in the bag and optionally driven from below the base of the tank.

[0060] The method may include steps consisting primarily of the following steps: - Open the front opening to the receiving compartment of the tank, which includes sidewalls that are rigid and provided with four panels extending upward from a rectangular base to define the receiving compartment; - Place the bag above the base in the receiving compartment; - When the front opening is open, the stirring device extending inside the bag is connected to the drive unit arranged below the receiving compartment. The stirring device is configured to be driven from below on the opposite side of the top wall. - Lift the top of the bag to begin unfolding the two opposing gusset plates of the bag; - Fill the bag with liquid, and the filling can be carried out simultaneously with the further unfolding of the bag to achieve the parallelepiped structure of the bag. Once the bag is placed inside the can and unfolds according to the unfolding structure, the bag: - Extends vertically parallel to the central axis of the can, which intersects the upper opening of the can. - A rectangular cross-section is provided, comprising four rounded corners, each rounded corner spaced apart from the sidewall of the tank. The rectangular cross-section corresponds to the rectangular distribution of the four panels. - Satisfies the following two relations: 0.1 < 4r / p < 0.45 V2 ≥ 1500 liters Where p is the inner perimeter at the base that defines the internal volume, r is the radius of curvature measured at any of the four rounded corners, and V2 is the capacity of the bag. Attached Figure Description

[0061] Now, we will describe several embodiments of the present invention with the aid of the accompanying drawings, in which: Figure 1 It is a perspective view showing a stirring operation performed in a mixing container type device according to one possible embodiment, which has vortices, wherein the vortices are obtained at the top surface of a liquid contained in a flexible bag of the device, the top wall of the bag being omitted. Figure 2 An apparatus according to one embodiment is shown for pouring powder from a powder transfer bag into a filling bag contained in a rigid outer can; the removable drive unit is indicated by dashed lines. Figure 3 A 3-D flexible bag is shown before it is filled with biopharmaceutical fluid according to the first embodiment; Figure 4A and Figure 4B A 3-D flexible bag according to the first embodiment before being filled with biopharmaceutical fluid is shown; Figure 5A It is a perspective view of an alternative 3-D flexible bag, which is adapted to place an impeller on a lower face defined by two parallel welds, wherein two end seals are arranged on two opposite faces of the bag sidewall. Figure 5B It is a perspective view of another alternative 3-D flexible bag, which is adapted to place the impeller above a lower face defined by two parallel welds, wherein two end seals are respectively distributed on the lower and upper faces of the bag. Figure 6 An exemplary manner of assembling four films / sheets to form a 3-D flexible bag is schematically shown in a cross-sectional view, with the sheets being assembled and welded at four longitudinal seams; Figure 7 The illustration shows a case where a white powder does not readily mix with a liquid due to the lack of vortex, the liquid being contained in a high-profile bag fitted into a container with a rectangular cross-section. Figure 8 It is a photograph showing a top view of the contents of another bag, reflecting the effective powder-liquid mixing due to the presence of eddies; Figure 9 A cross-section of a device according to one embodiment is schematically shown, wherein a noticeable corner gap is achieved due to a sufficient radius of curvature; Figure 10This is a top view showing the interior of a device above the liquid surface according to an embodiment involving a spacer. Detailed Implementation

[0062] Hereinafter, several embodiments of the present invention will be described in detail with reference to examples and the accompanying drawings.

[0063] In different accompanying drawings, the same reference numerals denote the same or similar elements. For example... Figure 1 , Figure 3 and Figures 5A-5B As shown, device 1 provides a flexible bag 2 that expands three-dimensionally in a filled state. The bag 2 initially has a flat construction, wherein two opposing wall elements define two main opposing outer surfaces of the flexible bag 2. It can be seen that the flexible bag 2 has openings and / or connection ports for filling and / or emptying. Device 1 includes a stirring device 3, the agitating / stirring portion of which extends within the internal volume V of the bag 2. Device 1 can be used as a mixer vessel adapted to receive biopharmaceutical fluids for mixing, or, where appropriate, for chemical and / or biological reactions (or bioreactors).

[0064] refer to Figure 3 and Figure 6 The bag 2 can be constructed to form a flexible bag-like object with a generally parallelepiped shape once filled with liquid. The bag 2, made of flexible plastic material, includes a bottom wall 2a, a top wall 2b, and tubular sidewalls 2c extending from the bottom wall 2a to the top wall 2b, such that the bag 2 defines an internal volume V. Here, the volume V is at least 1500 liters, with a significant height H, which can be the maximum size of a 3D bag. The term "parallelepiped" means that the tubular sidewalls 2c have a cross-section with four edges (two pairs of parallel edges) that define a square or rectangle. The bag 2 can be easily unfolded before being filled with liquid and can easily collapse after the flowable biopharmaceutical product 4 is discharged (i.e., after the liquid is mixed with at least one additional substance).

[0065] The stirring device 3 is configured to allow mixing of the biopharmaceutical ingredient / product 4 contained in the internal volume V, thereby potentially rapidly dispersing powdered materials or other suitable additives. The stirring device 3 may be arranged to have an impeller 13, typically a single impeller located inside the bag 2 and driven from below the bag 2 in the filled state. In other words, the rotor of the stirring device extends inside the bag 2, for example, where the impeller 13 is positioned as close as possible to the bottom wall 2a. The height of this impeller may be fixed.

[0066] like Figure 1 and Figure 2As shown, bag 2 is adapted to be received inside a rigid container that forms a can T with a significant height (e.g., exceeding 1000 mm or 2000 mm). Can T maintains its tubular sidewall 2c vertical, such that the tubular sidewall 2c extends longitudinally about the central axis X (here, the vertical axis) of can T. Can T can be designed as a rigid hollow tower with a height greater than 2000 mm, for example, about 3000 mm in a non-limiting option.

[0067] The can T may include one or more modules MT (which are stacked here) with substantially the same cross-section to define rigid can sidewalls 15. The can T typically includes a front opening 150 located above the base 5, which allows the still-folded bag 2 to be introduced into the interior of the can T. The front opening 150 is here vertically away from (far below) the upper edge of the can T. Figure 2 As shown in a non-limiting embodiment, the tank T can be designed to receive the drive unit 16 in a lower space 10, which is provided below the receiving compartment of the tank T.

[0068] Figures 4A-4B An exemplary module MT is shown, defining a rectangular cross-section with a 90° angle. The width L1 and length L2 can each exceed 700 mm or 800 mm. One or more slots may be provided near the top of this module MT to allow for quick and removable attachment of a cap or some insert element. In some embodiments, one or more elongated spacers 35 may be vertically positioned along a vertically elongated corner region 7 to cover the corresponding vertical edge of the can module MT. Non-limiting examples of such spacers 35 are shown in... Figure 10 As shown in the diagram. The spacer 35 may have two vertically arranged external guide surfaces or any suitable cross-section to provide a guiding effect along the corresponding can edge 17. Here, each spacer 35 overlaps with two vertically extending edge portions of two adjacent can panels connected at edge 17. Two or three of the four spacers 35 may be arranged along the corresponding edge 17 to facilitate proper positioning of the bag portion, wherein rounded corners RC1, RC2, RC3, RC4 rest on these spacers 35 without any contact with the rigid side panels 15a, 15b, 15c, 15d.

[0069] The tank T can be designed as a single block, or it can have a main section with a base opening O5 in its base 5, with one or more modules MT vertically added to this main section. The base opening O5 forms an inlet for driving the impeller 13 to rotate. The tank's panels can be distributed in multiple sections, particularly when using one or more additional tank modules MT. A drive bag interface can be formed using a tubular connector or similar suitable connection portion, allowing access to the interior of the tank through the base opening O5. This base opening O5 opens vertically upward in a receiving compartment defined by the tank T's panels 15a, 15b, 15c, 15d.

[0070] More generally, a drive bag interface is present, and a connection is obtained with the mixing section, typically occurring before any filling of the bag 2 resting on the base 5. In some embodiments, such as before any bag unfolding, a coupling clamp (for mechanical or magnetic coupling) is inserted along with its aligner. A movable motor of a known type (possibly the magnetic mixer drive unit 16) may be positioned directly below the tank T (in the lower space 10) using a tubular coupling member or similar connector that engages with the drive bag interface, typically protruding downward from the base 5 through the base opening O5. The lower structure 24 extends entirely below the receiving compartment and may be part of / integrated with the tank T, possibly with wheels for transport.

[0071] refer to Figure 2 The bag 2 is completely received inside the can T below the upper opening O. The can T has a parallelepiped shape, which forms a receiving compartment. The base 5 is rectangular (possibly square), and the upper opening O is also defined by a frame forming the perimeter of the rectangle. The cross-section of the can T can be the same along the entire height of the receiving compartment. In a preferred embodiment, the can sidewall 15 is provided with four panels 15a, 15b, 15c, 15d extending upward from the base 5 to define the receiving compartment. For example, the unfolding of the bag 2 can be facilitated by using a lifting system LS before filling. Furthermore, once the bag 2 is in its unfolded configuration, a clamping interface can be used to hold the cap element, neck, or similar portion of the top wall 2b.

[0072] Here, device 1 includes a typically rigid support B2 and a connecting element 6 connected to the support B2. The connecting element 6 can be flexible and can be pulled to lift the bag 2. The lifting system LS is suitable for: - The bag 2 is unfolded by lifting and displacing the top of the bag 2; - And while gradually unfolding bag 2, keep the top of bag 2 intact.

[0073] Additionally, device 1 may include a plate or similar rigid cover (not shown) supporting the powder conveying bag 2'. This cover includes a passage for powder dispensing operations, which may be positioned above the bag. The powder conveying bag 2' may contain at least 10 liters (e.g., at least 30 liters) of powder material. The powder conveying bag 2' can be lifted, optionally using a method such as... Figure 2 The same boosting system LS is used for boosting, as shown.

[0074] Powder addition can only be performed when bag 2 is located inside can T, below or horizontally above the upper opening O, and resting within a dedicated frame TC or upper support (the rectangular upper frame of the can forms all or part of the frame TC). This frame can also be used to support / secure the lifting system. Although in Figure 2 In the non-limiting example, the frame TC is designed as a rectangular frame, but any suitable construction can be used to stack the powder conveying bag 2' relative to the bag 2. A clamping device that clamps the lower end of the powder conveying bag 2' can be used to allow (simply by gravity) the powder material to be poured out.

[0075] refer to Figure 1 After a suitable connection is established between the shaft of the stirring device 3 and the removable drive unit 16, the liquid contained in the parallelepiped bag 2 can be effectively mixed from below by the impeller 13 of the stirring device 3. For example, the unit is inserted into a lower compartment below the receiving compartment of the tank (using the rear side or preferably any side other than the front side having the front opening 150 for introducing the bag 2), such a lower compartment or space in Figure 2 The middle is obvious.

[0076] Impeller 13 is a plastic component, preferably free of any metallic substances, suitable for contact with biopharmaceutical ingredients obtained as a mixture of a liquid (e.g., water) and one or more substances, which are initially in a solid, paste, semi-liquid, or possibly liquid state (optionally, wherein the active substance is dissolved in another liquid).

[0077] Now for reference Figure 1 , Figure 3 , Figures 5A-5B and Figure 6 An exemplary bag 2 is described.

[0078] Bag 2 can be produced by assembling four components (i.e., four plastic film or sheets). The two sheets are initially the outer sheets 21 and 22, and the other two sheets are the first gusset plate 11 and the second gusset plate 12, as shown below. Figures 5A-5B As clearly shown in the image. Two outer sheets 21 and 22 are used to form: - A first wall element, typically a flexible portion (outer sheet 21), which is composed of multiple layers of film and allows for the definition of the surface of the flexible bag 2 (e.g., Figure 3 (The front of the initially folded bag 2 shown). - A second wall element, similarly or identically produced (by a multilayer film), which is a flexible portion (outer sheet 22) such that the rear of the flexible bag 2 can be defined, for example, as Figure 3 As shown.

[0079] The first gusset plate 11 and the second gusset plate 12 may have similar materials and similar (preferably the same) thicknesses as those provided for the two outer sheets 21, 22. It should be understood that the first gusset plate 11 and the second gusset plate 12 are constituted by corresponding membranes, for example, cut from a single section. The cutting can occur before, during, or after the step of joining the sheets 21, 22. Advantageously, for filling with biopharmaceutical fluids, the inner layer of each membrane constituting the flexible bag 2 is made of a heat-weldable plastic material that is biocompatible with the transported medium. In a preferred embodiment, each membrane has a multilayer structure with multiple layers, which are typically non-metallic plastic layers. As a non-limiting example, the membranes may be transparent or translucent. These sheets may be made of the same plastic material.

[0080] According to some embodiments, the end seals W1, W2 and the longitudinal seam W are joined by locally heating them for a sufficiently long time using a welding head. Low-voltage electric pulse heating technology can be used, which preserves the appearance of the visible surfaces while ensuring good weld quality; in fact, no high pressure is required during welding.

[0081] Pulse welding, thermal welding, or laser welding techniques enable the production of resistance-welded seals W1, W2, and longitudinal seams W. In the case of thermal welding, it is preferable to use... Figure 6 The configuration shown applies a pressure of 4 to 8 bar between welding blades or rods to weld four membranes simultaneously, which may be done before a trimming operation to remove the edge portions. Each plastic sheet is typically much thicker than 100 micrometers, therefore an exposure duration of at least 2 or 3 seconds is preferably provided, for example, between 3 and 6 seconds.

[0082] refer to Figure 5A , Figure 5B Bag 2 may have longitudinal extensions and four longitudinal seams W. Due to welding, the seams include two longitudinal sheet edges (from the edges of two adjacent plastic sheets), which have been melted into a strip-shaped joint. At the end seals W1 and W2, the four longitudinal sheet edges may overlap.

[0083] refer to Figure 3 The initially folded bag 2 has a height H. Due to the retraction of the gusset plates, the useful height h in the unfolded state is lower than the height H. In the unfolded configuration, the height h is measured between the bottom wall 2a and the top wall 2b. The two end seals W1 and W2 are spaced apart (in the folded state) by an initial distance equal to the height H. The two parallel end seals W1 and W2 can each connect to two of the four longitudinal seams W at a first joint and to the other two of the four longitudinal seams W at a second joint.

[0084] Although Figure 5A The perspective view shows a 3-D flexible bag 2 with a K-shaped weld at at least one end, but other joints may also be used. For example, Figure 5B A bag 2 with a longitudinal seam W is shown, which is parallel to the entire length of the bag 2 in an unfolded configuration, in which the longitudinal seam W is the same length as the bag.

[0085] In a preferred embodiment, each gusset plate has: an inner heat-weldable layer made of a material selected from polyethylene (preferably linear low density) and ethylene-vinyl acetate copolymer; and an outer weldable layer made of a material selected from polyethylene (preferably linear low density, or possibly linear high density), polyamide, ethylene-vinyl acetate copolymer, polyamide, and polyethylene terephthalate.

[0086] An intermediate layer (e.g., EVOH-based or equivalent material) with a barrier effect can be provided in the multilayer structure of the elements defining the internal volume of the flexible bag 2.

[0087] Now for reference Figure 3 It can be noted that the first gusset plate 11 and the second gusset plate 12 are separated from each other by a lateral space. This lateral space defined between the initial fold lines 112 of the first gusset plate 11 and the second gusset plate 12 can correspond to a constant distance in a flat structure, such as in... Figure 3 As can be seen in the image. The first gusset plate 11 and the second gusset plate 12 may not have any ports, while at least one of the outer sheets 21 and 22 may include one or more openings 20 and 22 to form ports. When the bag 2 is filled with liquid and the top of the bag 2 is held at a high level in the tank T, the bag wall stretches so that the first gusset plate 11 and the second gusset plate 12 are separated from each other, having a gap higher than the initial lateral space between the fold lines 112. This gap may be greater than or equal to 150 mm, which is advantageous for setting ports and / or connecting parts, for example, allowing the stirring device 3 to be centered before unfolding, so that it can be arranged in a parallelepiped configuration at the midpoint between the first gusset plate 11 and the second gusset plate 12.

[0088] In some options, bag 2 is provided with one or more non-accommodating portions NCP (not defining the internal volume V), which can be used to secure to the linking element 6 of the lifting system LS and / or for manipulating bag 2. Possibly, four portions of NCP are connected to a cross bracket or similar lifting beam. In some options, a handle may be formed at the top of bag 2. At the bottom wall 2a, opening 20 may be associated with / covered by a rigid cup or any suitable fitting, which is part of a connection interface that allows the central area of ​​bottom wall 2a to be centered relative to base 5. Optionally, this connection interface holds bottom wall 2a, which is meaningful when moving the top of bag 2 upwards, thereby ensuring the centering of bottom wall 2a.

[0089] In some options, such as Figure 2 As shown, device 1 includes a support and a connecting element 6 connected to the support. The tank T may be provided with such a support for holding the top of the bag 2, the support extending above the top opening O of the tank T, or at least holding the top in a high position without interfering with the end of the liquid filling operation (filling of the bag) or any agitation that may begin before the end of filling.

[0090] More generally, the device may have a lifting system LS for controlling the unfolding of bag 2. Once the supports are secured and the connecting elements or cross supports are centered relative to the upper opening O, the tubular sidewalls 2c of bag 2 can gradually unfold by the lifting displacement of the top of bag 2. The bottom wall 2a may be held in place by the fastening elements of the connecting interface (for connection with drive unit 16) and / or by the weight of a portion of the liquid already present at the bottom of bag 2.

[0091] In some embodiments, the bag 2 is provided with a reinforcing portion at its top, the reinforcing portion having a through-hole arranged in and / or surrounded by the reinforcing portion. Using a bracket and a linking element 6, the linking element 6 can pass through the through-hole in a retaining configuration of the bag 2, wherein the top of the bag 2 is held in the top region of the receiving compartment.

[0092] Near the bottom side, bag 2 includes a first opening 20, for example, provided in Figure 3 The first opening 20 is in the outer plastic sheet 21. Therefore, when the bag 2 is unfolded, the first opening 20 can extend into the bottom wall 2a, allowing the impeller 13 to be driven from below, as... Figures 5A-5B As shown. The first opening 20 may be covered by a lower receiving cup adapted to partially accommodate the stirring device 3. The receiving cup may have an annular connecting flange and may project downward relative to the base 5. The stirring device 3 may extend below the base 5, opposite to the second opening O2 provided in the top wall 2b. The stirring device 3 may have a guide end extending along a vertical virtual axis and passing through the first opening 20.

[0093] When the stirring device 3 is driven by magnetic force, the first opening 20 is not noticeable from the outside of the bag 2 because it is covered by the receiving cup. The cup is typically fastened (in a tight manner) to the sheet 21 at the annular joint and completely covers the first opening 20.

[0094] The bag 2, which houses the stirring device 3 at the cup, can be associated with the drive unit 16 for suspending and / or rotating the stirring device 3. The drive unit may have a cylindrical receiving connector adapted to accommodate the protruding cup.

[0095] refer to Figures 2-3 The opening O2 is a port suitable for connection to the powder conveying bag 2' or any other suitable conveying device for adding material to the liquid already present in the bag 2. A third opening (not shown) may correspond to a filling and / or discharging port arranged in the bottom wall 2a, to which a flexible hose is connected. At least one flexible hose may also be connected to the top wall 2b (see [link to top wall]). Figure 5A ).

[0096] The opening O2 here is suitable for introducing this powdered material. In some variations, another additional substance can be supplied via a hose using a suitable opening in bag 2.

[0097] refer to Figures 1-2 and Figures 4A to 5B The space occupied by the bag-can will be described in detail. Although the first gusset plate 11, the second gusset plate 12, and the outer sheets 21, 22 can have the same height, in the stretched / unstretched state of the bag 2, the first gusset plate 11 and the second gusset plate 12 can have a given length L10 (a portion of the perimeter of the bag 2 measured in cross-section), which is: - Less than the length L20 of the outer sheets 21 and 22, - And it is lower than the width L1 of the can T.

[0098] In other words, the length L10 is typically the width of bag 2 because the first gusset plate 11 and the second gusset plate 12 have fold lines 112 that remain far apart from each other in the folded structure. Therefore, the outer sheets 21 and 22 define a larger surface area. In some embodiments of interest, the following relationship is satisfied: L2 > L20 > L1 > L10 exist Figure 1 In the unfolded structure, when the longitudinal seams W of bag 2 have a vertical extension, they project radially outward, facing the vertically elongated corner region 7. A narrow gap is locally formed between the inner surfaces of bag 2 and can T, corresponding to, for example, one of four corner regions extending along the same vertical edge 17 of can T. Figure 4BAs shown, only the area of ​​can T furthest from edge 17 will contact the outer surface of bag 2. For each can panel 15a, 15b, 15c, 15d, only a sub-section of the corresponding inner surface will contact bag 2. Four generally rectangular contact areas RA can be provided in the panel, each extending upward from base 5. Figure 4B In the example, only the top portion of the contact area RA is shown.

[0099] refer to Figure 1 The bag 2 is stretched by the weight of the liquid and thus acquires a parallelepiped shape, wherein the outer face of the bag 2 extends parallel to the corresponding can panel 15a, 15b, 15c or 15d. Under the pressure of the flowable contents (e.g., water pressure), the bag 2 is stretched to contact the wall / panel 15a, 15b, 15c or 15d of the outer can T, while the corners with longitudinal seams W are stretched less, thus creating a pronounced curvature. Figure 1 The diagram shows the curved surfaces CF obtained in the four corner sections of the bag extending longitudinally (vertically), each curved surface CF separating two adjacent rectangular contact areas that form the contact area RA.

[0100] The seam forms a relatively large overlap width at the welding area, which can be about 12 mm, for example greater than or equal to 7 mm and less than 15 mm.

[0101] Bag 2 is sized to stretch within the boundaries of a rectangular cross-section smaller than the rectangular cross-section defined by the inner surface of the can sidewall 15. (Reference) Figure 4A and Figure 9 Understandably, due to the reduction in length and width, bag 2 can have a shorter rectangular contact area than the corresponding panel of can T, typically reduced by at least approximately 90 mm or 100 mm, and possibly reaching 140 mm or 150 mm. The following relationship can be satisfied: 0.1 < 4r / p < 0.45 Where p is the inner perimeter at the base 5 that defines the internal volume V (the boundary of its lower portion), and r is the radius of curvature measured at any of the four rounded corners (see [reference]). Figure 9 ).

[0102] Bag 2 is provided here with a rectangular cross-section including four rounded corners. Due to the short dimensions L10 and L20, each rounded corner is spaced apart from the sidewall 15 of the container. The table below shows the experiments conducted to analyze the effect of the bag's occupied space on good mixing with the powder material. If there is no obvious eddy current at the top surface of the liquid, the powder material cannot easily dissolve into the liquid.

[0103] refer to Figure 7The photograph illustrates how powder 40 accumulates above the liquid without any satisfactory mixing due to the absence of vortex 100 (see [reference to vortex 100]). Figure 1 The eddy current 100 facilitates mixing, which reduces the time required to obtain a uniform composition within the internal volume V. Figure 7 The bag 2 shown is correctly unfolded and fills the corner area of ​​the can T: this helps to reduce the total height of bag 2 as much as possible.

[0104] However, for high bag capacities, a lack of mixing is a problem. The table below reflects the gains in mixing operation of sizes L10 and L20 due to the special rounding at the four vertically elongated corner areas of bag 2, despite the height being greater than or equal to 3000 mm (i.e., presenting the challenge of propagating the impeller rotational motion to the top surface of the liquid). Sizes L10 and L20 are remarkably efficient in achieving vortex 100.

[0105] The experiment depicted below was conducted using the same can T and a commercially available impeller 13 (here, a Rushton impeller) at the same rotational speed of 500 revolutions per minute (rpm). The filling level was 2400 liters (L) before the same amount (30 liters) of powder 40 was poured in, with water forming a liquid. At this point, once all powder 40 had been added, the addition of powder began to mix and fill to a total volume of 3000 L.

[0106]

[0107] surface

[0108] Test A reflects Figure 7 The situation is illustrated in the diagram. This cross-section is considered suitable for many applications where the total height of the can is typically less than or equal to 1000 mm or 1200 mm. According to Test A, bag 2 unfolds satisfactorily and matches the shape and size of can T appropriately. However, when the height is greater (3000 mm in this case, according to experiments), it is impossible to obtain vortex 100.

[0109] Compared to tests C1, C2, and C3, it can be seen that although this size is already about three times larger than the other two sizes (length and width), exceeding 3000 mm but not exceeding 3250 mm to have sufficient internal volume V, the bag height still increases despite the decrease in width L10 (only 788, 800, or 812 mm) and length L20 (988, 1000, or 1012 mm). Reference Figure 8 , Figure 8Reflecting on test C3, it was advantageously observed that bag 2 withstood the liquid pressure, in which circular corner regions extending vertically parallel to the can edge 17 were formed, resulting in a noticeable gap G along each edge 17. For any cross-section of bag 2, near the base 5 or also near the liquid top surface, each circular corner RC1, RC2, RC3, or RC4 was stretched into a rounded shape: vortices 100 can be seen at or near the center of the top surface of the component to be mixed. As a result, the powder 40 added from above dissolves rapidly.

[0110] refer to Figure 9 In the unfolded / stretched construction, the cross-section of bag 2 used in tests B1, B2, C1, C2, and C3 exhibits a distinct radius of curvature r at the rounded corners RC1, RC2, RC3, and RC4. For a given perimeter p between 4000 mm and 4200 mm, it should be understood that mixing can occur more quickly / more efficiently when the radius of curvature r is greater than 150 mm, or for example, between 180 mm or 190 mm and 340 mm or 350 mm. To avoid excessive rounding, which would lead to an increase in height, this radius of curvature can be less than 350 mm or 400 mm.

[0111] When the radius of curvature is much smaller than the width of the bag's cross-section (in the unfolded state), for example, when the width is about 900 mm, the radius of curvature is less than 90 mm or 100 mm, and the powder 40 or any other additives cannot be adequately mixed: there is a lack of downward attraction, which is reflected in the lack of suitable eddies.

[0112] Here, the height of bag 2 can vary. For example, bag 2 is at least 1600 mm high in the unfolded configuration, and for a capacity V2 greater than 1500 L, this height is, for example, about 2100 mm or 3000 mm. In some options, the cross-section of the bag is specifically chosen to have a circumference significantly lower than the inner circumference p of the can cross-section, while appropriately allowing contact (usually flat contact) with the corresponding four panel interior surfaces of the can T.

[0113] It is important to note that, for Figure 5A and Figure 5B Both scenarios shown exhibit positive effects from the mixing process. Compared to the space occupied by the bag-can assembly, the positions of the first and second corner brackets 11 and 12 within the can T, or the symmetrical position of the impeller relative to the bottom wall 2a, do not play a significant role. [The following is a possible interpretation:] It can provide... Figure 5A The impeller 13 is located more centrally, but using... Figure 5B The slight shift in the position of impeller 13 also confirms the results in the table above, rather than necessarily having the more central position mentioned above.

[0114] Here, the width of bag 2 is equal to twice the width of the first corner support 11 or the second corner support 12 in the folded state (e.g., Figure 3 As shown), for example, in case C1, the half-width of the first gusset plate 11 and the second gusset plate 12 is 400 mm. The length of the rectangular section (1000 mm in case C1) reflects the distance between the longitudinal seams W, which is measured along the width of the outer sheet 21 or 22.

[0115] The capacity V2 of bag 2 can be substantially equal to the internal volume V defined by the bag sidewall (tubular sidewall 2c). In fact, bag 2 has no undesirable folds, and the space occupied by impeller 13 (or other parts / instruments that may be located inside bag 2) has a low impact, such that in the fully stretched parallelepiped structure of bag 2, the verified volume V2 of bag 2 when unfolded inside tank T is close to or almost equal to the internal volume V of bag defined by tubular sidewall 2c.

[0116] Once received in the receiving compartment, the bag 2, resting on the base 5, is unfolded using the lifting system LS and filled with liquid (possibly water). Before the stirring operation begins, the bag 2 (in its filled state) has a parallelepiped structure and is held upright by the four panels 15a, 15b, 15c, and 15d. In practice, the bag 2 is in contact with each of the four vertical panels 15a, 15b, 15c, and 15d. The contact between the bag 2 and each of the four vertical panels 15a, 15b, 15c, and 15d can be achieved at four corresponding substantially rectangular contact areas, each extending upward from the base 5. Typically, a rectangular contact area RA is obtained along a given panel, wherein the contact width is greater than 50% of the panel width of the given panel, preferably at least 60%.

[0117] Once the bag is stretched under liquid pressure, but constrained by the side panels 15a, 15b, 15c, and 15d, it becomes a parallelepiped (with its sidewalls abutting against the four side panels 15a, 15b, 15c, and 15d to achieve contact), having a rectangular cross-section including four rounded corners RC1, RC2, RC3, and RC4, each rounded corner being spaced apart from the can sidewall 15, wherein the following relationship is satisfied: 0.1 < 4r / p < 0.45 Where p is the inner circumference at the base, and r is the radius of curvature d at the four rounded corners.

[0118] Therefore, a large portion of the bag perimeter does not contact the side panels 15a, 15b, 15c, 15d. Typically, more than 15% of the bag perimeter (the outer circumference of the bag in the filled state) is spaced apart from the tank boundary, with each rounded corner including a vertically elongated corner portion in which the liquid pressure is not balanced by the reaction force of the tank side panels.

[0119] After mixing, the connection port to a suitable flexible tube allows the bag to be emptied. This flexible tube can extend downwards from the bag 2 received above the lower space 10. More generally, the flexible bag 2 includes one or more connectors forming the connection port, which are optionally provided on the same outer sheet 21 or 22 to enable filling of the flexible bag 2 (typically having multiple inlets or supply openings). Here, the flexible tube connected to the connector (see, for example, [reference needed]) Figure 5A The type is known in itself; a lower flexible tube (not shown) may also be provided for discharge. The first gusset plate 11 and the second gusset plate 12 have predetermined folds formed during the design of the flexible bag 2, particularly fold lines 112 (see...). Figure 6 This helps to ensure proper unfolding as the fill level, which is typically for biopharmaceutical fluids, increases.

[0120] Of course, the location of one or more connection ports can vary, preferably by forming an opening in one (preferably only) of the outer sheets 21, 22. These connection ports are placed at a distance from the connection area (longitudinal seam W, end seals W1, W2) between the two outer sheets 21, 22, and they do not interfere with the deployment of the first gusset plate 11 and the second gusset plate 12 of the 3-D type flexible bag 2. The ports can be sealed in a manner known per se (the ports are sealed to a clamp commonly referred to as a "clamp" by those skilled in the art, a sterile connector, or may include a one-way damper or valve or other similar sealing and sealing system, a blocked, sealed section of pipe or conduit itself).

[0121] Examples of functional multilayer membranes that enable the formation of wall elements (i.e., the first gusset plate 11, the second gusset plate 12 and the outer sheets 21, 22 of the flexible bag 2) can be highly flexible membranes with satisfactory resistance connections, which facilitates the unfolding of the first gusset plate 11 and the second gusset plate 12 without any risk of membrane rupture caused by expansion in the bag ends or tubular sidewalls 2c during filling.

[0122] Therefore, the fold line 112 of each of the first gusset plate 11 and the second gusset plate 12 is a straight line and parallel to the side edges 8, 18 and 9, 19 defined by the wall elements. It can be seen that the fold line 112 is along the longitudinal axis (in this case, the central axis) of the flexible bag 2 in a flat construction. Figure 3Extends on either side of (as shown).

[0123] refer to Figure 1 and Figures 5A-4B , Figure 1 and Figures 5A-4B A flexible bag 2 in a biopharmaceutical fluid-filled state is shown, with a first gusset plate 11 connected to two side edges 8 and 9 of either a first outer sheet 21 or a second outer sheet 22. Similarly, a second gusset plate 12 is connected to two other side edges 18 and 19 of either the first outer sheet 21 or the second outer sheet 22. (See reference) Figure 6 The connections to the side edges 8, 18 of the first outer sheet 21 and the side edges 9, 19 of the second outer sheet 22 are achieved by direct welding, thereby securing the edge regions of the first gusset plate 11 and the second gusset plate 12 along the side edges 8, 9, 18, 19. Hereinafter, these edge regions will be referred to as longitudinal edges.

[0124] The first gusset plate 11 and the second gusset plate 12 can each be folded inward along their fold lines 112. In this example, at least in the flat construction of the flexible bag 2, for each of the first gusset plate 11 and the second gusset plate 12, the fold is completed in two equal halves. Each fold line 112 extends between the two opposite ends of the flexible bag 2, where the first gusset plate 11 and the second gusset plate 12 engage with the axial ends of the outer sheet.

[0125] Examples of bags 2 with specific circular corners RC1, RC2, RC3, RC4 forming a significant radius of curvature r are beneficial for mixing. Effective mixing, challenging at high volumes, can be repeatedly achieved. The relatively high radius r combined with effective containment in a rectangular can T cumulatively benefits: - Mixing, especially powder-liquid mixing (which requires good dispersion and dissolution of the particles), where there is a noticeable vortex at the top of the bag contents; and - Properly expand the bag during the filling operation, whereby the bag collapses once discharged / emptied to prevent product loss and / or wasted time during product discharge.

[0126] Although the stirring device 3 has been shown with a symmetrical impeller 13 (e.g., a turbine, which typically has a downwardly extending shaft 30), any suitable stirring section can be used. Furthermore, a magnetic connection can be provided to allow rotation of such a stirring section. A short shaft 30 can be provided to guide the rotation.

[0127] Furthermore, the stirring device 3 can include any suitable construction for stirring, wherein one or more impellers 13 are driven to initiate agitation near the tank base 5. The embodiments are not limited to the specific design of the one or more impellers, nor to the rotational speeds involved. Many options with sufficient agitation are available to allow liquid movement (from the bag region adjacent to the base 5) upward propagation. A rotational speed of 500 rpm has been shown only as a non-limiting example. In other options, the rotational speed can be lower, for example, about 400 rpm or less. This lower speed can be used for bag heights h below 2500 mm or 3000 mm. Higher rotational speeds can also provide effective results; for example, speeds of 700 rpm or 900 rpm can be included.

Claims

1. An apparatus having a disposable bag (2) filled with a liquid containing a biopharmaceutical ingredient, the apparatus being capable of mixing the biopharmaceutical ingredient (4), and the apparatus comprising: - The bag (2) is made of a flexible plastic material and has a bottom wall (2a), a top wall (2b) and a tubular sidewall (2c) extending from the bottom wall (2a) to the top wall (2b) such that the bag (2) defines an internal volume (V); - A can having a rectangular base (5) and a can sidewall (15) that is rigid and has four panels (15a, 15b, 15c, 15d) extending upward from the base (5) to define a receiving compartment. - A stirring device (3), which is located in the internal volume (V) and is adapted to be driven from below on the opposite side of the top wall (2b); The bag (2) is placed inside the can and is arranged in the receiving compartment above the base (5) and between the four panels (15a, 15b, 15c, 15d). In this configuration, the bag (2) has a parallelepiped structure due to the presence of liquid inside, and the bag (2) extends vertically parallel to the central axis (X) of the can, which intersects with the upper opening (O) of the can. The device is characterized in that the bag (2): - A rectangular cross-section is provided, comprising four rounded corners (RC1, RC2, RC3, RC4), each rounded corner being spaced apart from the tank sidewall (15). The rectangular cross-section corresponds to the rectangular distribution of the four panels (15a, 15b, 15c, 15d). - Satisfies the following two relations: 0.1 < 4r / p < 0.45 V2 ≥ 1500 liters Where p is the inner perimeter of the base (5) used to define the receiving compartment, r is the radius of curvature measured at any of the four circular corners (RC1, RC2, RC3, RC4), and V2 is the capacity of the bag (2).

2. The device according to claim 1, wherein, The bag (2) contacts each of the four panels (15a, 15b, 15c, 15d) that are vertical panels, and wherein the contact between the bag (2) and each of the four vertical panels (15a, 15b, 15c, 15d) is obtained at four corresponding rectangular contact areas, each rectangular contact area extending upward from the base (5).

3. The device according to claim 1 or 2, wherein, The bag (2) has a height (h) measured between the bottom wall (2a) and the top wall (2b) in the unfolded configuration, the height (h) being greater than 900 mm.

4. The device according to claim 1, wherein, The bag (2) has a longitudinal extension and includes four plastic sheets and four longitudinal seams (W), such that two of the four plastic sheets are gussets, and each of the four longitudinal seams (W) includes two longitudinal sheet edges distributed in two adjacent plastic sheets that are part of the bag (2).

5. The device according to claim 4, wherein, The two gusset plates are made of the same sheet material, which is made of multiple layers of plastic film.

6. The device according to claim 4 or 5, wherein, The bag has a height (h) measured between the bottom wall (2a) and the top wall (2b) in the unfolded configuration. The bag (2) includes two end seals that are spaced apart by an initial distance (H) in the folded state of the bag (2), the initial distance (H) being higher than the height (h). Each of the two parallel end seals is connected at a first joint to two of the four longitudinal seams (W) and at a second joint to the other two of the four longitudinal seams (W).

7. The device according to claim 4 or 5, wherein, The inner perimeter of the base (5) is the same as the inner perimeter defined by the four panels (15a, 15b, 15c, 15d), the bag (2) remains upright in the unfolded structure, and there is no contact between the four longitudinal seams (W) and the four panels (15a, 15b, 15c, 15d). Furthermore, the tubular sidewall (2c) has a given height (h) in the parallelepiped structure, wherein each longitudinal joint (W) has an elongated joint portion, the elongated joint portion being: - Extends vertically, and - Protruding outward from the tubular sidewall (2c) of the bag (2).

8. The device according to claim 6, wherein, The two end seals are located in the bottom wall (2a) and the top wall (2b), and the stirring device (3) includes an impeller (13) which is laterally displaced relative to the end seals located in the bottom wall (2a).

9. The device according to claim 6, wherein, The two end sealing parts are disposed in the tubular sidewall (2c), and the stirring device (3) includes an impeller (13) which is centrally arranged relative to the bottom wall (2a).

10. The device according to claim 1 or 2, wherein, The stirring device (3) is configured to rotate about a vertical virtual axis, and wherein the bag (2) includes an opening (O2) in the top wall (2b) adapted to introduce powder (40) into the internal volume (V) from above.

11. The device according to claim 10, wherein, The stirring device (3) consists of only a single impeller (13) driven by magnetic force, and the height of the gap between the impeller (13) and the top wall (2b) is between 2000 mm and 3400 mm.

12. The device according to claim 11, wherein, The single impeller (13) is a turbine propeller.

13. The device according to claim 1 or 2, comprising a support and a linking element (6) coupled to the support, for: - The bag (2) is unfolded by lifting displacement of the top of the bag, and the support belongs to the lifting system (LS). - And keep the top of the bag (2) closed.

14. The device according to claim 13, wherein, The bag (2) has a reinforcing portion at its top end, the reinforcing portion having a through hole arranged in and / or surrounded by the reinforcing portion, and the linking element (6) is configured to engage the bag (2) in the bag (2) in the retaining structure of the bag (2) by passing through the through hole at or through the reinforcing portion.

15. The device according to claim 1 or 2, comprising a fastening element configured to selectively hold a central region of the bottom wall (2a) in a predetermined position relative to the base (5) of the tank, wherein, The tubular sidewall (2c) unfolds in response to a lifting action applied at the top of the bag (2) by a lifting system (LS) that extends above and / or rests on an annular frame surrounding the upper opening (O) of the can, the annular frame projecting radially outward relative to the outer surface of the rectangular cross-section of the can. The height (h) of the bag (2) measured between the bottom wall (2a) and the top wall (2b) in the unfolded structure is greater than 1600 mm.

16. The device according to claim 1 or 2, wherein, The can is provided with a vertically elongated spacer (35) covering the vertical edge (17) of the can, such that in the unfolded configuration of the bag (2), the bag (2) contacts the four panels (15a, 15b, 15c, 15d) of the can and alternately contacts the spacer (35) along the periphery of the bag (2).

17. A method for mixing in a disposable bioreactor using a bag (2), said bag (2) being specifically designed to contain a biopharmaceutical component (4) comprising a liquid, wherein, The bag (2) made of flexible plastic material is suitable for having a three-dimensional structure with a parallelepiped structure, such that the bag (2) is provided with a bottom wall (2a), a top wall (2b) and tubular sidewalls (2c) extending from the bottom wall (2a) to the top wall (2b), the method comprising: - Open the front opening (150) leading to the receiving compartment of the tank, which includes a tank sidewall (15) that is rigid and provided with four panels (15a, 15b, 15c, 15d) extending upward from a rectangular base (5) to define the receiving compartment. - Place the bag (2) above the base (5) in the receiving compartment; - While the front opening (150) is open, a stirring device (3) extending inside the bag (2) is connected to a drive unit (16) arranged below the receiving compartment. The stirring device (3) is configured to be driven from below on the side opposite to the top wall (2b) to mix the liquid contents of the bag. - Raise the top of the bag (2) to begin unfolding the two opposing gusset plates of the bag (2); - Simultaneously, the bag (2) is filled with liquid and further expanded to achieve a parallelepiped structure. Wherein, once the bag (2) is placed inside the can and unfolded according to the unfolding structure, the bag (2): - Extends vertically parallel to the central axis (X) of the can, which intersects the upper opening (O) of the can. - A rectangular cross-section is provided, comprising four rounded corners (RC1, RC2, RC3, RC4), each rounded corner being spaced apart from the tank sidewall (15). The rectangular cross-section corresponds to the rectangular distribution of the four panels (15a, 15b, 15c, 15d). - Satisfies the following two relations: 0.1 < 4r / p < 0.45 V2 ≥ 1500 liters Where p is the inner perimeter of the base (5) used to define the receiving compartment, r is the radius of curvature measured at any of the four circular corners (RC1, RC2, RC3, RC4), and V2 is the capacity of the bag (2).

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