US20120193264A1

US20120193264A1 - Production of a biopharmaceutical product

Info

Publication number: US20120193264A1
Application number: US13/499,738
Authority: US
Inventors: Magali Barbaroux; Samuel Dorey; Mareva Gueneron; Oscar Reif
Original assignee: Sartorius Stedim Biotech SA
Current assignee: Sartorius Stedim FMT SAS
Priority date: 2009-10-02
Filing date: 2010-09-29
Publication date: 2012-08-02
Also published as: FR2950802B1; FR2950802A1; WO2011039472A2; WO2011039472A3; EP2483385A2

Abstract

Process of producing a biopharmaceutical product includes providing a pouch unit including a pouch and at least one port, and optionally, a functional device; filling the pouch with the product; carrying out the production process, and at at least one stage thereof, using or generating a liquid or small solid incident body within the biopharmaceutical product; the pouch unit incorporating a support and replacement element formed by or integrated in the pouch wall, or in the port or functional device so as to be accessible from the inside space and be in direct physical contact with the contents of the pouch, arranged so as to be able to be loaded with the incident body and pass between the support and replacement element and the contents, such that the incident body is loaded on the support and replacement element when it is not or should not be within the biopharmaceutical product.

Description

The invention relates to the production of a biopharmaceutical product, and its purpose is more particularly a process for the production of a biopharmaceutical product in and with a pouch unit that is selected for this purpose, such a pouch unit being specially designed for implementing this process, such a pouch unit before the filling of contents, and such a pouch unit that is filled with the finished biopharmaceutical product, and, finally, a unit that comprises, in the first place, a pouch unit, and, in the second place, means for activation of the inherent means of support and replacement of the pouch unit.
“Biopharmaceutical product” is defined as a product that is obtained from biotechnology—culture media, cellular cultures, buffer solutions, artificial nutrition liquids, blood products and derivatives of blood products—or a pharmaceutical product, or more generally a product that is designed to be used in the medical field. In the context of the invention, this biopharmaceutical product has the characteristic of being in a substantially liquid or paste form.
For the purposes of production of such a biopharmaceutical product, it is common to place it directly in a pouch that is part of a device that is designed for its production. Such a device first of all comprises a pouch unit that includes, in the first place, the pouch in question itself, defining an inside space that can contain the biopharmaceutical product, limited by a wall, continuous as a whole, made of a film of flexible plastic material that is airtight, and non-degradable, and that can be in direct contact by its inside face with the biopharmaceutical product, and can contain it, and, in the second place, combined with the pouch, at least one port, and, if necessary, at least one functional device such as a device for mixing, aeration, . . . . Such a device can next comprise, if necessary, an outside rigid container for receiving the pouch unit in its inherent inside space.
“Production process” is defined as one or more phases of a physical-chemical-biological process during which the biopharmaceutical product is partly or completely manufactured to reach the finished state that allows its immediate use or a semi-finished state that allows a subsequent use. Such a phase consists in, for example, the addition of one or more components using at least one port of the pouch unit, or in a mixture, an aeration, a filtration, a reaction, a heating or a cooling (with this list not being exhaustive), using at least one suitable functional device with which the pouch unit is provided. “Biopharmaceutical product” is defined both as the biopharmaceutical product in the finished state and an intermediate product of the process for producing the latter.
A pouch unit that has a pouch whose two large walls are directly joined to one another is known. Once expanded, such a pouch has a limited volume and remains relatively thin, which justifies the fact that this pouch is often called “pillow” pouch or “2D” pouch (with D meaning dimensions). A 3D pouch with gussets that comprises two end walls and one side wall that can be folded flat or deployed unfolded, welded to one another, with the volume then able to be at least 50 liters, up to 3,000 liters, and even more, is also known. Such a 3D pouch is described in the document WO00/04131 or is marketed by the company Sartorius Stedim Biotech under the trademark FLEXEL® 3D.
With such a pouch unit, the wall of the pouch performs a unique mechanical function that consists in, on the one hand, containing the substantially liquid or pasty biopharmaceutical product by absorbing the forces that result from its presence in the inside space of the pouch and its direct contact with its inside face, and, on the other hand, to support the at least one port and, if necessary, the at least one functional device.
The production of the biopharmaceutical product in the pouch unit uses or generates one or more bodies that are functionally intrinsic to the biopharmaceutical product within the scope of its production, i.e., being part of the biopharmaceutical product or a component of the latter or used for the production of the biopharmaceutical product or generated upon this occasion. Such a body is qualified here as an incident body.
Such an incident body is such that:

- At one or more times or in one or more stages of the process for the production of the biopharmaceutical product, it is necessarily substantially within the substantially liquid or pasty biopharmaceutical product,
- And at one or more other times or in one or more other stages of the production process, it is not or should not be substantially within the biopharmaceutical product.

Being and not being “substantially” within the biopharmaceutical product means, respectively, in a very predominant and quantitatively prominent way, that the incident body is located and is not located within the biopharmaceutical product.
Such a body is termed incident relative to the biopharmaceutical product, because it is necessary to understand that the weight and the volume of the body are low to very low and even minute relative to the weight and the volume of the biopharmaceutical product.
Such a body is solid and small in size or liquid (including paste form); in any case, it is not gaseous. “Solid” is defined as the fact of exhibiting a certain cohesion or a certain consistency and being neither liquid nor gaseous. A toxin or a microorganism is part of the definition of solid. “Small in size” is defined as a dimension on the order of, or less than, or significantly less than, a millimeter, down to molecular size.
Such a body, if it is solid, is individual or broken into a number, more specially a large number, of units or pieces. This is why, even though such a body is solid, it is possible to describe a biopharmaceutical product that contains it within itself as being in a substantially liquid or paste form. Consequently, a biopharmaceutical product that is in a “substantially” liquid or paste form means, in a very predominant and quantitatively prominent way, that the biopharmaceutical product is in liquid or paste form, even when it comprises such a solid body within itself.
Such an incident body can be varied, concerning its substance, its nature, its structure, its composition, its function, its origin, its properties, its usefulness or its harmfulness . . . . It may involve, for example, a body that falls within the final composition of the biopharmaceutical product or falls within its initial composition or active ingredients or wastes or reaction by-products or impurities or a catalyst, activator, regulator or a toxin or an antibiotic or a body that acts on one or more physical-biological-chemical conditions of the biopharmaceutical product or one or more physical-biological-chemical conditions that prevail(s) in the pouch or antibody, cells, or bacteria.
With a pouch unit for the production of biopharmaceutical products as known today, there is an obligation to abstract such an incident body, which is not always desirable or possible, or to implement an exogenic means with the pouch unit—structural or functional—which is suitable for this body. For example, the following are provided: a stage and the device for introduction into the pouch that is filled with biopharmaceutical product—or components of such a product or else intermediate products of such a final product—of such a body such as a nutrient, antibiotic, active substances, catalyst and/or a stage and the device for evacuating the pouch that is filled with biopharmaceutical product—or components of such a product or else intermediate products of such a final product—of such a body such as an undesirable or toxic substance. Such a device for introduction or evacuation is, for example, a port that can be closed or open based on the requirements.
“Patches” that are designed to be applied on the skin of an individual comprising one or more active substances that are released once the patch is applied to the skin for dermal or transdermal use are known. Reference can be made to, for example, the documents EP-A-0278473, U.S. Pat. No. 4,557,723, U.S. Pat. No. 4,638,043, U.S. Pat. No. 4,752,478 and US-A-2009/0142388.
Oxygen absorbers (oxygen scavengers) that are designed quite specially for the packaging of food products for the purpose of limiting or preventing their oxidation and thus to allow a more significant preservation period are known. Such an oxygen absorber can come in the form of a packet or a pellet or a label that is introduced into the packaging beside the food product or can be included or combined with the wall of the packaging itself. It is possible to refer to, for example, the documents WO 2008/084231 and WO 2005/033676. In the same way, moisture absorbers, corrosion inhibitors, absorbers of bad odors, gas emitters, and antibacterial agents are known.
Such devices are well suited to their own purpose but cannot be applied in the case of the production of a biopharmaceutical product, as it was defined above, in particular because the product concerned is in solid form and not in liquid or paste form, and/or because the purpose of the device is the preservation and not the production of the product, and/or because the body concerned is in gaseous form and not solid or liquid (including paste form), and/or because the device does not act directly on the product concerned but on its environment.
In the particular case of the production of a biopharmaceutical product in liquid or paste form—and not in solid form, using a pouch unit as indicated above, involving or implementing an incident body as defined above, namely in solid form and small in size and in particular fractionated—or liquid form (including paste form) and not in gaseous form, there is consequently the need to act directly on the biopharmaceutical product—and not on its environment alone, in such a way that at one or more times or stages, the incident body is necessarily within the biopharmaceutical product itself and at one or other times or stages, it is not or should not be within the biopharmaceutical product itself.
The purpose of the invention is therefore to meet this requirement.
For this purpose, according to a first aspect, the invention has as its object a process for the production of a biopharmaceutical product in substantially liquid or paste form by a physical-chemical-biological production process, in which:

- A pouch unit is provided that includes a pouch that defines an inside space that can contain the biopharmaceutical product during its production process, and said pouch unit is limited by a continuous wall that is flexible, airtight, and non-degradable, and that can be in direct contact by its inside face with the biopharmaceutical product and can contain it, and, combined with the pouch, at least one port, and, if necessary, at least one functional device,
- The biopharmaceutical product that is not totally finished or components of the latter is/are provided, and the pouch is filled with said product or components, thus constituting the contents of the pouch,
- The process for production is implemented in and with the pouch unit, and during this process, at least one incident body that is solid and small in size or liquid that is within the biopharmaceutical product is used or generated at at least one time or stage of the production process.

This process is such that:

- A pouch unit that is selected for incorporating an inherent means of support and replacement is provided:
  - Formed by or integrated in the wall of the pouch or in at least one port or functional device, in such a way as to be able to be accessible from the inside space of the pouch and in direct physical contact with the contents of the pouch,
  - Arranged in such a way as to be functionally able to be loaded with the incident body and to make possible the passage of the incident body between one and the other of the inherent means of support and replacement and within the contents of the pouch,
  - Being functionally active per se or as a consequence of a dedicated activation operation,
- And the pouch unit is used in such a way that the inherent means of support and replacement is in direct physical contact with the contents of the pouch and in such a way that with the inherent means of support and replacement being functionally active, the incident body passes substantially between one and the other of the inherent means of support and replacement and within the contents of the pouch in such a way that the incident body is substantially loaded on the inherent means of support and replacement when it is not or should not be substantially within the biopharmaceutical product.

According to the embodiments, the solid incident body is individual or is broken into a number, more specially a large number, of units or pieces.
According to the embodiments, the solid incident body is of a dimension on the order of, or less than, or significantly less than, a millimeter, down to molecular size.
According to the embodiments, the pouch unit is used in such a way that the incident body is moved, in a substantial way, between the biopharmaceutical product and the inherent means of support and replacement, in the direction that goes from the first to the second or in the direction that goes from the second to the first.
According to one embodiment and different possible variants, the inherent means of support and replacement is functionally active in response to the value taken on by at least one physical-biological-chemical condition of the contents of the pouch or in response to the value taken on by the variation of such a physical-biological-chemical condition or in response to a dedicated activation operation of a physical, biological, or chemical nature.
According to the embodiments, before filling with contents, the inherent means of support and replacement is not loaded with the incident body or, in contrast, is substantially loaded with the incident body.
According to the embodiments, once the biopharmaceutical product has been produced and is in the pouch, the inherent means of support and replacement is not loaded with an incident body, or, in contrast, is substantially loaded with the incident body.
According to a second aspect, the invention has as its object a pouch unit that is specially designed for the implementation of the process for the production of a biopharmaceutical product in the substantially liquid or paste form that was just described, including a pouch that defines an inside space that can contain the biopharmaceutical product during its production process, limited by a continuous wall that is flexible, airtight, and non-degradable, and that can be in direct contact by its inside surface with the biopharmaceutical product, and can contain it, and, combined with the pouch, at least one port, if necessary at least one functional device.
The pouch unit incorporates an inherent means of support and replacement:

- Formed by or integrated in the wall of the pouch or in at least one port or functional device, in such a way as to be able to be accessible from the inside space of the pouch and in direct physical contact with the contents of the pouch,
- Arranged in such a way as to be functionally able to be loaded with the incident body and to make possible the passage of the incident body between one and the other of the inherent means of support and replacement and within the contents of the pouch itself,
- Functionally active per se or as a consequence of a dedicated activation operation.

The pouch unit is implemented such that the inherent means of support and replacement is in direct physical contact with the contents of the pouch and such that, with the inherent means of support and replacement being functionally active, the incident body passes substantially between one and the other of the inherent means of support and replacement and within the contents of the pouch itself and is substantially loaded on the inherent means of support and replacement when it is not or should not be substantially within the biopharmaceutical product.
According to the embodiments, the inherent means of support and replacement consists of or comprises a membrane or a coating or a surface treatment of the wall of the pouch or at least one port or functional device, or a body of support and replacement, or a compartment of support and replacement.
According to one embodiment, the inherent means of support and replacement is located toward the inside surface of the wall of the pouch or at least one port or functional device that forms it or integrates it.
According to the embodiments, the inherent means of support and replacement is located on the entire surface or only a portion of the surface of a face of the pouch or at least one port or functional device that forms it or integrates it by then being either located on or distributed over this surface.
With the pouch unit having, during the process for the production of the biopharmaceutical product, a lower part, an upper part, and a median part, according to the embodiments, the inherent means of support and replacement is located at least in the lower part or at least in the lower part and in the median part of the unit.
According to the embodiments, an inherent means of support and replacement has a surface area for replacement with the contents of the pouch during the process for the production of the biopharmaceutical product that is larger than, more specially significantly larger than, more specially on the order of a multiple of, the surface area of the inside face of the wall of the pouch or at least one port or functional device that forms it or integrates it, and that is in direct contact with the contents of the pouch, in particular as a result of the composition of the inherent means of support and replacement, or the wall of the pouch or at least one port or functional device that forms it or in which it is integrated or the configuration of the inherent means of support and replacement on the wall of the pouch or at least one port or functional device that forms it or in which it is integrated.
According to the embodiments, the pouch is a 2D pouch or a 3D pouch.
According to a third aspect, the invention also has as its object a pouch unit before filling with contents in which, according to the embodiments, the inherent means of support and replacement is not loaded with the incident body or, in contrast, is substantially loaded with the incident body.
According to a fourth aspect, the invention also has as its object a pouch unit that is filled with finished biopharmaceutical product, in which, according to the embodiments, the inherent means of support and replacement is not loaded with the incident body or, in contrast, is substantially loaded with the incident body.
According to a fifth aspect, the invention also has as its object a unit that comprises, in the first place, a pouch unit as it was described in which the inherent means of support and replacement is functionally active as a consequence of a dedicated activation operation, and, in the second place, means for activation of the inherent means of support and replacement of a physical, biological or chemical nature.
According to one embodiment, the activation means consist of the biopharmaceutical product that is in the inside space of the pouch unit and that has properties that can activate the inherent means of support and replacement.
According to one embodiment, the activation means are located outside of the pouch unit.

Several embodiments of the invention will now be described using drawings, in which:

FIG. 1 is a diagrammatic perspective view of a 3D pouch with gussets that is part of a pouch unit that is specially designed for implementing a process for the production of a biopharmaceutical product in a substantially liquid or paste form according to the invention, with the pouch unit incorporating an inherent means of support and replacement, whereas during the process for the production of biopharmaceutical product, at least one incident body is used or generated and whereas the pouch unit is implemented in such a way that the inherent means of support and replacement is in direct physical contact with the contents of the pouch and in such a way that with the inherent means of support and replacement being functionally active, the incident body passes substantially between one and the other of the inherent means of support and replacement and within the contents of the pouch in such a way that the incident body is substantially loaded on the inherent means of support and replacement when it is not or should not be substantially within the biopharmaceutical product.

FIG. 2 illustrates, on the one hand, the relative arrangement of the inherent means of support and replacement relative to the pouch unit and to the contents of the pouch, and, on the other hand, the two functions of the inherent means of support and replacement.

FIGS. 3 to 13 are eleven views, in transverse cutaways, on a larger scale illustrating different possible embodiments of the inherent means of support and replacement that the pouch unit incorporates.

The description refers to the definitions provided above that involve the biopharmaceutical product P, its substantially liquid or paste form, the process for the production of such a biopharmaceutical product P, a 2D pouch or a 3D pouch, the incident body C, and, for this product, the qualification of solid and small size, etc.
A pouch unit 1 as shown in FIG. 1 is part of a device that is designed for the production of a biopharmaceutical product P, i.e., a product that is obtained from biotechnology—culture media, cellular cultures, buffer solutions, artificial nutrition liquids, blood products and derivatives of blood products—or a pharmaceutical product or more generally a product that is designed to be used in the medical field. Such a biopharmaceutical product P has the characteristic of being in a substantially liquid or paste form, being totally or at least in a very predominant and quantitatively prominent way, in liquid or paste form, even when, if necessary, it comprises within itself a solid body in a very small quantity.
The production of the biopharmaceutical product P consists of one or more phases of a physical-chemical-biological process during which the biopharmaceutical product P is completely or partly manufactured before reaching the finished state that makes possible its direct use or a semi-finished stage that makes possible a subsequent use, such as, for example, an addition of one or more components, a mixture, an aeration, a filtration, a reaction, a heating or a cooling . . . .
According to one characteristic of the production process, during the course of the latter, one or more incident body(ies) C is/are used or generated (which includes the case where it is used and generated). Such an incident body C is solid and small in size or is liquid (including paste form) and, at at least one time or stage of the production process, it is necessarily substantially within the biopharmaceutical product P while at at least one other time or stage of the production process, it is not or should not be within the biopharmaceutical product P, in that in a very predominant and quantitatively prominent way, the incident body C, respectively, is located and is not located within the biopharmaceutical product P. Such an incident body C has a small to very small and even minute weight and volume relative to the weight and volume of the biopharmaceutical product P.
Such an incident body C is solid and small in size, having a certain cohesion or a certain consistency, or is liquid (including paste form), in any case not being gaseous, and having, if it is solid, a dimension on the order of, or less than, or significantly less than, a millimeter, down to molecular size, where this is understood for each unit or piece.
As appropriate, such an incident body C, if it is solid, is individual or broken into a number, more specially a large number, of units or pieces.
Such an incident body C is varied, concerning its substance, its nature, its structure, its composition, its function, its origin, its properties, its usefulness or its harmfulness . . . . It may involve, for example, a body that falls within the final composition of the biopharmaceutical product P or falls within its initial composition or active ingredients or wastes or reaction by-products or impurities or a catalyst, activator, regulator or a toxin or an antibiotic or a body that acts on one or more physical-biological-chemical conditions of the biopharmaceutical product P or one or more physical-biological-chemical conditions that prevail(s) in the pouch or antibody, cells, or bacteria.
The pouch unit 1 includes a pouch 2 that, according to the embodiments, is a so-called 3D pouch with gussets as shown in FIG. 1, or a so-called 2D pouch, not shown.
The pouch 2 defines an inside space 2 a, able to contain the contents of the pouch during the production of the biopharmaceutical product P, in particular the biopharmaceutical product P itself, during its production.
The pouch 2 is limited by a wall 3, continuous as a whole, made of a plastic film. It is flexible, airtight and non-degradable. The film that forms the wall 3 is single-material or not, single-layer or not. The—or each of the—constituent material(s) of the film is/are selected from among the materials that satisfy the above-mentioned requirements, as well as the mechanical strength requirements.
The wall 3 has an outside face 3 a and an inside face 3 b. “Outside” is defined as what is not located in the pouch 2, and “inside” is defined as what is located in the pouch 2 and limits the inside space 2 a.
The pouch 2 can be in direct contact by its inside face 3 b with the contents of the pouch 2, in particular the biopharmaceutical product P, and can contain it.
The pouch 2 is arranged to support at least one port 4, for example a port for filling and a port for emptying. “Port” is defined as any means of communication between the outside and the inside of the pouch 2, which is open at one or more times or in one or more stages when the communication is desired, or, if not, is sealed.
At least one functional device 5, such as a device for mixing, aeration, filtration, measuring (whereby this list is not exhaustive), and comprising a suitable element, such as a mixing propeller, aerator, filter, probe (whereby this list is not exhaustive), is combined in general, and if necessary, with the pouch 2. Such an element is at least partly placed in the inside space 2 a of the pouch 2.
The at least one port 4 or functional device 5 has, in line with the wall 3 of the pouch 2, an inside face that is located in the pouch 2.
The pouch unit 1, at least during the process for the production of the biopharmaceutical product P, is arranged to have a lower part 2 b, an upper part 2 c, and a median part 2 d.
In a typical embodiment, the pouch 2 comprises one or a number of ports 4 for filling in the upper part 2 c (such as the port 4 shown in FIG. 12) and a port 4 for emptying into the lower part 2 b, and a functional device 5 for mixing in the lower part 2 b (FIG. 13). Such an embodiment does not exclude others.
The device that is designed for the production of the biopharmaceutical product P can comprise, if necessary, an outside rigid container for receiving the pouch unit 1 in its inherent inside space.
The pouch unit 1 incorporates an inherent means of support and replacement 6. “Incorporating” means that the means 6 forms a cohesive, in particular an inseparable, unit with the pouch unit 1. “Inherent” means that the functions of support and replacement that describe the means 6 belong to the latter and characterize it.
The inherent means of support and replacement 6 is formed by or integrated in the wall 3 of the pouch 2 or in at least one port 4 or functional device 5. In so doing, the inherent means of support and replacement 6 is able to be accessible from the inside space 2 a of the pouch 2 and in direct physical contact with the contents of the pouch 2, in particular the biopharmaceutical product P.
The inherent means of support and replacement 6 is arranged in such a way as to be functionally capable of being able to be loaded with an incident body C and to make possible the passage of this incident body C between one and the other of the inherent means of support and replacement 6 and within the contents of the pouch 2. The means 6 is therefore able to ensure a first function that consists in being able to be loaded with the incident body C and also a second function that consists in making possible the passage of the incident body C between one and the other of the inherent means of support and replacement 6 and within the contents of the pouch 2, in particular the biopharmaceutical product P.
“Loaded” means that the incident body C is carried or captured by or held or located on or assimilated or adsorbed or absorbed by the inherent means of support and replacement 6 in such a way that under normal conditions and without other intervention, it cannot disseminate or be disseminated, at least substantially, outside of the inherent means of support and replacement 6 or its immediate proximity.
“Passage” means that the incident body C migrates and is moved from the inherent means of support and replacement 6 or its immediate proximity to the biopharmaceutical product P or to one or more of the components of the latter, in the direction that goes from the first to the second (arrows F1, FIG. 2) or from the second to the first (arrows F2, FIG. 2). In the case where there are two (or more) incident bodies C1 and C2, they can “pass” in the two directions (arrows F3 and F4, FIG. 2).
The inherent means of support and replacement 6 is functionally active per se, in particular permanently or as a consequence of a dedicated activation operation, in particular from a given time.
The process for the production of the biopharmaceutical product P is such that a pouch unit 1 is used as it was described above, and the biopharmaceutical product P, not totally finished, or components of the latter, and the pouch 2, then in particular empty, is filled by thus constituting the contents of the pouch 2.
The production process is implemented in and with the pouch unit 1, and during this process, the incident body C is used or generated, or the latter is used or generated. For example, with the latter's sole object being to illustrate the invention, the production process can consist in adding a component, for example, in finely-divided solid form—from the outside of the pouch 2 and via a port 4—to the contents in liquid or paste form that are already in the pouch 2 for having been placed there previously and in mixing the whole by means of a functional device 5, here a mixer. With the process generating, for example, wastes constituting here the incident body C, it is necessary to remove them from within the biopharmaceutical product P during production. This is the dual function performed by the inherent means of support and replacement 6 that will capture the wastes/incident body C in such a way that the finally finished biopharmaceutical product P is free thereof.
As appropriate, the pouch unit 1 is totally filled, or it is only partially filled, in its lower part 2 b or at least in the lower part 2 b and in all or part of the median part 2 d.
As is expressly evident from FIG. 2, which illustrates, on the one hand, the relative arrangement of the inherent means of support and replacement 6 relative to the pouch unit 1 and to the contents of the pouch 2, and, on the other hand, the two functions of the inherent means of support and replacement 6, the pouch unit 1 is used in such a way that the inherent means of support and replacement 6 that is submerged at least partially by the contents of the pouch 2 are in direct physical contact with these contents, in particular the biopharmaceutical product P, and in such a way that with the inherent means of support and replacement 6 then being functionally active, the incident body C passes directly substantially between one and the other of the inherent means of support and replacement 6 and within the contents of the pouch 2, in particular the biopharmaceutical product P.
Thus, the incident body C is substantially loaded on the inherent means of support and replacement 6 when it is not or should not be substantially within the biopharmaceutical product P, whereas at at least a time or stage of the production process, it is necessarily substantially within the biopharmaceutical product P.
For example, the incident body C is a waste that is produced within the biopharmaceutical product P during the production process, and this waste is then captured by the inherent means of support and replacement 6 by being isolated and separated from the biopharmaceutical product P. Or, conversely, the incident body C is an activator of the process of the production of the biopharmaceutical product that is not present within the latter at the beginning of the process, but is found there subsequently, released by the inherent means of support and replacement 6 on which it is originally loaded.
According to the embodiments, the inherent means of support and replacement 6 consists of, or comprises, a membrane (FIGS. 3, 5, 6, 7, 8) or a coating (FIG. 4) or a surface treatment (FIG. 9) of the wall 3 of the pouch 2 (FIGS. 3 to 11) or at least one port 4 (FIG. 12) or functional device 5 (FIG. 13), or a support and replacement body (FIGS. 10), or a support and replacement compartment (FIG. 11).
According to one embodiment, the inherent means of support and replacement 6 is located toward the lower face 3 b of the wall 3 of the pouch 2 (FIGS. 2 to 5 and 7 to 11) or at least one port 4 (FIG. 12) or functional device 5 (FIG. 13) that forms it or integrates it. This embodiment does not exclude others, whereby the inherent means of support and replacement 6 can be located toward the outside face 3 a of the wall 3 of the pouch 2 whereas it is able to be accessible from the inside space 2 a of the pouch 2 and in direct physical contact with the contents of the pouch 2 (FIG. 6).
According to one embodiment, the inherent means of support and replacement 6 is located on the entire surface of the face of the wall 3 of the pouch 2 (FIGS. 3 to 6, 8 and 9) or at least one port 4 (FIG. 12) or functional device 5 (FIG. 13), which forms it or integrates it. According to another embodiment, the inherent means of support and replacement 6 is located on one portion of the surface of the face of the wall 3 of the pouch 2 or at least one port 4 or functional device 5 that forms it or integrates it by then being either located (FIG. 7) or distributed over this surface.
According to one embodiment, the inherent means of support and replacement 6 is located in the lower part 2 b of the pouch unit 1 or in this lower part 2 b and in all or part of the median part 2 d.
According to one embodiment, quite specially in the case where the pouch unit 1 is only partially filled, the inherent means of support and replacement 6 is located in the lower part 2 b of the pouch unit 1 or in this lower part 2 b and all or part of the median part 2 d. According to another embodiment in the case where the pouch unit 1 is totally filled, the inherent means of support and replacement 6 can be located in the upper part 2 c of the pouch unit, as is the case if it is located on a port 4 such as the port 4 that is shown in FIG. 12.
According to possible embodiments, the inherent means of support and replacement 6 has a surface area for replacement with the contents of the pouch 2 during the process for the production of the biopharmaceutical product P that is larger than, more specially significantly larger than, more specially on the order of a multiple of, the surface area of the inside face 3 b of the wall 3 of the pouch 2 or at least one port 4 or functional device 5 that forms it or integrates it, and that is in direct contact with the contents of the pouch 2.
Such a larger surface area for replacement is obtained as a result of the composition of the inherent means of support and replacement 6, or the wall 3 of the pouch 2 or at least one port 4 or functional device 5 that forms it or in which it is integrated or the configuration of the inherent means of support and replacement 6 on the wall 3 of the pouch 2 or at least one port 4 or functional device 5 that forms it or in which it is integrated (FIGS. 8 and 9).
According to a functional embodiment, which can be combined with structural embodiments, the inherent means of support and replacement 6 is active per se, for example, because its nature makes it possible to capture or release the incident body C at any time and permanently, without requiring an action to be taken to do so.
According to another functional embodiment, the inherent means of support and replacement 6 is not active per se at any time and permanently but it requires being made active as a consequence of a dedicated activation operation.
Such a dedicated activation operation of the inherent means of support and replacement 6 and the means for its implementation may be the object of different embodiments.
According to one embodiment, the inherent means of support and replacement 6 is made active in response to the value taken on by at least one physical-biological-chemical condition of the biopharmaceutical product P or at least one physical-biological-chemical condition existing in the pouch 2. Such a physical-biological-chemical condition is, for example, the temperature, the pH, the composition, the contents of a certain body, the presence of a certain microorganism . . . .
According to another embodiment, the inherent means of support and replacement 6 is made active in response to the value not of the physical-biological-chemical condition as such, but in response to the variation of such a physical-biological-chemical condition.
According to another embodiment, the inherent means of support and replacement 6 is made active in response to a dedicated activation operation of a physical, biological or chemical nature, such as heat, stirring . . . .
Thus, in these embodiments, means for activating the inherent means of support and replacement 6 of a physical, biological or chemical nature are provided that are structurally separate from the pouch unit 1 but are designed to be combined functionally with it during the activation of the inherent means of support and replacement 6. If necessary, these activation means consist of the biopharmaceutical product P that has properties of a physical, biological or chemical nature and that can activate the inherent means of support and replacement. According to the embodiments, these activation means are located outside of the pouch unit 1 or in the inside space 2 a when, for example, they consist of the biopharmaceutical product P.
In the case of FIG. 3, the inherent means of support and replacement 6 is formed by a layer 7 that totally and continuously coats the inside face 3 b of the film of the wall 3 or the wall 3 itself. In such an embodiment, the inherent means of support and replacement 6 has a surface area for replacement with the biopharmaceutical product P during its production and/or its preservation that is substantially equal to the surface area of the inside face 3 b of the pouch 2 of the pouch unit 1.
In the case of FIG. 4, the inherent means of support and replacement 6 is formed by a continuous coating 8 over the entire inside face 3 b of the film of the wall 3 or the wall 3 itself.
In the case of FIG. 5, the inherent means of support and replacement 6 is formed by a continuous layer 9 that is sandwiched between the outside face 3 a and the inside face 3 b of the film of the wall 3 or the wall 3 itself, over the entire surface of the film, or the wall.
In the case of FIG. 6, the inherent means of support and replacement 6 is formed by a layer 10 that totally and continuously coats the outside face 3 a of the film of the wall 3 or the wall 3 itself, with the film of the wall 3 or the wall 3 itself then being able to allow the replacement of the incident body C, in its entire thickness, from the inside space 2 a of the pouch 2 to the outside, and vice versa.
In the case of FIG. 7, the inherent means of support and replacement 6 is formed by a layer 11 that forms a type of part (or “patch”) 11 that locally coats the inside face 3 b of the film of the wall 3 or the wall 3 itself. In this case, either a single such part 11 of suitable surface and shape, located at the desired spot of the film of the wall 3 or the wall 3 itself, or several parts 11, arranged and distributed according to a suitable distribution, can be provided.
In the case of FIG. 8, the inherent means of support and replacement 6 is or comprises a membrane 12 that is more or less an integral part of the film of the wall 3 or the wall 3 itself, on the inside face 3 b. For example, the membrane can be folded in a more or less significant way on itself.
In the case of FIG. 9, the inherent means of support and replacement 6 is formed by crevices 13 or an irregular surface condition with recesses or cavities of the film of the wall 3, obtained by particle bombardment, chemical attack, . . . . In such an embodiment, the inherent means of support and replacement 6 has, by the very fact of the configuration that is provided thereto, a surface area for replacement with the biopharmaceutical product P during its production that is larger than the surface area of the inside face 3 b of the pouch 2. For example, the inherent means of support and replacement 6 can have a surface area for replacement on the order of several times, and even a large number of times, the surface area of the inside face 3 b of the pouch 2.
In the case of FIG. 10, the inherent means of support and replacement 6 is a solid body 14, for example carried by the film of the wall 3 or by the wall 3 itself, over or toward the inside face 3 b. In such an embodiment, the inherent means of support and replacement 6 has, in itself, a surface area for replacement with the biopharmaceutical product P during its production that is larger than the surface area of the inside face 3 b of the pouch 2. For example, the means 6 can have a surface area for replacement on the order of several times, and even a large number of times, the surface area of the inside face 3 b of the pouch 2.
In the case of FIG. 11, the inherent means of support and replacement 6 consists of a compartment 15 that is limited by a wall 16 that makes possible the replacement between the inside and the outside of the compartment 16. As above, the inherent means of support and replacement 6 occupies the entire surface or only a portion of the surface of the film of the wall 3 or by the wall 3 itself by being either located or distributed relative to this surface.
In the case of FIG. 12, the inherent means of support and replacement 6 is formed by or integrated in a port 4, while being, as above, able to be accessible from the inside space 2 a of the pouch 2 and in direct physical contact with the contents of the pouch 2. This embodiment includes the case where the inherent means of support and replacement 6 is formed by or integrated not directly in the port 4 itself, but indirectly, namely in an element for supporting the port 4.
In the case of FIG. 13, the inherent means of support and replacement 6 is formed by or integrated in a functional device 5, while being, as above, able to be accessible from the inside space 2 a of the pouch 2 and in direct physical contact with the contents of the pouch 2. This embodiment includes the case where the inherent means of support and replacement 6 is formed by or integrated not directly in the functional device 5 itself, but indirectly, namely in an element for supporting the functional device 5.
Of course, different structural embodiments of those described above can be combined with one another, either for the same incident body C or for different incident bodies C.
The process for production and the pouch unit 1 can be the object of several different embodiments relative to the time when the inherent means of support and replacement 6 is loaded with the incident body C and the time when it is not loaded with the incident body C, relative to the time before the filling of the pouch 2 and once the biopharmaceutical product P is produced.
In one embodiment, before filling with contents, the inherent means of support and replacement 6 is not loaded with the incident body C.
In another embodiment, before filling with contents, the inherent means of support and replacement 6 is substantially loaded with the incident body C.
In one embodiment, after the biopharmaceutical product P has been produced, the inherent means of support and replacement 6 is not loaded with the incident body C.
In another embodiment, after the biopharmaceutical product P has been produced, the inherent means of support and replacement 6 is substantially loaded with the incident body C.
These embodiments are combined with one another for the same inherent means of support and replacement 6 and the same incident body C.
Thus, before filling the pouch 2, the inherent means of support and replacement 6 is not loaded with the incident body C, and after the biopharmaceutical product P has been produced, in contrast, it is loaded with the incident body C. This embodiment is applied, for example, with an incident body C that is an undesirable body that does not exist at the beginning of the process for the production of the biopharmaceutical product P, but is produced during this production process and that is desired to be eliminated within the biopharmaceutical product P itself.
In another embodiment, before filling the pouch 2, the inherent means of support and replacement 6 is substantially loaded with the incident body C, and after the biopharmaceutical product P has been produced, in contrast, it is not loaded with the incident body C. This embodiment that is applied, for example, with a body C can then be an incident body that is necessary to the process for the production of the biopharmaceutical product P, existing at the beginning of the production process, consumed during this process, and not existing at the end.

Claims

1-27. (canceled)

28. Process for the production of a biopharmaceutical product in substantially liquid or paste form by a physical-chemical-biological production process, in which:

A pouch unit (1) is provided that includes a pouch (2) that defines an inside space (2 a) that can contain the biopharmaceutical product during its production process, and said pouch unit is limited by a continuous wall (3) that is flexible, airtight, and non-degradable, and that can be in direct contact by its inside face (3 b) with the biopharmaceutical product and can contain it, and, combined with the pouch (2), at least one port (4), and, if necessary, at least one functional device (5),

The biopharmaceutical product that is not totally finished or components of the latter is/are provided, and the pouch (2) is filled with said product or components, thus constituting the contents of the pouch (2),

The process for production is implemented in and with the pouch unit (1), and during this process, at least one incident body that is solid and small in size or liquid that is within the biopharmaceutical product is used or generated at at least one time or stage of the production process,

characterized by the fact that:

The at least one incident body that is solid and that is broken into a number, more specially a large number, of units or pieces of a dimension on the order of, or less than, or significantly less than, a millimeter, down to molecular size, is generated,

A pouch unit (1) that is selected for incorporating an inherent means of support and replacement (6) is provided:

Formed by or integrated in the wall (3) of the pouch (2) or in at least one port (4) or functional device (5), in such a way as to be able to be accessible from the inside space (2 a) of the pouch (2) and in direct physical contact with the contents of the pouch (2),

Arranged in such a way as to be functionally able to be loaded with the incident body and to make possible the passage of the incident body between one and the other of the inherent means of support and replacement (6) and within the contents of the pouch (2),

Being functionally active per se or as a consequence of a dedicated activation operation,

The pouch unit (1) is used in such a way that the inherent means of support and replacement (6) is in direct physical contact with the contents of the pouch (2) and in such a way that with the inherent means of support and replacement (6) being functionally active, the incident body passes substantially between one and the other of the inherent means of support and replacement (6) and within the contents of the pouch (2) in such a way that the incident body is substantially loaded on the inherent means of support and replacement (6) when it is not or should not be substantially within the biopharmaceutical product.

29. Process according to claim 28, wherein the inherent means of support and replacement (6) is functionally active in response to the value taken on by at least one physical-biological-chemical condition of the contents of the pouch (2) or in response to the value taken on by the variation of such a physical-biological-chemical condition or in response to a dedicated activation operation of a physical, biological, or chemical nature.

30. Process according to claim 28, wherein once the biopharmaceutical product has been produced and is in the pouch (2), the inherent means of support and replacement (6) is substantially loaded with the incident body, whereas before filling with contents, the inherent means of support and replacement (6) is not loaded with the incident body.

31. Process according to claim 28, wherein before filling with contents, the inherent means of support and replacement (6) is substantially loaded with the incident body, whereas once the biopharmaceutical product has been produced and is in the pouch (2), the inherent means of support and replacement (6) is not loaded with the incident body.

32. Pouch unit (1) that is specially designed for the implementation of the process for the production of a biopharmaceutical product in substantially liquid or paste form according to claim 28, including a pouch (2) that defines an inside space (2 a) that can contain the biopharmaceutical product during its production process, limited by a continuous wall (3) that is flexible, airtight, and non-degradable, and that can be in direct contact by its inside face (3 b) with the biopharmaceutical product and can contain it, and, combined with the pouch (2), at least one port (4), and if necessary at least one functional device (5), which:

Incorporates an inherent means of support and replacement (6):

Arranged in such a way as to be functionally able to be loaded with the incident body and to make possible the passage of the incident body between one and the other of the inherent means of support and replacement (6) and within the contents of the pouch (2) itself,

Functionally active per se or as a consequence of a dedicated activation operation,

Is implemented such that the inherent means of support and replacement (6) is in direct physical contact with the contents of the pouch (2) and such that, with the inherent means of support and replacement (6) being functionally active, the incident body passes substantially between one and the other of the inherent means of support and replacement (6) and within the contents of the pouch (2) itself, and is substantially loaded on the inherent means of support and replacement (6) when it is not or should not be substantially within the biopharmaceutical product.

33. Pouch unit (1) according to claim 32, wherein the inherent means of support and replacement (6) consists of or comprises a membrane or a coating or a surface treatment of the wall (3) of the pouch (2) or at least one port (4) or functional device (5), or a body of support and replacement, or a compartment of support and replacement.

34. Pouch unit (1) according to claim 32, wherein the inherent means of support and replacement (6) is located toward the inside face (3 b) of the wall (3) of the pouch (2) or at least one port (4) or functional device (5) that forms it or integrates it.

35. Pouch unit (1) according to claim 32, wherein the inherent means of support and replacement (6) is located over the entire surface or on only one portion of the surface of a face of the pouch (2) or at least one port (4) or functional device (5) that forms it or integrates it by then being either located or distributed over this face.

36. Pouch unit (1) according to claim 32, that has, during the process for the production of the biopharmaceutical product, a lower part (2 b), an upper part (2 c), and a median part (2 d), wherein the inherent means of support and replacement (6) is located at least in the lower part (2 b) or at least in the lower part (2 b) and in all or part of the median part (2 d) of the pouch unit (1).

37. Pouch unit (1) according to claim 32, characterized by an inherent means of support and replacement (6) that has a surface area for replacement with the contents of the pouch (2) during the process for the production of the biopharmaceutical product that is larger than, more specially significantly larger than, more specially on the order of a multiple of, the surface area of the inside face (3 b) of the wall (3) of the pouch (2) or at least one port (4) or functional device (5) that forms it or integrates it, and that is in direct contact with the contents of the pouch (2), as a result of the composition of the inherent means of support and replacement (6), or the wall (3) of the pouch (2) or at least one port (4) or functional device (5) that forms it or in which it is integrated or the configuration of the inherent means of support and replacement (6) on the wall (3) of the pouch (2) or at least one port (4) or functional device (5) that forms it or in which it is integrated.

38. Pouch unit (1) according to claim 32, wherein the inherent means of support and replacement (6) is functionally active in response to the value taken on by at least one physical-biological-chemical condition of the contents of the pouch (2) or in response to the value taken on by the variation of such a physical-biological-chemical condition or in response to a dedicated activation operation of a physical, biological, or chemical nature.

39. Pouch unit (1) according to claim 32, wherein the pouch (2) is either a 2D pouch or a 3D pouch.

40. Pouch unit (1) according to claim 32 before filling with contents, wherein the inherent means of support and replacement (6) is not loaded with the incident body.

41. Pouch unit (1) according to claim 32 before filling with contents, wherein the inherent means of support and replacement (6) is substantially loaded with the incident body.

42. Pouch unit (1) according to claim 32 that is filled with finished biopharmaceutical product, wherein the inherent means of support and replacement (6) is not loaded with the incident body.

43. Pouch unit (1) according to claim 32 that is filled with finished biopharmaceutical product, wherein the inherent means of support and replacement (6) is substantially loaded with the incident body.

44. Unit that comprises, in the first place, a pouch unit (1) according to claim 32, wherein the inherent means of support and replacement (6) is functionally active as a consequence of a dedicated activation operation, and, in the second place, means of activation of the inherent means of support and replacement (6) of a physical, biological or chemical nature.

45. Unit according to claim 44, wherein the activation means either consist of the biopharmaceutical product P that is in the inside space (2 a) of the pouch unit (1) and that has properties that can activate the inherent means of support and replacement (6) or are located outside of the pouch unit (1).