Mixing of the content of a flexible container for biopharmaceutical use

A receptacle (1) for biopharmaceutical use includes a flexible container (2) having a wall (4), an internal space (5) for receiving a liquid or pasty biopharmaceutical content, mixing elements (20) adjacent to a given portion (21) of the wall (4), elements (22) for rigid and leaktight connection between the mixing elements (20) and the given portion (21), the mixing elements (20) including a sleeve (24), a suction-delivery opening (26), a suction-delivery part (28), a suction-delivery cavity (29), drive elements (23) for driving in an alternating forward/backward axial sliding sequence, elements (32) for immobilizing the sleeve and the given portion (21), including during the axial sliding movement of the suction-delivery part (28).

FIELD OF THE INVENTION

The invention relates to mixing the content of a flexible container for biopharmaceutical use.

It more specifically concerns a receptacle for biopharmaceutical use, a rigid assembly for receiving and retaining the flexible container of such a receptacle for biopharmaceutical use, and, lastly, a method for making use of such a receptacle for biopharmaceutical use.

BACKGROUND OF THE INVENTION

It is known in the biopharmaceutical field to provide and make use of receptacles able to receive a biopharmaceutical product that is generally liquid or pasty at least when it is to be mixed, as its content. Such receptacles are typically intended for the preparation of a biopharmaceutical product, for storage, for transport, or for carrying out a specific process that is physical, chemical, or biological in nature, for example a freezing/thawing process.

“Biopharmaceutical product” is understood here to mean a product obtained from biotechnology (culture media, cell cultures, buffer solutions, artificial nutrition liquids), or a pharmaceutical product, or more generally a product intended for use in the medical field.

Such a receptacle for biopharmaceutical use firstly comprises a flexible container having a flexible wall delimiting at the front an inside space for receiving the biopharmaceutical product. Such a flexible container or bag is disposable, closed, sealed, sterile, and of plastic material such as polyethylene or a complex including polyethylene. Such a container comprises means for introducing into and means for extracting from the inside space the biopharmaceutical product or components of the product, it being possible to place these means, depending on the moment and on requirements, in the open or closed state.

There are known bags of this type in which the two large walls are directly joined to each other. Once expanded, such bags have a limited volume and remain relatively thin, which is why they are often referred to as “pillow bags” or “2D bags” (where D stands for dimensional). Also known are 3D bags which have two large walls connected by and welded to two side gussets, which can be folded flat or unfolded when deployed, the volume then reaching at least 50 liters and up to 3000 liters or more. Such 3D bags are described in document WO00/04131a or sold under the trademark FLEXEL® 3D.

Such a receptacle for biopharmaceutical use secondly comprises mixing means which mix the content of the inside space. These mixing means are adjacent to a defined local part of the flexible wall, for example but not limited to the bottom wall or the top wall. These mixing means include movable displacement means, which are adjoining the inside space and are able to displace the content within it.

Such a receptacle for biopharmaceutical use comprises, thirdly, means for driving the movable displacement means, and fourthly, rigid and leaktight connection means ensuring a rigid and leaktight connection between the mixing means and the given part of the flexible wall.

The prior art is illustrated in particular by patents WO 02/062458, WO 03/028869, WO 2006/002091, WO 2006/0630a87 and WO 2009/143925.

In the known embodiments, the movable displacement means of the mixing means are typically a propeller rotatably mounted within the inside space itself. As a result, these known embodiments have the disadvantages inherent in the presence within the inside space of movable displacement means such as a rotating fan. These disadvantages include the space required and the risk of damaging the flexible wall. Another disadvantage arises when the mixture concerns a content that is to undergo a freezing/thawing sequence, because such mixing means cannot be caught within the solidified content.

The invention aims to provide a solution to these disadvantages by proposing mixing means based on a completely different concept.

There are known studies which seek to apply the water-jet propulsion process of squids and jellyfish to industry. This involves generating a jet stream which can be efficiently used to set an adjacent fluid in motion. To achieve this, a casing is provided which defines an inside chamber and has an opening. A flexible membrane is mounted in the casing and, by its movements, it modifies the volume of the chamber. Eddies are thus ejected from the chamber through the opening. U.S. Pat. No. 5,894,990, U.S. Pat. No. 6,123,145, U.S. Pat. No. 6,457,654, U.S. Pat. No. 5,988,522, U.S. Pat. No. 6,056,204, U.S. Pat. No. 5,957,413 and U.S. Pat. No. 5,758,823 refer to this technology. This technology has been suggested for various applications, such as motors and aeronautics, but not in the field of receptacles for biopharmaceutical use in which the flexible container has a flexible wall. The existence of such a flexible wall further discourages the application of this technology in this field, because the flexible wall does not allow setting the mixing means in motion.

The invention aims to solve these problems.

OBJECT AND SUMMARY OF THE INVENTION

For this purpose, the object of a first aspect of the invention is a receptacle for biopharmaceutical use comprising:a flexible container having a flexible wall delimiting at the front an inside space able to receive content that is a biopharmaceutical product which is generally liquid or pasty at least when it is to be mixed,mixing means able to mix the content of the inside space, adjacent to a given part of the flexible wall, including movable displacement means adjoining the inside space and able to displace the content,means for driving the movable displacement means,and rigid and leaktight connection means ensuring a rigid and leaktight connection between the mixing means and the given part of the flexible wall.

This receptacle for biopharmaceutical use is such that:the mixing means comprise:an axial guiding and peripheral closure sleeve which is rigid with a constant transverse cross-section along its axis, having towards its front part a suction-discharge opening adjoining the inside space,a suction-discharge part which is unpierced and arranged transversely in the sleeve in a leaktight manner, and of which at least one movable part is mounted to slide alternately forwards and backwards axially,a suction-discharge cavity, delimited by the lateral inside face of the sleeve and the front inside face of the suction-discharge part, in communication with the inside space via the suction-discharge opening,the drive means are able to drive the movable part of the suction-discharge part and assure its movement in at least one sequence of sliding alternately forwards and backwards axially such that the volume of the suction-discharge cavity has at least one sequence of alternately compressing and expanding, and thus the content of the flexible container adjacent to the suction-discharge opening is moved about and the content of the flexible container is mixed,immobilization means ensure the relative immobilization of the axial guiding and peripheral closure sleeve and of the given part of the flexible wall, including during the sliding axial movement of the movable portion of the suction-discharge part.

In a first embodiment, the given part of the flexible wall comprises a through-hole with which the mixing means are axially associated, and the rigid and leaktight connection means are secured in a leaktight manner on the one hand to the sleeve by a side part peripheral and external to the sleeve, and on the other hand to the given part of the flexible wall by a peripheral portion around the mounting hole and lying flat on the flexible wall.

In a first variant, the hole in the given part of the flexible wall allows the passage of the sleeve, and the suction-discharge opening is axially substantially adjacent to the flexible wall, with the mixing means extending axially substantially rearwards from the given part of the flexible wall.

In a second variant, the hole in the given part of the flexible wall provides the communication between the suction-discharge cavity and the inside space, and the suction-discharge opening is axially offset rearwards from the given part of the flexible wall, with the mixing means extending axially substantially rearwards from the given part of the flexible wall.

In a third variant, the hole in the given part of the flexible wall allows the passage of the sleeve, and the suction-discharge opening is axially offset frontwards from the given part of the flexible wall, with the mixing means extending axially either partially frontwards and partially rearwards or substantially frontwards from the given part of the flexible wall.

In a second embodiment, the given part of the flexible wall is unpierced; the rigid and leaktight connection means are secured in a leaktight manner on the one hand to the sleeve by a part external to the sleeve and on the other hand to the given part of the flexible wall by a part lying flat on the flexible wall; and the mixing means extend axially substantially frontwards from the given part of the flexible wall.

In one embodiment, the rigid and leaktight connection means comprise a transverse face adjoining the sleeve, rigidly secured, to lie flat, in a leaktight manner, to the flexible wall at or near the given part. In particular, said transverse face is part of a rigid wall, and more specifically is rigidly secured, to lie flat, in a leaktight manner to the flexible wall, by welding or adhesive bonding.

In one embodiment, the axial guiding and peripheral closure sleeve comprises a front part laterally delimited by the lateral inside face of the sleeve, delimited at the back by the front inside face of the suction-discharge part in the extreme rearward sliding position, and delimited at the front by the suction-discharge opening. In one embodiment, the sleeve comprises a rear part laterally delimited by the lateral inside face of the sleeve and delimited at the front by the rear face of the suction-discharge part in the extreme rearward sliding position. In one embodiment, the sleeve comprises a rear part delimited at the back by a transverse terminal rear wall.

In a first embodiment, the suction-discharge part is a rigid piston mounted in the sleeve. In a second embodiment, the suction-discharge part is a deformable membrane having a fixed peripheral part attached to the lateral inside face of the sleeve and a central movable part.

In one embodiment, the suction-discharge part is mounted to slide axially between an extreme rearward position and an extreme forward position, respectively the furthest from and the closest to the suction-discharge opening. In particular, in its extreme forward position, the suction-discharge part closes off the suction-discharge opening.

In one embodiment, the suction-discharge cavity is transversely flattened, its size in the transverse direction being larger than its size in the axial direction.

In some embodiments, the suction-discharge opening is formed either by a single opening able to shape a single flow or by a plurality of basic openings able to shape a plurality of basic flows. In the latter case, in some possible implementations, several basic openings are associated with a single suction-discharge cavity, or a given basic opening is associated with a given basic suction-discharge cavity, and/or several basic openings are placed side by side in the transverse direction and/or are spaced apart in the axial direction and/or the axes of several basic openings are either parallel to each other or are angled relative to each other.

In one embodiment, the suction-discharge opening comprises a peripheral edge which extends either in an axial direction or in a direction that is angled relative to the axis, able to form a flow which extends either in the axial direction or in a direction that is angled relative to the axis.

In one embodiment, a suction-discharge opening is associated with flow orientation means and/or shaping means and/or concentration means and/or spreading means, able to orient and/or shape and/or concentrate and/or spread out the flow.

In a first embodiment, the drive means comprise means for driving an axial movement in one direction combined with means for axial return in the opposite direction. For example, the means for driving an axial movement in a direction are electromechanical or electromagnetic means and the means for axial return in a direction are elastic means such as a spring. In one embodiment, a movable plunger core is provided, arranged transversely in the sleeve behind the suction-discharge part and mounted to slide alternately forwards and backwards axially, and an axially sliding connection member connecting the movable plunger core and the suction-discharge part, with the means for driving an axial movement and the means for axial return acting on the movable plunger core.

In a second embodiment, the drive means comprise means for driving an axial movement in the two opposing directions, for example pneumatic means.

In some embodiments, the drive means extend axially substantially behind the given part of the flexible wall, extend axially substantially behind the suction-discharge part, and are located externally to the inside space where the content can be found.

In a first embodiment, a drive means unit is associated with a suction-discharge part unit and/or suction-discharge cavity unit. In a second embodiment, a drive means unit is associated with several suction-discharge part units and/or suction-discharge cavity units.

In one embodiment, the immobilization means comprise, on the one hand, an application face rigidly adjoining the sleeve and an abutting face of a supporting part, the given part of the flexible wall and the abutting face of the supporting part having a fixed relative position, and on the other hand, fixed and rigid retention means for retaining said application face applied in a fixed and rigid manner to said abutting face. In particular, and depending on the case, said means for fixedly and rigidly retaining said application face applied in a fixed and rigid manner to said abutting face are arranged in a detachable or a non-detachable manner, the mixing means being mounted on the flexible container in a manner that is respectively removable or permanent.

In a variant execution, the fixed and rigid retention means for retaining said application face applied in a fixed and rigid manner to said abutting face comprise a clamping member rigidly adjoining the sleeve which cooperates, in clamping, with a complementary clamping member of an immobilization part having a second application face applied to and retained in a fixed and rigid manner on a second abutting face of a second supporting part, the given part of the flexible wall and the second abutting face of the second supporting part having a fixed relative position. For example, the immobilization means comprise the first application face rigidly adjoining the sleeve and the first abutting face of the first supporting part and the second application face and the second abutting face of the second supporting part, the first application face and the second application face being arranged transversely and oriented in two opposite axial directions, the first abutting face and the second abutting face being arranged transversely and oriented in two opposite axial directions. For example, the first application face rigidly adjoining the sleeve is a transverse shoulder of the peripheral lateral outside face of the sleeve, oriented towards the rear, the sleeve having a front part of greater external transverse size and a rear part of smaller external transverse size. For example, the immobilization part is a nut and the clamping member is a complementary screw thread of a clamping member adjoining the sleeve being a screw thread. For example, the first supporting part is a first rigid wall and the second supporting part is a second rigid wall, the first rigid wall and the second rigid wall being arranged substantially parallel to each other and comprising two facing through-holes to allow the passage of the sleeve. For example, the first rigid wall and/or the second rigid wall comprise a cavity for respectively housing the front part and/or the rear part of the sleeve. For example, the mixing means and the immobilization means are substantially between the two free opposing faces, respectively in front of the first rigid wall and behind the second rigid wall. For example, the first supporting part and the second supporting part are parts of a same rigid assembly for receiving and retaining the flexible container, comprising a bottom wall and a side wall, within which is received and externally retained the flexible container whose flexible wall is able to press against the inside face of the bottom wall and of the side wall. Where necessary, said means of fixedly and rigidly retaining said application face applied in a fixed and rigid manner to said abutting face are adhesive bonding means or welding means.

In another variant execution, the application face is the rear face of a transverse shoulder at the end of the sleeve, the abutting face is the front face of a supporting part, the fixed and rigid retention means for retaining said application face applied in a fixed and rigid manner against said abutting face are mutual clamping means, with the supporting part being part of a rigid receiving and retention assembly of a freezing/thawing system. In this variant, the supporting part and the rigid receiving and retention assembly of the freezing/thawing system comprises two walls pressing against one another within the area of the application face and spaced apart from one another in one or more area distanced from the area of the application face in order to leave a free space suitable for accommodating a heat transfer means. In addition, the supporting part of the rigid receiving and retention assembly of the freezing/thawing system comprises a passage to allow the passage of the drive means.

In one embodiment, the container for biopharmaceutical use additionally comprises control means for controlling—starting, stopping, speed, frequency, displacement—the drive means of the movable displacement means. And, where necessary, it additionally comprises means which respond to a control parameter of the control means, to which the control means are responsively coupled. For example, if in its extreme forward position the suction-discharge part closes off the suction-discharge opening, the control means control the drive means of the movable displacement means so that when finished functioning, the suction-discharge part is in its extreme forward position where it closes off the suction-discharge opening.

In the embodiments, a mixing means unit is located either on the bottom part or on the side part or on the top part of the flexible wall of the flexible container.

In the embodiments, the receptacle for biopharmaceutical use comprises a single mixing means unit or comprises a plurality of mixing means units. In the latter case, in one embodiment, the locations—coaxially opposite or offset or angled—on the flexible wall of the flexible container of the plurality of mixing means units and the programming of their control means—phase synchronized or in phase opposition or non-synchronized—are chosen so that the mixing means units operate in synergy.

In one development, the invention also relates to a receptacle for biopharmaceutical use which additionally comprises aeration means able to deliver aeration gas to the content, comprising aeration gas supply means having at least one tubular element extending in a fluid communication from outside the flexible container to the aeration gas distribution means located within the inside space of the flexible container and rigidly supported by a part forming a fixed peripheral support which is part of the mixing means or of the rigid and leaktight connection means. In particular, the aeration gas distribution means are arranged at the periphery of the mixing means or of the rigid and leaktight connection means, in an adjoining manner or at a distance away.

In another development, the invention also relates to a receptacle for biopharmaceutical use which additionally comprises means for collecting a sample of the content of the inside space, opening into the suction-discharge cavity.

In one characteristic, the receptacle constitutes a mixing vessel or a bioreactor or a freezing/thawing vessel.

In a second aspect, the object of the invention is a rigid receiving and retention assembly for receiving and retaining the flexible container of a receptacle for biopharmaceutical use as described above, comprising a bottom wall and a side wall, within which is received and externally retained the flexible container whose flexible wall is able to press against the inside face of the bottom wall and of the side wall, said inside face forming, facing the mixing means of a receptacle, an abutting face which is part of the immobilization means of the mixing means.

In one embodiment, the flexible wall of the flexible container is able to press against the inside face of the bottom wall and of the side wall, said inside face forming, facing the mixing means of a receptacle, an abutting face which is part of the immobilization means of the mixing means.

In one embodiment, the rigid assembly for receiving and retaining the flexible container of such a receptacle for biopharmaceutical use comprises two rigid walls arranged substantially parallel to one another and two facing through-holes to allow the passage of the sleeve of the mixing means. In one characteristic, one and/or the other of the two rigid walls comprises a cavity for respectively housing the front part and/or the rear part of the sleeve of the mixing means.

In a third aspect, the object of the invention is a method for making use of a receptacle for biopharmaceutical use as described above, in which:a receptacle for biopharmaceutical use as described above is provided,biopharmaceutical product is provided which is generally liquid or pasty at least when it is to be mixed, or one or more components of such a product,the inside space of the flexible container is filled with the biopharmaceutical product or with one or multiple components, thus forming the content of the flexible container, the suction-discharge cavity, in communication with the inside space, being filled with said content,when the content of the flexible container is to be mixed, the drive means are used such that:the movable part of the suction-discharge part is displaced in at least one sequence of axially sliding alternately forwards and backwards,the volume of the suction-discharge cavity follows at least one sequence of alternately compressing and expanding, and, in alternation, the content located in the suction-discharge cavity is discharged into the inside space through the suction-discharge opening and the content of the inside space is sucked into the cavity through the suction-discharge opening,the content of the flexible container adjacent to the suction-discharge opening is displaced,and in this manner the content of the flexible container is mixed.

In one embodiment, a series of sequences of sliding the suction-discharge part alternately forward and backward axially and a series of alternating sequences of compression and expansion of the volume of the suction-discharge cavity are carried out.

In one embodiment, when stopping the use of the drive means, the suction-discharge part is brought to its extreme forward position where it closes off the suction-discharge opening.

In one embodiment, the method comprises at least one additional step in which the inside space of the flexible container is filled with biopharmaceutical product or with one or more components.

In one embodiment, the drive means are controlled—starting, stopping, speed, frequency, displacement—as a function of a control parameter, such as time or the degree of homogeneity/heterogeneity of the content of the flexible container.

In one embodiment, where immobilization means ensure the relative immobilization of the axial guiding and peripheral closure sleeve and of the given part of the flexible wall, including during the axial sliding motion of the movable part of the suction-discharge part:a rigid assembly for receiving and retaining the flexible container of a receptacle for biopharmaceutical use as described above is additionally provided,and said flexible container is placed in said rigid receiving and retention assembly.

In one characteristic, the receptacle is used as a mixing vessel or as a bioreactor or as a freezing/thawing vessel.

MORE DETAILED DESCRIPTION

We will now refer specifically toFIG. 1, which illustrates a receptacle for biopharmaceutical use1having a flexible container2, filled with content C, namely a generally liquid or pasty biopharmaceutical product, received and externally retained in a rigid receiving and retention assembly3. Either the content is always liquid or pasty or it is only at a particular moment or period. For example, the content C may be in a solid state following a freezing operation or in a fluid state when it is thawed.

“Biopharmaceutical product” is understood here to mean a product originating from biotechnology (culture media, cell cultures, buffer solutions, artificial nutrition liquids), or a pharmaceutical product, or more generally a product intended for use in the medical field. The biopharmaceutical product is generally liquid or pasty, at least when it is to be mixed, so as to allow such mixing. It may only have one fluid phase or may have multiple fluid phases, including products that are originally solid or have a certain consistency that are to be mixed in a fluid medium.

Such a receptacle1is typically intended for preparing a biopharmaceutical product, for storage, for transport, or for performing a specific process that is physical, chemical, or biological in nature such as mixing, or a bioreactor or a freezing/thawing system.

The flexible container2comprises a flexible wall4which delimits an inside space5able to receive the content and here having actually received it.

By convention, “forward” and “front” are understood to refer to that which is closest to the flexible wall4or facing towards the inside space5, and “backward”, “back”, and “rear” refer to that which is furthest away from the flexible wall4or facing away from the inside space5.

Such a container2is typically a 3D bag which comprises two large walls connected by and welded to two side gussets, which may be folded flat (such as for storage and transport) or unfolded and deployed (for filling with content), the volume of the inside space5being at least 50 liters and up to 3000 liters or more. Such 3D bags are described in patent WO00/04131a or sold under the trademark FLEXEL® 3D. It is understood that this bag embodiment is provided purely as an example, as the flexible container can be implemented differently. In principle, the arrangement and implementation of such a flexible container2are part of the general knowledge of a person skilled in the art or are within his reach. In all cases, the container2has a certain flexibility, being made of a film of plastic material having a certain flexibility, of a single layer or most often of multiple layers. It is in order to assure the external retention of such a flexible container2once it is filled with content C, that it is placed and externally retained in the rigid receiving and retention assembly.

The flexible container2is most often equipped with ports, such as, for example, a port6for the entry or introduction of a product to be mixed with the content of the container2, located in the upper part7of the flexible container2, a port8for supplying an aeration gas (sparging), a port9which allows mounting a functional member or measurement means9a, for example for measuring a parameter reflecting or related to the homogeneity, heterogeneity, or blending of the content in the inside space5. For example, such measurement means9aare light-sensitive and measure the transparency or opacity or homogeneity or heterogeneity of the content in the flexible container2or the content mixing time. The principles of the arrangement of such ports6,8,9are part of the general knowledge of a person skilled in the art or are within his reach.

The flexible container2, once filled and in place, has a lower part10a, arranged horizontally, a side part10b, arranged vertically, and the upper part7, also arranged horizontally. It also has a main axis AA which is substantially vertical, which the qualifiers “top”, “bottom”, “upper”, “lower”, “side”, “horizontal”, and “vertical” are understood as being relative to for the flexible container in general.

The rigid receiving and retention assembly3typically comprises, in this context, a lower bottom wall11, arranged horizontally, and a side wall12, arranged vertically, and an opening13in the upper part to allow placing and removing the flexible container2. The rigid receiving and retention assembly2delimits an inside space14accessible through the opening13. The flexible container2is received and externally retained within this space14, where the lower portion10aand upper portion10bof the container's flexible wall4press against the inside face of the bottom wall11and of the side wall12. In addition, the rigid receiving and retention assembly3is usually equipped with holes15which cooperate with the ports of the flexible container2. Where necessary, the rigid receiving and retention assembly3also comprises restraining means able to come press against the upper part7of the flexible container2.

In one embodiment, the bottom wall11, the side wall12, and where applicable the upper restraining wall of the rigid receiving and retention assembly3, are each composed of two rigid walls arranged substantially parallel to each other, the internal one16towards the front and the external one17towards the back. In this case, each hole15consists of two holes arranged substantially parallel to each other, the internal one18towards the front and the external one19towards the back.

In principle, the arrangement and implementation of such a rigid receiving and retention assembly3are part of the general knowledge of a person skilled in the art or are within his reach. In all cases, the rigid receiving and retention assembly3is rigid and constitutes a fixed and non-deformable part which supports the flexible container2. Of course, the rigid receiving and retention assembly3can be transported, and possibly disassembled or folded.

As indicated, the content of the receptacle1is to be mixed within the context of its preparation, its storage, its transport, or the execution of a specific process that is physical, chemical, or biological in nature such as mixing or a bioreaction or a freezing/thawing sequence. The purpose of this mixing can be to obtain a certain degree of homogeneity either of the components or of the phases of the content when it has several or of the content itself, for example typically during a freezing-thawing sequence. This mixing is to be understood as having the usual meaning in the biopharmaceutical field. It is based on an agitation of the content of the flexible container2.

For this purpose, the container1comprises what we will refer to in general as the mixing means20. These mixing means are able to mix the content in the inside space5. These mixing means20, as a whole, are adjacent to a given part21of the flexible wall4, which thus contributes to retaining the mixing means20. Rigid and leaktight connection means22ensure a rigid and leaktight connection between the mixing means20as a whole and the given part21of the flexible wall4. “Rigid connection” is understood to mean the fact that with the means22, no relative general movement is possible between the mixing means20as a whole and the given part21of the flexible wall4. The connection between them is therefore fixed.

The mixing means20also include movable displacement means, adjoining the inside space5and able to displace the content by acting on it. Drive means23are associated with these movable displacement means.

In the context of the invention, the mixing means20firstly comprise an axial guiding sleeve24, of axis BB, and with peripheral closure. This sleeve24is rigid and has a constant transverse cross-section along its axis BB, for example a circular cross-section. This sleeve comprises a front part25(“front” being understood to be that which, relative to the flexible wall4, is closest to or facing the inside space5), near which is located a suction-discharge opening26adjoining the inside space5, and a rear part27(“rear” being understood to be that which, relative to the flexible wall4, is the furthest or facing away from the inside space5).

The mixing means20next comprise a suction-discharge part28which is solid, arranged transversely relative to the axis BB in the sleeve24, and leaktight. This suction-discharge part28has at least one movable part28amounted to slide alternately forwards and backwards axially, said movable part constituting the previously mentioned movable displacement means comprised in the mixing means20and associated with the drive means23.

In the description of such a mixing means unit20, the term “axial” refers to axis BB of the mixing means20. It is also in reference to axis BB that the terms “peripheral” and “lateral” are to be understood.

The mixing means20next comprise a suction-discharge cavity29, delimited by the lateral inside face30aof the sleeve24and the front inside face31aof the suction-discharge part28. This suction-discharge cavity29communicates with the inside space5through the suction-discharge opening26, which is open.

The expression “suction-discharge” expresses the functional process that is the basis of the mixing. It involves, in one and generally multiple sequences, the suction and discharge of the content of the inside space5, by means of the suction-discharge cavity29, the suction-discharge part28which cooperates with it, and the suction-discharge opening26which provides the communication between the inside space5and the suction-discharge cavity29.

In fact, the drive means23are able to drive the movable part28aof the suction-discharge part28by causing its movement in at least one, and generally multiple, sequence(s) of sliding alternately forwards and backwards axially.

Thus the volume of the suction-discharge cavity29undergoes at least one, and generally multiple, alternating sequence(s) of compression and expansion. And thus the content of the flexible container2adjacent to the suction-discharge opening26is displaced. In this manner the content of the flexible container is mixed.

The receptacle1also comprises immobilization means32which ensure the relative immobilization of the axial guiding and peripheral closure sleeve24and of the given part21of the flexible wall4, including during the axial sliding movement of the movable part28aof the aspiration/suction part28.

The presence of the immobilization means32allows the drive means23acting on the movable part28aof the suction-discharge part28to assure an effective axial relative forward/backward displacement of the movable part28aof the suction-discharge part28relative to the sleeve24, while a rigid connection is established between the mixing means20as a whole and the given part21of the flexible wall4which is deformable and subjected to the forces from the drive means23.

In a preferred manner, the axis BB is arranged perpendicularly to the given part21, as illustrated inFIGS. 2A to 2E. However, it is possible for the axis BB to be arranged at an angle to the perpendicular to the given part21, as illustrated inFIG. 2F.

The receptacle1also comprises control means33for controlling the stopping, starting, speed, frequency, displacement, of the drive means23for the movable part28of the suction-discharge part28forming the movable means for displacing the content of the flexible container2. Thus one can combine a high or low or intermediate amplitude of motion with a high or low or intermediate speed, with or without stop time, as needed. These control means33, which are electrical or electronic, programmable or including a programmable logic controller, can be housed in a shell arranged outside the receptacle1. They may be responsively coupled to means9awhich respond to a control parameter such as the transparency or opacity or homogeneity or heterogeneity of the content of the flexible container2or the content mixing time.

We will now refer toFIGS. 2A to 2F, which illustrate different arrangements of mixing means20on a receptacle1. These different arrangements are provided as examples and are in no way limiting.

In one possible arrangement, the receptacle1comprises a single mixing means unit20(FIGS. 2A to 2C). In other arrangements, it comprises a plurality of mixing means units20(FIGS. 2D to 2F).

Depending on the arrangements, a mixing means unit20is located either (FIG. 2A) on the lower or bottom part10a,11(respectively the flexible container2and the rigid receiving and retention assembly3), or (FIG. 2B) on the side part10b,12, or (FIG. 2C) on the top upper part7of the flexible wall4of the flexible container which is associated with restraining means such as a plate, forming part of the rigid receiving and retention assembly3.

Depending on the arrangements, a mixing means unit20acts upwards (FIG. 2A), or acts laterally in a generally horizontal direction (FIG. 2B), or acts downwards (FIG. 2C).

Depending on the arrangements, the axis BB of a mixing unit20is perpendicular to the given part21of the flexible wall4(FIGS. 2A to 2E), or is angled relative to the perpendicular to the given part21(FIG. 2F).

When a plurality of mixing means units20are provided, their locations on the flexible container2as well as the programming of their control means38are chosen so that the mixing means units20operate in synergy and not in opposition to one another. The choice of such locations and such programming are part of the general knowledge of a person skilled in the art or are within his reach. For the locations, these may be coaxially facing or be off-centered (FIG. 2E) or angled (FIG. 2F) or parallel to each other (FIG. 2D). For the programming of the control means32, this in particular may be phase synchronized or in phase opposition or not synchronized.

Two families of embodiments can be defined concerning the structure of the flexible wall4in the area of the predetermined part21and its arrangement with the mixing means20and the rigid and leaktight connection means22.

In the first family of embodiments, in a typical representation as shown inFIGS. 3 to 16 and 18 to 20, the given part21of the flexible wall4contains a through-hole34with which the mixing means20are axially associated. In this case, the rigid and leaktight connection means22are solidly attached in a leaktight manner, on the one hand, to the sleeve24by a side part35aperipheral and external to the sleeve24, and on the other hand, to the given part21of the flexible wall4by a peripheral part35baround the assembly hole and flat on the flexible wall4. These two parts, side part35aand peripheral part35b, can have numerous configurations, each adapted to the arrangement of the predetermined part21of the flexible wall4with the mixing means20and the rigid and leaktight connection means22.

In one possible configuration illustrated inFIGS. 3 to 11, the hole34in the given part21of the flexible wall4allows the passage of the sleeve24, and the suction-discharge opening26is substantially adjacent axially (relative to the axis BB) to the flexible wall4, meaning that it is located within the envelope of the wall4. With such a configuration, the mixing means20extend axially substantially behind the given part21of the flexible wall4.

In another possible configuration illustrated inFIG. 15, the hole34in the given part21of the flexible wall4establishes the communication between the suction-discharge cavity29and the inside space5, and the suction-discharge opening26is axially distanced rearwards relative to the given part21of the flexible wall4. With such a configuration, the mixing means20extend axially substantially behind the given part21of the flexible wall4. With such a configuration, there can be considered to be two suction-discharge openings, one at the rear, consisting of the suction-discharge opening26, and the other at the front, consisting of the hole34.

In another possible configuration illustrated byFIGS. 14 and 19, the hole34in the given part21of the flexible wall4allows the passage of the sleeve24, and the suction-discharge opening26is set axially forwards relative to the given part21of the flexible wall4. With such a configuration, the mixing means20extend axially either partly frontwards from and partly behind or substantially frontwards from the given part21of the flexible wall4.

In the second family of embodiments, shown in a typical representation inFIG. 17, the given part21of the flexible wall4is unpierced and the rigid and leaktight connection means22are solidly attached in a leaktight manner, on the one hand to the sleeve24by a part36aexternal to the sleeve24, and on the other hand to the given part21of the flexible wall4by a part36bthat lies flat on the flexible wall4. With such a configuration, the mixing means20extend axially substantially frontwards from the given part21of the flexible wall4.

In one possible embodiment which can be the object of various variants in its execution, the rigid and leaktight connection means22are a transverse face22aof a rigid wall22b. This rigid wall22bis created for example of metal and is in the form of a flat plate. This rigid wall22brigidly adjoins the sleeve24and is rigidly secured, lying flat, in a leaktight manner, to the flexible wall4at or near the given part21, typically achieved by welding or adhesive bonding although this does not exclude attachment by another equivalent means (for example crimping).

In the first structural family of the predetermined part21and the arrangement with mixing means20and rigid and leaktight connection means22(FIGS. 3 to 16 and 18 to 20), the rigid wall22bcan have an annular contour, for example circular, its inside edge22cadjoining the sleeve24and its outer edge22dat a sufficient radial distance to allow receiving the flexible wall4lying flat around the through-hole34.

In the second family (FIG. 17), the rigid wall22bmay have a circular outline, the outside edge22dhaving a sufficiently large radius for the rigid wall to be able to receive the sleeve24in its middle part while including a border area for receiving the flat flexible wall4.

The front part25of the axial guiding and peripheral closure sleeve24is delimited internally and laterally by the lateral inside face30aof the sleeve24, and towards the back by the front inside face31aof the suction-discharge part28in the extreme rearward sliding position. The front part25of the axial guiding and peripheral closure sleeve24is delimited at the front by the aspiration-suction opening26. The portion of the front part25of the sleeve24located at the front of the front inside face31aof the suction-discharge part28forms the suction-discharge cavity29.

The rear part27of the axial guiding and peripheral closure sleeve24is delimited inside and laterally by the lateral inside face30aof the sleeve24, and towards the front by the rear face31bof the suction-discharge part28in the extreme rearward sliding position. In addition, preferably, the axial guiding and peripheral closure sleeve24comprises a rear portion delimited at the back by a transverse terminal rear wall37.

Two families of embodiments can be defined concerning the structure and the arrangement of the suction-discharge part28.

In the first family of embodiments, shown in a typical representation inFIGS. 3 to 5 and 18, the suction-discharge part28is a rigid piston mounted to be leaktight at its peripheral part28b, said piston sliding along axis BB, within the axial guiding and peripheral closure sleeve24.

In the second family of embodiments, shown in a typical representation inFIGS. 8 to 17, 19 and 20, the suction-discharge part28is a deformable membrane having a fixed peripheral part28battached to the lateral inside face30aof the axial guiding and peripheral closure sleeve24and a central movable part28a.

In one embodiment, the suction-discharge part28is mounted to slide axially along axis BB between an extreme rearward position illustrated inFIGS. 8A, 9 to 17, 19 and 20, and an extreme forward position illustrated inFIGS. 3 to 5 and 18, respectively the furthest away from and the closest to the suction-discharge opening26. In addition, in one embodiment, the suction-discharge part28, in its extreme forward position, closes off the suction-discharge opening26, particularly with a certain leaktightness.

Moreover, in an embodiment shown in a typical illustration inFIGS. 8A to 8C, the suction-discharge cavity29is flattened transversely (perpendicularly to its axis BB), its size in the transverse direction being larger than its size in the axial direction (in the direction of the axis BB).

Various embodiments can be defined concerning the suction-discharge opening26.

In a first aspect, the embodiments differ in the number of suction-discharge openings26. In the embodiments illustrated inFIGS. 3 to 9, 18 and 20, the suction-discharge opening26is formed by a single opening able to form a single flow. In the embodiments illustrated inFIGS. 10 to 17 and 19, the suction-discharge opening26is formed by a plurality of basic openings26a, able to form a plurality of basic flows. In this case, and depending on the embodiments, it may be arranged so that several basic openings26aare associated with a single suction-discharge cavity, as illustrated byFIGS. 10, 12 to 17 and 19, or that a given basic opening26ais associated with a given basic suction-discharge cavity, as illustrated inFIG. 11.

Various embodiments can be defined concerning the basic openings26awhen the suction-discharge opening26is constructed in this manner.

For the arrangement of the basic openings26arelative to the axis BB, it can be arranged so that there are several basic openings26alocated side by side in a same transverse direction perpendicular to the axis BB, as illustrated inFIGS. 10, 11, 15 and 17, or several basic openings26aspaced apart in the axial direction along the axis BB, as illustrated inFIGS. 14 and 16, or it is possible to combine basic openings26alocated side by side in a same transverse direction and spaced apart in the axial direction, as illustrated inFIGS. 12, 13 and 19. These constructional features allow creating a flow of content that will achieve effective mixing and is adapted to the context.

Concerning the arrangement of the basic openings26arelative to each other, it can be arranged so that the axes CC of several basic openings26aare parallel to each other, as illustrated inFIGS. 10 and 12, 15 and 17, or are angled relative to each other as illustrated inFIGS. 12 to 14, 16 and 19, for example forming an acute or 90° angle. These constructional features allow creating a flow of content that will achieve effective mixing and is adapted to the context.

Whether there is one suction-discharge opening or multiple basic suction-discharge openings26a, there can be different embodiments concerning the shape of the opening, and particularly the shape of its peripheral edge26b. For example, the peripheral edge26bmay extend in the axial direction (along axis BB or axis CC), as illustrated inFIGS. 5 to 8 and 10 to 20, or in a direction that is angled relative to axis BB or CC, as illustrated inFIG. 9. Thus a flow of content can be formed which extends either in the axial direction or in a direction that is angled relative to axis BB or CC, and, more generally, which will achieve effective mixing and is adapted to the context.

It is also possible to arrange a suction-discharge opening26,26ain association with flow orientation means and/or shaping means and/or concentration means and/or spreading means, allowing the flow to be oriented and/or shaped and/or concentrated and/or spread out, these constructional features aiming to create a flow of content which will achieve effective mixing and is adapted to the context. For example, in the embodiment inFIG. 6, there is a baffle guide38bordering the suction-discharge opening26along part of its circumference, located outside the suction-discharge cavity29.

The constructional features which have just been described may be combined with each other except where clearly impossible, as the embodiments represented in the figures are only non-limiting examples. In addition, they may be combined with the different variant arrangements of the mixing means units20on a flexible container2, as was described above in relation toFIGS. 2A to 2F. For example,FIG. 7shows an embodiment with three mixing means units20arranged with their axes BB parallel to each other and side by side to form a triangle, in the same region of the flexible wall4, and with the suction-discharge openings26comprising baffle guides38judiciously oriented relative to one another.

Various embodiments can be defined concerning the drive means23.

In a first family, illustrated inFIGS. 5 and 18, the drive means23comprise means39afor driving axial movement in one direction, combined with axial return means39bfor the opposite direction. In a second family, illustrated inFIG. 16, the drive means23comprise means39cfor driving axial movement in the two opposing directions sequentially.

Thus, for example, in the case of the first family of drive means23(FIGS. 5 and 18), the means39afor driving an axial movement in a direction can be electromechanical or electromagnetic means, while the means39bfor axial return in a direction can be elastic means such as a spring. There can be a movable plunger core40arranged transversely in the sleeve24behind the suction-discharge part28, mounted to slide alternately forward and backward axially. On the other hand, an axially sliding connection member41can be arranged to connect the movable plunger core40and the suction-discharge part28, which is a piston here. The means39afor driving an axial movement and the axial return means39bact on the movable plunger core40which is moved in an axial direction by the effect of these means39aand39b, alternately forwards and backwards, due to the electromechanical or electromagnetic means provided for this purpose.

In the case of the second family (FIG. 16), the means39cfor driving an axial movement sequentially in the two opposing directions can be pneumatic means which move the suction-discharge part38, specifically its movable part38a.

In the above embodiments, the drive means23extend axially substantially behind the suction-discharge part28and are positioned externally to the inside space5where the content can be found. In certain embodiments previously described, as illustrated inFIGS. 5, and 9 to 13, the drive means23extend axially substantially behind the given part21of the flexible wall4.

Various embodiments can be defined concerning the structure of a drive means unit23, a suction-discharge part unit28, and the suction-discharge cavity unit29. In the embodiments represented, a drive means unit23is associated with a suction-discharge part unit28. In other possible embodiments, the same drive means unit23is associated with multiple suction-discharge part units28and/or suction-discharge cavity units29. This arrangement is well-suited for the case of multiple adjacent mixing means units.

In general, the immobilization means32firstly comprise an application face42rigidly adjoining the sleeve24and an abutting face43of a supporting part44, in an arrangement where the given part21of the flexible wall4and the abutting face43of the supporting part44have a fixed relative position. The immobilization means32secondly comprise fixed and rigid retention means45for retaining the application face42applied in a fixed and rigid manner to the abutting face43.

In the embodiments, the fixed and rigid retention means45are arranged in a detachable or non-detachable manner, the mixing means20then being mounted on the flexible container in a manner that is respectively removable or permanent.

Various embodiments can be defined concerning the immobilization means32.

We will now refer toFIGS. 3 to 5 and 18which illustrate a first embodiment of the immobilization means32. In this first embodiment, the fixed and rigid retention means45comprise a clamping member in the form of an external thread46arigidly adjoining the sleeve24, which cooperates, in clamping, with a complementary clamping member in the form of an internal thread46bof an immobilization part47having a second application face48placed against and retained in a fixed and rigid manner on a second abutting face49of a second supporting part, it being noted that the given part21of the flexible wall4and the second abutting face49of the second supporting part have a relative fixed position. In this embodiment, the immobilization means32secondly comprise the application face42which constitutes a first application face42rigidly adjoining the sleeve24, and the abutting face43which constitutes a first abutting face43of the supporting part44which constitutes a first supporting part44. In this embodiment, the first application face42and the second application face48are arranged transversely and are oriented in two opposite axial directions, and the first abutting face43and the second abutting face49are also arranged transversely and oriented in two opposite axial directions.

For example, the first application face42is in the form of a transverse shoulder42aof the peripheral lateral external face30bof the sleeve14, said shoulder42afacing rearwards, such that the sleeve24has a front part25of larger external transverse size (radius) and a rear part27of smaller external transverse size (radius). Also, the immobilization part47is then a nut whose internal screw thread46bis the clamping member46b, said screw thread46bcooperating with an external screw thread46awhich is the clamping member46aadjoining the sleeve24.

For example, the first supporting part44is a first rigid wall and the second supporting part50is a second rigid wall. These two rigid walls44and50are arranged substantially parallel to each other and are spaced apart while remaining near one another. They comprise two through-holes51aand51b, arranged facing one another and in communication with each other to allow the passage of the sleeve24, both when it is in motion when it slides into place and statically when it is immobilized.

In addition, and for example, the first rigid wall44and/or the second rigid wall50comprise a housing cavity, respectively52aand52b, which respectively seats the front part25and/or the rear part27of the sleeve24. With this constructional feature, it is possible to arrange the mixing means20and the immobilization means32so that they are substantially between the two free opposing faces, respectively the front face53aof the first rigid wall44and the rear face53bof the second rigid wall50.

In addition, and for example, the first supporting part44and the second supporting part50are an integral part of the receiving and retention assembly3for the flexible container.

In another embodiment, the fixed and rigid retention means45for the application face42applied in a fixed and rigid manner to the abutting face43are adhesive bonding means or welding means.

In an embodiment in which the suction-discharge part28, in its extreme forward position, closes off the suction-discharge opening26, it is arranged so that the control means33control the drive means23of the movable displacement means (28,28a) so that when finished functioning the suction-discharge part28is in its extreme forward position where it closes off the suction-discharge opening26.

In one development of the invention illustrated inFIGS. 18 and 19, the receptacle for biopharmaceutical use1additionally comprises aeration means54, able to deliver aeration gas to the content in the inside space5.

Such aeration means54firstly comprise aeration gas supply means55having at least one tubular element extending upstream in a fluid communication from outside the flexible container2.

Such aeration means54next comprise aeration gas distribution means56, communicating downstream with the supply means55. The distribution means56are typically in the form of a wall equipped with aeration holes. For example, this wall has a general toric shape with an axial cross-section that is generally circular. Such distribution means56are located within the inside space5and they are rigidly supported by a part forming a fixed peripheral support which is part of the mixing means20or the rigid and leaktight connection means22. Thus the mixing means and the aeration means are combined into the same structural assembly.

The arrangement of the structure of the association of the distribution means56and the mixing means20or rigid and leaktight connection means22can be the object of different variant embodiments. Thus the distribution means56may be placed at the edge of the mixing means20(FIG. 19) or at the edge of the rigid and leaktight connection means22(FIG. 18). In addition, the distribution means56may either be adjacent to or distanced from the mixing means20or rigid and leaktight connection means22.

In another development of the invention illustrated inFIG. 20, the receptacle for biopharmaceutical use1additionally comprises means57for collecting a sample of the content in the inside space5, opening into the suction-discharge cavity29, with a movable shut-off valve where necessary.

The invention also concerns the rigid receiving and retention assembly3for the flexible container2of a receptacle for biopharmaceutical use1as described above.

This assembly3is such that the inside face of the bottom wall11and of the side wall12forms, facing the mixing means20of a receptacle1, an abutting face43,50that is part of the immobilization means32for the mixing means20.

As indicated, such an assembly3comprises two rigid walls arranged substantially parallel to each other,16and17or44and50, which comprise two facing through-holes51aand51bto allow the passage during assembly or the retention of the sleeve24of the mixing means20.

In addition, such an assembly3can comprise the cavities42aand52balready described.

To make use of a receptacle for biopharmaceutical use1as described above, one begins by being provided with a receptacle for biopharmaceutical use1as well as a generally liquid or pasty biopharmaceutical product or one or more components of such a product.

Then the inside space5of the flexible container2is filled with the biopharmaceutical product or with one or more components, to form the content C of the flexible container2. The suction-discharge cavity29, which is in communication with the inside space5, is filled with said content.

When the content C of the flexible container2is to be mixed, the drive means20are put to use.

During said use, the movable part28aof the suction-discharge part28is displaced in at least one (and usually several) sequence of sliding alternately forwards and backwards axially.

Thus the volume of the suction-discharge cavity29undergoes at least one (and usually several) sequence of alternately compressing and expanding.

In this manner, in alternation, the content inside the suction-discharge cavity29is discharged into the inside space5through the suction-discharge opening26and the content of the inside space5is sucked into the suction-discharge cavity29through the suction-discharge opening26.

Due to this or these sequences, the content C of the flexible container2adjacent to the suction-discharge opening26is moved about. And due to this movement, the content of the flexible container2is mixed.

In one embodiment, when the use of the drive means23ends, the suction-discharge part28is brought to its extreme forward position where it closes off the suction-discharge opening26.

In one embodiment, there is at least one additional step, in which the inside space5of the flexible container2is filled with biopharmaceutical product or one or several components.

In one embodiment, the drive means23are controlled—starting, stopping, speed, frequency, displacement—as a function of a control parameter, such as the time or the degree of homogeneity/heterogeneity of the content in the flexible container, using the measurement means9a.

In another embodiment, the rigid receiving and retention assembly3for the flexible container2is put to use.

In another embodiment, the mixing and the aeration of the content C in the inside space5are combined.

In another embodiment, the mixing is combined with collecting the sample of content C in the inside space5.

The above description more particularly relates to a receptacle1which constitutes a mixing vessel.

However, the invention also applies to the case where the receptacle1constitutes a freezing/thawing vessel, as illustrated in a possible embodiment provided purely as a non-limiting example inFIG. 21.

In this embodiment, the application face42is the rear face of a transverse shoulder at the end of the sleeve24and the abutting face43is the front face of a supporting part44which is part of the rigid receiving and retention assembly3belonging to a freezing/thawing system.

The supporting part44here comprises two walls58and59, pressing against one another within the region of the application face42. Wall58is internal and at the front and wall59is external and at the back.

Wall58delimits the side part of the rigid receiving and retention assembly3. The flexible wall4presses against its front face. This wall58, more specifically each side panel of this wall, has a front face that is planar or substantially planar.

Wall59is undulated parallel to the inlet/outlet axis of the flexible container2in the rigid receiving and retention assembly3. It thus has front parts60and rear parts61connected by connecting parts.

In its front parts60, the front face of the rear wall59presses against the rear face of the front wall58. Where applicable, the two walls58and59are positively secured at these parts60, or at least adjusted. It is here at these parts60that the two walls58and59press against one another, in the area of the application face42.

Away from the area of the application face42, in the rear parts61, the two walls are spaced apart from one another and thus define a free space62between them.

This free space62is able to receive and accommodate a heat transfer means63, such as a source of heat or cold. This heat transfer means63thus comprises parts shaped like flat parallelograms in order to cooperate with the successive free spaces62. These parts can be connected at their upper end, giving the heat transfer means63a general comb shape.

In this manner, the fixed and rigid retention means45for the application face42applied in a fixed and rigid manner to the abutting face43can be screws traversing holes in the walls58and59, screwed from the back into holes tapped in the transverse shoulder at the end of the sleeve24, the head of the screws resting on the beveled edges of the holes in walls58and59.

A passage64, to allow the passage of the drive means28, is arranged in the front part60of the walls58and59.

Attachment means for the drive means23are also provided.

With such a freezing/thawing system, the flexible container2is arranged so that the mixing means20are placed facing the passage64. Then the mixing means are attached by means of the screws of the fixed and rigid retaining means45. Then the drive means23are attached.

When necessary, the heat transfer means63is placed in the free space62. And, when necessary, the mixing means20are put to use.