EP2621829A1

EP2621829A1 - Detection of the integrity of a tight, closed, soft plastic pouch for receiving and protecting a product or a biopharmaceutical device

Info

Publication number: EP2621829A1
Application number: EP11758531.5A
Authority: EP
Inventors: Lars BÖTTCHER; Martin Dahlberg
Original assignee: Sartorius Stedim Biotech SA
Current assignee: Sartorius Stedim Biotech SA
Priority date: 2010-09-30
Filing date: 2011-08-22
Publication date: 2013-08-07
Also published as: US9005978B2; FR2965556B1; CN103282285A; US20130210153A1; FR2965556A1; WO2012042139A2; EP2662307A1; CN103282285B; EP2662307B1

Abstract

The package i.e. three-dimensional (3D) stricto sensu pouch (1), has a flexible main outer wall (3) for assuring gas and pathogenic germ sealing, and an opening/closing unit e.g. colorimetric detection layer (12), for closing and opening an intake passage (7) with a sterilization gas permeable membrane forming a downstream distribution opening (9). The wall, the passage and the unit are connected together to form the package enclosing the biopharmaceutical content subjected to differential pressure integrity tests requiring gas sealing for the package at any desired time after sterilization. An independent claim is also included for a method for implementing a sterilisable biopharmaceutical package.

Description

Detecting the integrity of a flexible, sealed, sealed plastic bag for receiving and protecting a biopharmaceutical product or device

The invention relates to the detection of the integrity of a flexible, sealed, sealed plastic bag for receiving and protecting a biopharmaceutical product or device, such as a sterile bag.

The invention aims, more specifically, an integrity / non-integrity indicator pouch, such a pouch which is integral, the method of producing such an integrity / non integrity integrity pouch, the method of obtaining a pouch stricto sensu integrates, and finally, a process of implementation of a pocket stricto sensu which, integrates, is intended to receive and protect a product or a biopharmaceutical device.

By biopharmaceutical product is meant a product derived from biotechnology - culture media, cell cultures, buffer solutions, artificial nutrition liquids, or a pharmaceutical product or more generally a product for use in the medical field. The term "biopharmaceutical device" means a device intended to be implemented in a process of the biological or pharmaceutical domain - measuring or control means, means for treating biopharmaceutical products, containers or parts of containers, means for transferring or closing . Such biopharmaceutical products or devices are of high added value and it is important to ensure their integrity, including the absence of any contamination.

For the purposes of storage, transport or the carrying out of a certain process of a physical, chemical or biological nature, it is customary to place such biopharmaceutical products or devices in flexible, closed, leakproof, sterile disposable disposable bags. plastic such as polyethylene or a complex comprising polyethylene. Such a pocket comprises means for introducing into its interior space and extraction means from its interior space of the product or biopharmaceutical device, able to be brought, according to the moments and the needs in the open state or in the state closed.

Such pockets are known whose two large walls are directly joined to one another. Once expanded, such bags have a limited volume and remain relatively thin, which justifies that they are often called "pillow" pockets, or pockets "2D" (D meaning dimensions). There are also known 3D pockets which comprise two large walls connected by and welded to two side gussets, which can be folded flat or folded unfolded, the volume can then be at least 50 liters, up to 3000 liters or more. Such 3D bags are described in WO00 / 04131 or sold under the trade mark FLEXEL ^® 3D.

In order to be able to effectively receive and protect a biopharmaceutical product or device as previously defined, it is essential that the interior space of the pocket - here called pocket stricto sensu - and its possible contents are preserved from any possible deterioration of origin outside the pocket stricto sensu, such as contamination. This preservation is here referred to as "sealing". The pocket stricto sensu must be waterproof or at least have a degree of sealing considered satisfactory. Such a pouch stricto sensu is designed and manufactured to have the required seal. But, manufacturing defects of the pocket stricto sensu affecting its tightness can not be excluded. And it is possible on the other hand that the tightness of a pouch stricto sensu originally waterproof is affected after its manufacture.

The tightness of the pouch stricto sensu is affected when the pouch stricto sensu comprises one or more passages through the envelope that it forms, including a porosity, this or these passages having one or more outlets on the outer face of the pouch stricto sensu, including the welds between the constituent parts of the pouch stricto sensu in question.

Before using or considering using such a pouch stricto sensu, it is essential to ensure that it has the required seal. Such a pocket stricto sensu presenting this seal is said to be integral and is able to receive and protect a product or biopharmaceutical device. Such a pocket stricto sensu does not have this seal is said to be unhealthy and, being unfit to receive and protect a biopharmaceutical product or device, must be discarded and not used.

Methods and devices for checking the integrity of pockets implemented online are known on all the pockets during their manufacture. Thus, ASTM International Standard F 2095-01, which is entitled "Standard Test Methods for Pressure Decay Leak Test for Nonporous Flexible Packages With and Without Restraining Plates" is more specifically concerned with the so-called pressure drop process. This method is envisaged according to two embodiments: with or without expansion limiting plates (for example the device known under the trademark SARTOCHECK ^® 4). In all cases, such devices are complex and bulky and difficult to transport or use on the end use of the pockets. On the other hand, assuming the pocket integrates with manufacturing, an accidental loss or breakage of integrity may occur after manufacture and before end use, for example in the storage, transport, distribution, delivery or still in the phase immediately preceding the implementation of the pocket. This risk is even greater than one of these phases is long (for example the storage phase can reach several years) or it involves manipulation of the pocket or its contact with objects conducive to its damage. However, such a non-integrity can not be detected by an integrity control method implemented on the single place of manufacture of the pocket, before the breach of integrity occurs.

US 6892567 and US 6196056 disclose methods and apparatus for determining the integrity of a package or compartment based on the transmission of a test gas through the packaging or the wall of the compartment. This apparatus and the associated measuring instruments form a complex and bulky whole.

US 2007/0220956 discloses a method and apparatus for detecting leakage from a biological process carrying pouch containing a conductive fluid, placed in a rigid outer container, consisting of an operating leak detector electric. Such a method and apparatus have the same limitations mentioned above, besides they find application only in the case of a filled bag, a conductive fluid and finally the presence of a rigid outer container.

US 4098577 discloses a method and an indicator for detecting the loss of integrity of a transparent package containing a product which is sealed to the package. The packaging is filled with an artificial atmosphere such as carbon dioxide or nitrogen. A pH sensitive detector is placed in the package and is visible through it. The detector changes color in case of loss of the artificial atmosphere due to a loss of integrity of the package. In the embodiments envisaged, the packaging is rigid, the product is a solid object and the detector is removed from the latter. This method is unsuitable in the case of a package for receiving a fluid product coming into contact with the detector. Furthermore, it is neither described nor suggested, on the contrary, that the detection occurs before the product is placed in the package.

US 4813541 discloses a tamper evident method and packaging. The package comprises a first internal container, rigid, hermetically sealed filled with a first atmosphere and containing a substance and a second outer container, rigid, hermetically closed in which is - in spaced position by means of spacers - the first container, the internal cavity of the second outer container to the first container being filled with a second atmosphere at a pressure different from that of the first atmosphere, and detection means being placed in the cavity and being sensitive to a change in the second atmosphere due to a break in integrity of the first container or the second container. US 4813541, which describes a very particular structure, does not suggest that detection occurs before the substance is placed in the first container.

WO 01/04624 discloses a colorimetric system comprising a detector sensitive to carbon dioxide. WO96 / 12659 discloses a so-called tamper-evident package comprising an inner membrane delimiting an inner compartment, which contains a first medium composed of air, and an outer membrane delimiting an outer compartment which surrounds the inner compartment and contains a second composite medium of carbon dioxide. An indicator tab, sensitive to the surrounding medium is disposed inside the outer compartment and it can give an indication of a change in the first and second medium. US 4434893 discloses a package for receiving products comprising inner and outer cases. In one embodiment, the inner case and the outer case respectively have only one flexible wall and these inner and outer cases are pressurized with a gas having a pressure greater than atmospheric pressure. so as to inflate their flexible wall. In another embodiment, the two walls of each of the inner and outer cases are flexible. The products - capsules, capsules or the like - to be protected are included inside the inner case and the inner case is itself located in the outer case so as to form a protection preventing access to the products. .

US 4436203 discloses a package comprising an internal container of predefined size, filled with a product and pressurized before being placed inside an external container. After its internal pressure has been lowered below atmospheric pressure, said outer container is closed. Thus, when one of the walls of the package is pierced, the consumer is alerted that the product could be affected.

The document FR 2252 619 describes a device intended to be used with a hermetically sealed closed package. It comprises a detector arranged so that it is in communication with the inside of the package but also visible from the outside. This detector contains a pH-sensitive dye, which has a first color at a normal atmospheric pH, and a second color at a pH slightly above or below the normal atmospheric pH.

The document FR-A-2822445 relates to a package of infectious samples of the type comprising a sealed plastic bag intended to contain a container containing said sample housed in a sheet of an absorbent fabric characterized in that said fabric is colored and is as any trace of moisture changes its initial color, the plastic bag being transparent.

US 5219524 relates to a system for preserving an acid-containing article that is in contact with an alkaline substrate material and an artificial atmosphere that is substantially free of gaseous oxygen. The article, alkaline substrate material and artificial atmosphere are hermetically sealed in a container, at least a portion of the container being at least partially transparent to allow viewing of the article from outside the container.

The invention therefore aims to overcome the aforementioned problems and to identify the integrity or non-integrity of a pouch stricto sensu at any desired time after its manufacture and at least just before its intended use, and this safe, easy, fast, without the need for a dedicated heavy or complex device, or difficult or delicate operations, and without the need to have recourse to specialized personnel specially and exclusively dedicated to integrity control, and without the need to have to test the pocket positively to ensure its integrity, the non-integrity being revealed automatically, and therefore without the need, when the pocket is part of a plurality of pockets, having to test each pocket positively. For this purpose, according to a first aspect, the subject of the invention is an integrity / non-integrity witness bag for receiving and protecting a biopharmaceutical product or device, comprising:

^■ a first casing, inside, flexible, closed, sealed, plastic, having a wall delimiting a first space, forming strictly speaking a pocket for receiving the biopharmaceutical product or device, comprising first introducing means and first means extracting the product or device in the closed state,

^■ a second envelope, outer, closed, sealed, plastic, having a wall delimiting a second space in which is located the first envelope / bag stricto sensu, comprising second means for introducing and second extracting means of the first envelope / pouch stricto sensu, being in the closed state, an intermediate space being thus formed in the second space outside the first envelope / pouch stricto sensu,

^Spacer means interposed between the wall and the wall, such that the inner face of the wall does not block any possible outlet of non-integrity on the external face of the wall,

^■ at least a tracer gas, is located in either the first space is in the intermediate space, at a different partial pressure of the one of the intermediate space or the first space, respectively, introduced into the first space and / or intermediate space by tracer gas introducing means, being in the closed state,

^■ at least one continuous layer of colorimetric detection of the tracer gas, responsive to the concentration of tracer gas that reaches through a first color to a second different color, forming an integral part of a wall of the first envelope / bag stricto sensu and / or a wall of the second envelope and / or spacer means,

^■ the provision of the walls of the first envelope / pouch stricto sensu and the second casing, spacer means of the tracer gas and the colorimetric detection layer on the one hand, the permeability or impermeability to the tracer gas colorimetric detection layer, and spacer means, on the other hand, being chosen so that the colorimetric detection layer can not be reached by tracer gas in the intermediate space or in the first space with a concentration passing through the transition value, with the first envelope / pocket stricto sensu integrates, and that the colorimetric detection layer is necessarily reached by tracer gas in the intermediate space or in the first space with a concentration passing the transition value, with a first envelope / pocket stricto sensu not integrity.

Thus, if the colorimetric detection layer is identified with the first color, the first envelope / pouch stricto sensu is considered to be intact and capable of receiving and protecting the biopharmaceutical product or device, whereas if it is identified with the second color, it is considered to be non-integral and unfit to receive and protect the biopharmaceutical product or device.

According to the embodiments, the spacer means comprise at least one porous layer integrally covering the outer face of the wall of the first envelope / pocket stricto sensu and / or the inner face of the wall of the second envelope and / or the face of the colorimetric detection layer facing the intermediate space or the spacer means comprise at least one porous layer which is structurally covering the outer face of the wall of the first envelope / pouch stricto sensu and / or the inner face of the wall of the second envelope and / or the face of the colorimetric detection layer facing the intermediate space, either is placed in the intermediate space.

According to the embodiments, the tracer gas is in the first space at a greater partial pressure than in the intermediate space, the colorimetric detection layer passing from the first color to the second color in response to the passage of the tracer gas concentration which reaches it above a transition value, ie the tracer gas is in the first space at a smaller partial pressure than in the intermediate space, the colorimetric detection layer passing from the first color to the second color in response to the passage of the tracer gas concentration which reaches below a transition value.

According to a first family of embodiments, a colorimetric detection layer is permeable to the tracer gas and forms an integral part of the wall of the first envelope / pouch stricto sensu, being either located on the outer face and in the intermediate space, or located on the inner face and in the first space, is inserted into the wall, interposed between its outer face and its inner face and between the first space and the intermediate space.

According to a second family of embodiments, a colorimetric detection layer is an integral part of the wall of the second envelope, being either located on the inner face and in the intermediate space, or inserted in the wall, interposed between the inner face and its outer face, the layer of the wall of the second envelope adjacent one side to the colorimetric detection layer and the other side to the inner face then being permeable to the tracer gas.

According to a third family of embodiments, a colorimetric detection layer is an integral part of a porous layer of the spacer means being either located towards the outer face of the wall of the first envelope / pocket stricto sensu, or located towards the inner face of the second envelope or a colorimetric detection layer and a porous layer spacer means are structurally combined to form a single layer.

Achievements according to these different families can, if necessary, be combined with each other. Depending on the case, the first envelope / pouch stricto sensu is a 2D pocket, or a 3D pocket with two gussets. In the latter case, and in one embodiment, the spacer means comprise at least one porous layer covering functionally integrally, and if necessary so structured, the outer face of the inside of the gussets.

According to possible embodiments, the spacer means comprise at least one porous layer covering functionally and, where appropriate, structurally, the first introduction means and the first extraction means of the biopharmaceutical product or device and the gas introduction means. tracer of the first envelope / pocket stricto sensu. Or, the spacer means comprise at least one porous layer of fabric, nonwoven, PE, PP, PTFE.

According to possible embodiments, a tracer gas is chosen from the group comprising oxygen, carbon dioxide and helium.

According to two possible embodiments, one of the first space or of the intermediate space contains tracer gas and the other of the intermediate space or of the first space contains no or substantially no tracer gas. In one embodiment, the second envelope is able to identify from outside itself whether the colorimetric detection layer is of the first color or the second color.

In one embodiment, the second envelope is flexible. According to one embodiment, the integrity / non-integrity indicator bag further comprises an outer protective overpack in which is housed the second envelope, in which is the first envelope / pouch stricto sensu.

According to a second aspect, the subject of the invention is an integral integrity / non-integrity indicator pouch constituted by an integrity / non-integrity indicator pouch as previously described, the colorimetric detection layer of which is of the first color.

According to a third aspect, the subject of the invention is a method for producing an integrity / non-integrity witness bag as previously described, in which:

A first envelope / pouch stricto sensu, a second envelope, the second means of introduction of the first envelope / pouch stricto sensu are in the open state, spacer means, tracer gas, layer colorimetric detection device forming an integral part of a wall of the first envelope / pocket stricto sensu and / or a wall of the second envelope and / or spacer means, ^■ introducing the first envelope / pouch stricto sensu in the second space of the second casing via the second input means in the open state, the spacer means being interposed between the wall and the wall so that the inside of the wall does not hide a possible outlet of non-integrity on the outer face of the wall,

The tracer gas, either in the first space or in the intermediate space, is introduced at a partial pressure different from that of the intermediate space or of the first space, respectively, via the tracer gas introduction means, located in the open state, then bring these introduction means to the closed state,

^■ choosing the arrangement for the colorimetric detection layer can not be achieved or, conversely, is necessarily achieved by tracer gas as required and is chosen accordingly the permeability or impermeability to the tracer gas detection layer colorimetric and spacing means so that the colorimetric detection layer is effectively reached by tracer gas when necessary,

^■ the first envelope / pocket stricto sensu and the second envelope being closed.

According to a fourth aspect, the subject of the invention is a process for obtaining a pouch stricto sensu that is integrated and ready to receive and protect a biopharmaceutical product or device, in which:

^■ there is a bag with tamper evident / no integrity as previously described,

It is identified whether the colorimetric detection layer is of the first color or the second color,

^■ if the colorimetric detection layer is identified of the first color:

the second extraction means of the first envelope / pocket stricto sensu is provided with which the second envelope is provided in the open state,

o the first envelope / pouch stricto sensu is extracted from the second space of the second envelope,

o and introducing the first means of introduction of the product or biopharmaceutical device which is provided with the first envelope / pouch stricto sensu considered to be integral, in the open state in order to place the product or biopharmaceutical device,

■ whereas if the colorimetric detection layer is identified with the second color, the first envelope / pouch stricto sensu is not retained with a view to placing the biopharmaceutical product or device therein, the first envelope / pouch stricto sensu being considered as no integrated. According to a fifth aspect, the subject of the invention is a process for implementing a pouch stricto sensu which, integrated, is intended to receive and protect a biopharmaceutical product or device, comprising:

^■ at a place of manufacture, initial operations consisting in making a pocket stricto sensu,

^■ at a place of use, final operations consisting in using the pouch stricto sensu by placing the biopharmaceutical product or device therein, ^■ in one or more places, intermediate operations of storage, transport, manipulation, and including:

^■ the embodiment, at the place of manufacture, a control bag integrity / non-integrity comprising a first envelope / bag stricto sensu, by the method of embodiment as described above,

^■ the transport of the integrity / non-integrity pouch from the place of manufacture to the place of use, if necessary by storage and handling operations,

^■ and, at least at the place of use and prior to extracting the first envelope / bag strict sense of the second casing in order to place the biopharmaceutical product or device, identifying that the colorimetric detection layer is the first color or the second color,

^■ if the colorimetric detection layer is identified by the first color, the use of the first envelope / pouch stricto sensu considered as integral for the purpose of placing the biopharmaceutical product or device therein to receive and protect it,

■ whereas if the colorimetric detection layer is identified of the second color, the non-use of the first envelope / pouch stricto sensu considered as unintegrated in order to place the product or biopharmaceutical device therein.

According to one embodiment, the identification that the colorimetric detection layer is of the first color or the second color is performed in masked time during the intermediate operations of storage, transport, manipulation.

According to one embodiment, the identification that the colorimetric detection layer is of the first color or the second color is carried out at the place of use just before extracting the first envelope / pouch stricto sensu from the second envelope in order to place the biopharmaceutical product or device.

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

FIG. 1 is a top view of an integrity / non-integrity indicator pouch of the type in which the pouch stricto sensu is of the 3D type and the integrity / non-integrity witness pouch housed in an outer overpack of protection, this pocket being shown folded flat as it is for example during storage or transport.

- Figure 2 is a cross-sectional view of the integrity / non-integrity indicator bag of Figure 1, without the outer protective overwrap, in a possible embodiment and not limiting.

FIGS. 3A, 3B and 3C are three partial cross-section views, on a larger scale, illustrating three possible embodiments of the integrity / non-integrity indicator pouch, in which the colorimetric detection layer is located towards the face external wall of the first envelope / pocket stricto sensu of which it forms an integral part, the spacer means being, respectively, associated with the inner face of the wall of the second envelope (Figure 3A), associated with the wall of the first envelope / pouch stricto sensu towards its outer face (Figure 3B), located between the walls of the first envelope / pouch stricto sensu and the second envelope (Figure 3C).

FIGS. 4A, 4B and 4C are three partial cross-section views, on a larger scale, illustrating three possible embodiments of the integrity / non-integrity indicator pouch, in which the colorimetric detection layer is located towards the face internal wall of the first envelope / pouch stricto sensu which it is an integral part, the spacer means being respectively associated with the inner face of the wall of the second envelope (Figure 4A), associated with the outer face of the wall the first envelope / pocket stricto sensu (Figure 4B), located between the walls of the first envelope / pouch stricto sensu and the second envelope (Figure 4C).

FIGS. 5A, 5B and 5C are three partial cross-section views, on a larger scale, illustrating three possible embodiments of the integrity / non-integrity indicator pouch, in which the colorimetric detection layer is inserted into the wall of the first envelope / pouch stricto sensu of which it forms an integral part, the spacer means being, respectively, associated with the inner face of the wall of the second envelope (FIG. 5A), associated with the outer face of the wall of the first envelope / pocket stricto sensu (Figure 5B), located between the walls of the first envelope / pocket stricto sensu and the second envelope (Figure 5C).

FIGS. 6A, 6B and 6C are three partial cross-section views, on a larger scale, illustrating three possible embodiments of the integrity / non-integrity indicator pouch, in which the colorimetric detection layer is located towards the face inside the wall of the second envelope of which it forms an integral part, the spacer means being, respectively, associated with the wall of the second envelope towards its inner face (FIG. 6A), associated with the external face of the wall of the first envelope / pocket stricto sensu (Figure 6B), located between the walls of the first envelope / pocket stricto sensu and the second envelope (Figure 6C).

FIGS. 7A, 7B and 7C are three partial cross-section views, on a larger scale, illustrating three possible embodiments of the integrity / non-integrity indicator pouch, in which the colorimetric detection layer is inserted into the wall of the second envelope of which it forms an integral part, the spacer means being, respectively, associated with the inner face of the wall of the second envelope (FIG. 7A), associated with the external face of the wall of the first envelope / pocket stricto sensu (Figure 7B), located between the walls of the first envelope / pocket stricto sensu and the second envelope (Figure 7C).

FIGS. 8A and 8B are two partial cross-section views, on a larger scale, illustrating three possible embodiments of the integrity / non-integrity indicator pouch, in which the colorimetric detection layer is an integral part of a layer porous spacing means, the colorimetric detection layer being located towards the outer face of the first envelope / pocket stricto sensu wall (Figure 8A), located towards the inner face of the second envelope (Figure 8B).

A flexible 3D pocket 1, closed (during the phases where it is desired), sealed in its entirety, sterile, made of plastic material, in particular for single use, intended in the field biopharmaceutical to be received and protected for the purposes of storage, transport or carrying out a certain process of a physical, chemical or biological nature, a biopharmaceutical product or device is known from the state of the art (see, for example, document WO00 / 04131 and the pocket known under the trademark FLEXEL ^® 3D).

In order to be able to effectively receive and protect the biopharmaceutical product or device, the internal space of the bag 1 and its possible contents must be preserved from any possible deterioration of origin external to the bag 1, such as a contamination. Pocket 1 must therefore be watertight as defined. Such a pocket 1 is designed and manufactured to be waterproof, but manufacturing defects can not be excluded and the seal can be affected after manufacture.

The tightness is affected when the pocket 1 has one or more passages T passing through the envelope that it forms, including a porosity, this or these passages having one or more outlets D on the outer face 1a of the pocket 1 , including the welds 5 between the constituent parts of the pocket 1 in question.

Before using or considering using such a pocket 1, it is therefore essential to be able to ensure that it has the required seal. Thus qualified as "integrity", the pocket 1 is able to receive and protect a product or biopharmaceutical device, while a pocket 1 not having this seal is said to be unhealthy and, being unfit to receive and protect a product or device biopharmaceutical, must in the framework of the implementation process of pocket 1 be discarded and not used. The invention aims to identify the integrity or non-integrity of such a pocket 1 at any desired time after its manufacture and at least just before its intended use.

For this, it implements a pocket 2 which receives the pocket 1. To distinguish the pockets 1 and 2, the pocket 1 is described as "pocket stricto sensu" while the pocket 2 is qualified as "pocket with integrity indicator / non integrity".

The expression "pouch stricto sensu" therefore refers to the pocket 1 intended to directly receive and protect the biopharmaceutical product or device, which pouch stricto sensu 1 is incorporated in the subject-matter of the invention called "integrity check bag". / no integrity "2.

A pocket stricto sensu 1 3D can be of large volume of at least 50 liters, up to 1,000 liters, or even more. Such pocket stricto sensu 1 typically comprises a main wall 3 in two parts fixedly connected and sealed to two lateral gussets 4 by welds 5. Such a pouch stricto sensu 3D can be folded flat - for example for storage, transport, handling - or unfolded unfolded, when receiving a product or biopharmaceutical device.

The walls 3, 4 constituting the pocket 1 and the sealed welds 5 form an envelope, here called "first envelope", also designated by the reference 1. By convention, the term "the" wall 3, 4 as well as the all the walls of the pocket stricto sensu 1 that each of them.

The wall 3, 4 is made from one or more flexible plastics, at least some of which are non-porous so that the pouch stricto sensu 1 is watertight as a whole. The wall 3, 4 may be monolayer or multilayer. It can incorporate a high-capacity plastic gas barrier material, such as EVOH, this being only an example and not limiting.

The pocket stricto sensu 1, namely its wall 3, 4, has an outer face 1a and an inner face 1b. The terms "external" and "internal" are understood in relation to what is located, respectively, out of and in the pocket stricto sensu 1. The pocket stricto sensu 1 delimits within itself a first space 6 whose limit is the inner face 1b and whose volume is suitable to be able to receive the product or biopharmaceutical device when it is desired that it be in the pocket stricto sensu 1.

The pouch stricto sensu 1 comprises first introduction means 7 associated with the wall 3, with a view to the introduction, when desired, of the biopharmaceutical product or device in the first space 6. Such an introduction takes place while the strict pocket sensu 1 was previously extracted from the pocket 2 with integrity / non integrity indicator. Such first introduction means 7 may be in the form of one or more passages arranged in the wall 3 to, when necessary, be brought or be in the open state. Such passages are generally also arranged so that they can then be brought to the closed state, in particular by welding, once the biopharmaceutical product or device has been introduced into the first space 6. The pocket stricto sensu 1 also comprises first associated extraction means. at the wall 3, for the purpose of extraction, when desired, of the biopharmaceutical product or device from the first space 6. Such an extraction necessarily occurs while the bag stricto sensu 1 has been previously extracted from the bag 2 with witnesses integrity / non integrity for the introduction of the product or biopharmaceutical device as just described. Such first extraction may be an irreversible tear or the like of the wall 3 of the pouch stricto sensu 1, which is generally for single use only.

Such a pouch stricto sensu 1 is typically either in a folded flat state, for example for storage, transport, handling or in an expanded unfolded state to receive and protect the biopharmaceutical product or device, which is still in an intermediate state. The pocket stricto sensu 1 can be deformed to pass from one to the other of these states.

Such pocket stricto sensu 1 can, if necessary, be associated with a rigid container contention pochel from the outside. A container such as that considered is for example described in a possible variant embodiment in the document EP-A-1012073 or sold under the trademark PALLETTANK ^® .

The process of implementing such a pocket stricto sensu 1 comprises:

^■ at a place of manufacture, initial operations consisting of manufacturing the pouch stricto sensu 1,

^■ at a place of use, most often different and distant from the place of manufacture, the final operations of using the pouch stricto sensu 1 placing the biopharmaceutical product or device there for the desired purposes

^■ and at one or more places (fixed or mobile), intermediate storage, transport, handling or other operations, which may extend over a long period of time, for example several months or even years, with regard to storage .

In order to identify the integrity or non integrity of the pouch stricto sensu 1 at any desired moment after its manufacture and at least just before its intended use, the process of implementing the pockets stricto sensu is modified, in accordance with the invention.

This process comprises, first of all, the production, at the place of manufacture, of an integrity indicator bag 2 comprising the pouch stricto sensu 1. We now describe a pocket 2 with integrity / non integrity indicator comprising a pocket stricto sensu 1 which is either a 3D pocket, as previously mentioned, or a 2D pocket, which is devoid of the gussets 4.

The bag 2 with integrity / non integrity indicator comprises, first of all the pocket stricto sensu 1, also designated "first envelope" 1.

In the bag 2 with integrity / non-integrity, the first envelope / pocket stricto sensu 1 is closed and empty of the product or biopharmaceutical device. Its first introduction means 7 and its first extraction means are in the closed state.

The bag 2 with integrity / non-integrity indicator then comprises a second outer envelope 8, the first envelope / pocket stricto sensu 1 being internal and intended to be placed in the second envelope 8. The second casing 8 has a wall 13 having most often several parts welded together along sealed welds. By "wall" 13 is meant both the single wall 13 and all of these wall parts, or each of them if there are several of them. The second envelope 8 is closed and sealed. It is preferably flexible, so that it can be flat for storage, transport, handling.

The wall 13 is made from one or more plastics, flexible if the second envelope 8 is flexible, non-porous so that the second envelope 8 is sealed as a whole. The wall 13 may be monolayer or multilayer. It can incorporate a high-capacity plastic gas barrier material, such as EVOH, this being only an example and not limiting.

The second envelope 8, namely its wall 13, has an inner face 8a and an outer face 8b. The terms "inside" and "outside" are understood in relation to what is located, respectively, in and out of the second envelope 8. The second envelope 8 delimits inside itself a second space 9, of which the limit is the inner face 8a and the volume is suitable to be able to receive the bag stricto sensu 1, then empty of the product or biopharmaceutical device.

The second envelope 8 comprises second insertion means 10 associated with the wall 13, with a view to the prior introduction, when desired, of the first envelope / pocket stricto sensu 1 in the second space 9. Such an introduction takes place for and during the realization of the pocket 2 with integrity / non integrity indicator. Such second insertion means 10 may be in the form of one or more passages arranged in the wall 13 to, when necessary, be brought or be in the open state and then be brought to the closed state , in particular by welding, once the first envelope / pocket stricto sensu 1 introduced in the second space 9.

The second envelope 8 also comprises second extraction means associated with the wall 13, with a view to extracting, when desired, the first envelope / pouch stricto sensu 1 from the second space 9. Such extraction occurs at the opportunity of, and before, the introduction of the biopharmaceutical product or device into the first space 6. Such second extraction means may be an irreversible tear or the like of the wall 13 of the second envelope 8, which is generally Disposable. In the bag 2 with integrity / non integrity indicator, the first envelope / pouch stricto sensu 1 is in the second space 9 of the second envelope 8, the second insertion means 10 and the second extraction means are are in the closed state.

Outside the first envelope / pocket stricto sensu 1 but inside the second envelope 8 is formed a space 14 called "intermediate space", located in the second space The boundaries of the intermediate space 14 are the outer face 1a of the first envelope / pouch stricto sensu 1 and the inner face 8a of the second envelope 8. The pocket 2 to the outside of the first envelope / pouch stricto sensu 1. The limits of the intermediate space 14 are Integrity / non-integrity indicator then comprises spacer means 1 1, housed in space 14, interposed between the wall 3, 4 of the first envelope / pouch stricto sensu 1 and the wall 13 of the second envelope 8. These spacer means 1 1 are adapted so that the inner face 8a of the wall 13 of the second envelope 8 does not obscure a possible outlet of non-integrity D on the outer face 1a of the wall 3, 4 of the first envelope / pouch stricto sensu 1 .

The spacer means 11 comprise one or more porous layers integrally covering the outer face 1a of the wall 3, 4 of the first envelope / pouch stricto sensu 1 and / or the inner face 8a of the wall 13 of the second envelope 8 and / or the face of a colorimetric detection layer 12 facing the intermediate space 14, which is returned thereafter.

A layer of the spacer means 11 is porous as a result of either a porous arrangement or the use of one or more porous materials. For example, the spacer means 11 comprise one or more porous layers of fabric, nonwoven fabric, PE, PP, PTFE or the like.

Here, the term "porosity" means that the spacer means January 1 comprise a multiplicity of interstices adjacent to each other, crossing from one side to the other the layer or layers which constitute the spacer means 1 1, of so that, on the one hand, any possible outlet of non-integrity D on the outer face 1a of the wall 3, 4 of the first envelope / pocket stricto sensu 1 is necessarily with respect to and in communication with at least one outlet of interstice and that, on the other hand, a gas, such as a tracer gas which is returned thereafter, can pass through the spacer means from one side to the other.

Here, the term "fully functional covering" means that the spacer means 1 1 extend over the entire surface of the external face 1 a, of the inner face 8 a, of the face of the colorimetric detection layer 12 facing the intermediate space 14, even if the spacer means 1 1 are not in contact with the face in question, provided that any possible outlet of non-integrity D on the face in question is prevented from being obscured by means of spacers 1 1 Four embodiments are envisaged with regard to the arrangement of the structure of the layer-shaped spacer means 11 with respect to the first envelope / pocket stricto sensu 1 and the second envelope 8. Where appropriate, these four embodiments may to be combined with each other. In a first embodiment (FIGS. 3B, 4B, 5B, 6B, 7B), the spacer means 1 1 in the form of a layer structurally cover the outer face 1a of the wall 3, 4 of the first envelope / pocket stricto sensu 1. In a second embodiment (FIGS. 3A, 4A, 5A, 7A), the spacer means 1 1 in the form of a layer structurally cover the inner face 8a of the wall 13 of the second envelope 8.

In a third embodiment (FIGS. 3B, 6A), the spacer means 1 1 in the form of a layer structurally cover the face of the colorimetric detection layer 12 facing the intermediate space 14.

In a fourth embodiment (FIGS. 3C, 4C, 5C, 6C, 7C, 8A, 8B, the spacer means 1 1 in the form of a layer are placed in the intermediate space 14. In this case, the term "structurally covering" means that the spacer means 1 1 extend in contact with the outer face 1a, the inner face 8a, the face of the colorimetric detection layer 12 facing the intermediate space 14, including that the spacer means 1 1 do structurally part of a wall or layer 3, 4, 13 and 12 inseparably or almost inseparably or similar manner.

In the case where the first envelope / pouch stricto sensu 1 is a 3D pocket, the layer-shaped spacer means 1 completely and functionally and, if appropriate, structurally cover the outer face of the inside of each of the two gussets 14 as well. The "external face" of which we are speaking here is understood as the external face 1 a. By "inside of a gusset" is meant the portion of the gusset adjoining the incoming fold. With a gusset 4, it would be possible, in the absence of spacer means such as spacer means 1 1, that the two outer faces of the two parts of the gusset 4 adjacent to the incoming ply come against each other and that a possible outlet of non-integrity D on one of the external faces is obscured by the other external face. Thanks to the presence of spacers 1 1 in each gusset 14, there is no risk of occultation because any occultation is prevented.

According to one embodiment, the layer-shaped spacer means 1 completely and functionally cover, if necessary structurally, the first introduction means 7 and the first extraction means of the biopharmaceutical product or device, as well as the introduction means. tracer gas 15 which is optionally provided with the first envelope / pocket stricto sensu 1.

The spacer means 1 1 in the form of a layer have a flexibility such that they can match the shape of the wall or layer 3, 4, 13 and 12, itself flexible. The integrity / non-integrity indicator bag 2 then comprises one or more tracer gases chosen and one or more colorimetric detectors 12 of this or these tracer gases adapted thereto or thereto. The tracer gas is either in the first space 6 of the first envelope / pouch stricto sensu 1, or in the intermediate space 14 of the second envelope 8, at a partial pressure different from the partial pressure it has in the intermediate space 14 or first space 6, respectively. This definition also includes the case where one of the first space 6 or of the intermediate space 14 contains tracer gas and the other of the intermediate space 14 or the first space 6 contains no trace gas or substantially no tracer gas , the partial pressure p being zero or almost zero.

The tracer gas is introduced into the first space 6 of the first envelope / pouch stricto sensu 1 and / or in the intermediate space 14 of the second envelope 8 by tracer gas introduction means 15, associated, respectively, with the first envelope / pocket stricto sensu 1 and / or the second envelope, namely, respectively, to the wall 3 and / or wall 13 corresponding. Such tracer gas introducing means may be a valve, a port, a closable port, or the like. The tracer gas introduction means 15 can be brought to the open state for the introduction of the tracer gas, if necessary its evacuation if this is desired. They can also be brought to the closed state, outside of these circumstances and in particular during the storage and transport of the pocket 2 with integrity / non integrity witness, when the process leading to identify the integrity or no integrity of the pocket 2 with integrity indicator / no integrity.

In the pocket 2 with integrity / non-integrity indicator, the tracer gas introduction means 15 are in the closed state,

Such a tracer gas may be selected from the group comprising oxygen, carbon dioxide, helium, this list being only exemplary and not limiting.

A colorimetric detector 12 of tracer gas comprises one or more continuous colorimetric detection layers of the tracer gas.

Such a continuous colorimetric detection layer 12 is responsive, that is to say sensitive, to the concentration of the tracer gas which reaches it by passing from a first color to a second color different from the first color, when the concentration in tracer gas reaching it passes a certain transition value. Such a transition value is known for each pair of tracer gas / continuous colorimetric detection layer 12.

Such a colorimetric detection layer 12 has the structural or functional structural feature of being an integral part of a wall 3, 4 of the first envelope / pouch stricto sensu 1 and / or of a wall 13 of the second envelope 8 and / or spacers means 1 1, according to the envisaged configurations. By this is meant that the colorimetric detection layer 12 is not located in the breast, that is to say in the middle of the first space 6 or the second space 9, except in the case where it is an integral part of spacer means 1 1 themselves located within the intermediate space 14.

The colorimetric detection layer 12 has a flexibility such that it can marry, as much as necessary, the shape of the wall or layer 3, 4, 13 and 1 1, itself flexible.

Such a colorimetric detection layer 12 forms an autonomous colorimetric detector, devoid of internal energy source and external connections.

The first color and the second color that the colorimetric detection layer 12 may have to differentiate from one another so that it is possible to identify whether the colorimetric detection layer 12 is of the first color or of the first color. the second color, without ambiguity or error. Such color identification can be human (through an outside observer) or more or less automated.

The integrity / non-integrity indicator pouch 2 which comprises the spacer means 1 1, the tracer gas and the colorimetric detection layer 12 is able to be flattened or substantially flattened on itself and thus easily adapted for storage, transport , to manipulation.

In one embodiment (FIGS. 3A, 3B, 3C, 4A, 4B, 4C, 5A, 5B, 5C, 6A, 6B, 6C, 8A, 8B), the tracer gas is in the first space 6 at a larger partial pressure P that the partial pressure p in the intermediate space 14. In this case, the colorimetric detection layer 12 passes from the first color to the second color in response to the passage of the tracer gas concentration which reaches it above the transition value.

In another embodiment (FIGS. 7A, 7B, 7C), the tracer gas is in the first space 6 at a partial pressure p smaller than the partial pressure P in the intermediate space 14. In this case, the colorimetric detection layer 12 passes from the first color to the second color in response to the passage of the tracer gas concentration which reaches it below the transition value.

It is understood that the presence and choice of the tracer gas and the pressure difference Pp thereof have no other function than to change the color of the colorimetric detection layer 12, depending on the presence or absence of a non-integrity outlet on the outer face 1a of the wall 3, 4. The quantity and the pressure of the tracer gas do not have to be important. The integrity / non-integrity indicator pocket 2 which comprises the two envelopes 1 and 8, the spacer means 1 1, the tracer gas and the colorimetric detection layer 12 may be flat for storage, transportation, handling . If the wall 3, 4 (including the welds 5) of the first envelope / pocket stricto sensu 1 is intact, the tracer gas remains in the initial state in which it was introduced into the pocket 2 with integrity indicator / no integrity, the initial pressure difference on either side of the first wall 3, 4 being maintained.

If the wall 3, 4 is not integral, as a result of one or more passages T passing through the first envelope / pouch stricto sensu 1, with one or more outlets D on the outer face 1a, the initial pressure difference of the gas tracer decreases with time, to the limit until disappearing, the tracer gas passing through the first envelope / pouch stricto sensu 1 through the passage (s) T and the outlet (s) D, in the direction from the enclosure where the partial pressure is greatest at the enclosure where the partial pressure is the smallest. The partial pressure of the tracer gas in the chamber where it has the largest partial pressure decreases and, simultaneously, the partial pressure of the tracer gas in the chamber where it has the smallest partial pressure increases.

The colorimetric detection layer 12 judiciously disposed is then reached by the tracer gas whose partial pressure and concentration vary (decrease or increase), so that, according to the arrangement, the concentration passes below or above the value of transition. In any case, the colorimetric detection layer 12 changes color, from the first color to the second color in response to the passage of the tracer gas concentration which reaches it below or above the transition value. .

Thus, if the colorimetric detection layer 12 is of the first color, it can be concluded that the first envelope / pocket stricto sensu 1 is intact and therefore is able to receive and protect the product or biopharmaceutical device. As part of the process of implementing a pocket stricto sensu 1, such a first envelope / pocket stricto sensu 1 can be used, that is to say first extracted from the second envelope 8, then open to introduce the biopharmaceutical product or device.

If, on the other hand, the colorimetric detection layer 12 is of the second color, it must be concluded that the first envelope / pouch stricto sensu 1 is unhealthy and therefore is unfit to receive and protect the biopharmaceutical product or device. As part of the process of implementing a pocket stricto sensu 1, such a first envelope / pouch stricto sensu 1 should not be used and in general it is immediately discarded and destroyed.

The arrangement of the integrity / non-integrity witness pocket 2 is chosen, in the first place, so that the colorimetric detection layer 12 can not be reached by tracer gas. found in the intermediate space 14 or in the first space 6 with a concentration passing the transition value, with the first envelope / pocket stricto sensu 1 integrates.

The layout of the bag 2 with integrity / non-integrity indicator is then chosen so that, and the colorimetric detection layer 12 is necessarily reached by tracer gas in the intermediate space 14 or in the first space 6 with a concentration passing the transition value, with a first envelope / pocket stricto sensu 1 not integrated,

The permeability or impermeability to the tracer gas of the colorimetric detection layer 12 and the spacer means 11 are therefore chosen so that the colorimetric detection layer 12 is effectively reached by tracer gas in the intermediate space 14 or in the first space 6 with a concentration passing the transition value, with a first envelope / pouch stricto sensu 1 not integrity.

Several particular arrangements are now described, from the bag 2 to the integrity / non-integrity witness, the particular arrangements described being only exemplary and non-limiting.

According to a first arrangement illustrated by FIGS. 3A, 3B and 3C, the colorimetric detection layer 12 is permeable to the tracer gas so that the tracer gas can reach it if the first envelope / pocket stricto sensu 1 is not integrated, and it makes integral part of the wall 3, 4 of the first envelope / pouch stricto sensu 1 being located on the outer face 1a thereof and in the intermediate space 14.

According to a second arrangement illustrated in FIGS. 4A, 4B and 4C, the colorimetric detection layer 12 is permeable to the tracer gas, so that the tracer gas can reach it if the first envelope / pouch stricto sensu 1 is unhealthy, and it is an integral part of the wall 3, 4 of the first envelope / pouch stricto sensu 1 being located on the inner face thereof and in the first space 6.

According to a third arrangement illustrated by FIGS. 5A, 5B and 5C, the colorimetric detection layer 12 is permeable to the tracer gas so that the tracer gas can reach it if the first envelope / pouch stricto sensu 1 is unhealthy, and is an integral part of the wall 3, 4 of the first envelope / pocket stricto sensu 1 being inserted into the thickness of the wall 3, 4, interposed between its outer face 1a and its inner face 1b and interposed between the first space 6 and the intermediate space 14.

According to a fourth arrangement illustrated in FIGS. 6A, 6B and 6C, the colorimetric detection layer 12 is an integral part of the wall 13 of the second envelope 8 being situated on the inner face 8a and in the intermediate space 14. According to a fifth arrangement illustrated by FIGS. 7A, 7B and 7C, the colorimetric detection layer 12 is an integral part of the wall 13 being inserted into the thickness of the wall 13, interposed between its inner face 8a and its outer face 8b. In this case, the layer 16 of the wall 13 of the second envelope 13 adjacent one side to the colorimetric detection layer 12 and the other side to the inner face 8a of the second envelope 8 is permeable to the tracer gas, so that the tracer gas can reach the colorimetric detection layer 12 of the first envelope / pocket stricto sensu 1 unhealthy. According to a sixth arrangement illustrated in FIG. 8A, the colorimetric detection layer 12 is an integral part of a porous layer of spacer means 11 being located towards the inner face 8a of the second envelope (8).

According to a seventh arrangement illustrated in FIG. 8B, the colorimetric detection layer 12 is an integral part of a porous layer of the spacer means 1 1 being located towards the outer face 1a of the wall 3, 4 of the first envelope / pocket stricto sensu 1 The tracer gas necessarily reaches the colorimetric detection layer 12, the spacer means 11 being porous, that is to say permeable to the tracer gas. According to a not shown variant of the sixth and seventh arrangements, a colorimetric detection layer 12 and a porous layer of the spacer means 11 are structurally combined to form a single same layer, instead of forming two distinct layers, even associated with each other. the other. With the structural or functional constructions described, it is possible to identify the integrity or non-integrity of a pouch stricto sensu 1 at any desired time after its manufacture and at least just before its intended use.

This can be done safely, easily, quickly, without the need for a dedicated heavy or complex device, or difficult or delicate operations, and without the need to have dedicated personnel dedicated to integrity control, and without the need of having to test the bag positively to ensure its integrity, the non-integrity being automatically revealed, and therefore without the need, when the bag is part of a plurality of pockets, have to test each pocket in a positive way.

This identification is performed by identifying the color of the colorimetric detection layer 12.

The second envelope 8 is designed to be able to identify from the outside of itself whether the colorimetric detection layer 12 is of the first color or the second color. As indicated, such identification can be humanly performed by an observer outside the integrity / non-integrity witness pocket 2. For this purpose, the second envelope 8 may be, depending on the embodiments, transparent or translucent or comprise a transparent or translucent window to observe the color of the colorimetric detector 12 located opposite or in the vicinity of this window.

According to one possible embodiment, illustrated in FIG. 1, there is further provided an outer protective overpack 16 in which is housed the pocket 2 with integrity / non integrity witness, the first envelope / pouch stricto sensu 1 being then in the second envelope 8.

The invention relates to the pocket 2 to integrity / non integrity witness as it has been described, and as it was performed.

The invention also relates to such a pocket 2 integrity / non integrity indicator which is integral, the colorimetric detection layer 12 being of the first color.

The invention also relates to a pouch stricto sensu 1 integrates, intended to receive and protect a product or biopharmaceutical device. Such a pouch stricto sensu 1 integrates is constituted by the first envelope / pocket stricto sensu 1 extracted from a pocket 2 integrates integrity / non integrity witness, that is to say whose colorimetric detection layer 12 is the first color.

The invention also relates to a method for producing a pocket 2 to integrity / non integrity witness as it has been described.

At the base, there is a first envelope / pouch stricto sensu 1, a second envelope 8, the second insertion means of the first envelope / pouch stricto sensu 1 are in the open state, spacer means 1 1, of tracer gas, the colorimetric detection layer 12 forming an integral part of a wall 3, 4 of the first envelope / pouch stricto sensu 1 and / or a wall 13 of the second envelope 8 and / or spacer means 1 1, as has been described.

Then, the first envelope / pocket stricto sensu 1 is introduced into the second space 9 of the second envelope 8 via the second introduction means in the open state, the spacer means 1 1 being interposed between the wall 3, 4 and the wall 13 so as to fulfill their function of non-occlusion as has been described.

Then, the tracer gas, either in the first space (6) or in the intermediate space (14), is introduced at a partial pressure different from that of the intermediate space (14) or the first space (6), respectively, via the tracer gas introduction means 15, which are then in the open state. These tracer gas introducing means 15 are then brought into the closed state.

The arrangement of the bag 2 with integrity / non-integrity control is chosen so that the colorimetric detection layer 12 can not be reached or, on the contrary, is necessarily reached by tracer gas, as has been previously described and one chooses consequently, the permeability or the impermeability to the tracer gas of the colorimetric detection layer 12 and the spacer means 11 so that the colorimetric detection layer 12 is effectively reached by tracer gas when this is necessary.

Finally, the first envelope / pouch stricto sensu 1 and the second envelope 8 are closed.

The invention also relates to a method for obtaining a bag stricto sensu 1 integrates and thus ready to receive and protect a biopharmaceutical product or device without any possible deterioration of origin outside the pocket stricto sensu 1, such as a contamination .

Basically, there is a pocket 2 with integrity / non integrity witness as described.

At any time desired after its manufacture and at least just before the intended use of the pouch stricto sensu 1, it is identified whether the colorimetric detection layer 12 is of the first color or the second color.

If the colorimetric detection layer 12 is of the first color, the second extraction means of the first envelope / pocket stricto sensu 1 which is provided with the second envelope 8 in the open state is extracted, the first envelope / pocket is extracted. stricto sensu 1 of the second space 9 of the second envelope 8, and the first means 7 for introducing the biopharmaceutical product or device is provided, which is provided with the first envelope / pouch stricto sensu 1 considered as integral, in the open state in order to to place the biopharmaceutical product or device. If, on the other hand, the colorimetric detection layer 12 is of the second color, the first envelope / pouch stricto sensu 1 is not retained for the purpose of placing the biopharmaceutical product or device therein, the first envelope / pouch stricto sensu 1 being considered to be unhealthy. The process of implementing a pouch stricto sensu 1 which, if it is integral, is intended to receive and protect a biopharmaceutical product or device, comprising at a place of manufacture, initial operations, at a place of use, final operations and on one or more places, intermediate operations is as it is now described. The process comprises producing, at the place of manufacture, an integrity / non-integrity indicator bag 2 comprising a pouch stricto sensu 1, by the production method as previously described. The process also includes transporting the integrity / non-integrity witness bag 2 from the place of manufacture to the place of use, with storage and handling operations where appropriate.

The process finally includes, at least at the place of use and before - especially just before - extracting the first envelope / pouch stricto sensu 1 of the second envelope 8 in order to place the product or biopharmaceutical device therein. identifying that the colorimetric detection layer 12 is of the first color or the second color.

As it follows from the foregoing description, if the colorimetric detection layer 12 is identified with the first color, the process then comprises the use of the pouch stricto sensu 1 considered as integral with a view to placing the product therein or biopharmaceutical device to receive and protect it.

If, on the other hand, the colorimetric detection layer 12 is identified with the second color, the process consists in not using the bag stricto sensu 1, which is considered to be unintegrated in that it is incapable of receiving and protecting a biopharmaceutical product or device. . The pocket stricto sensu 1 is then discarded and most often destroyed.

Where appropriate, the identification that the colorimetric detection layer 12 is of the first color or the second color is performed in masked time, during intermediate operations of storage, transport, manipulation.

Claims

1. Sterilizable biopharmaceutical packaging (1), capable of enclosing a biopharmaceutical content to be sterilized, comprising:

An outer wall (3) that is flexible and impervious to gases and pathogenic germs,

^■ a (6) insertion opening from the outside towards the inside of the package (1) of the biopharmaceutical contents to be sterilized, adapted thereafter to be sealed,

^■ an internal space (2) adapted to receive the biopharmaceutical contents,

^{A feed} passage (7) for sterilization gas from outside the package (1), comprising at least one upstream feed port (8) adapted to be associated in communication (10) with a source of sterilizing gas, at least one downstream distribution port (9) of sterilization gas opening into the interior space (2), and a communication (10) between the upstream supply port (8) and the downstream distribution port (9)

^■ the insertion opening (6) being separate from the feed passage (7) and directly adjacent to the interior (2),

^■ and means (12) for controlling the sterilization gas distribution in the interior (2) being means (12) opening / closing the inlet passage (7),

characterized by the fact that:

^{The feed} passage (7) includes at least one surface-permeable sterilization gas permeable membrane (9) forming a downstream distribution orifice (9) for sterilization gas distributed on the surface of the membrane (9), the membrane (9) forming part of the envelope of the interior space (2) and constituting a filtration means adapted to retain any pathogenic germs,

^■ the means (12) for opening / closing the supply passage (7) being either a closure member or the outer wall (3) folded on itself and sealingly sealed,

After sterilization, the outer wall (3), the feed passage (7) for sterilization gas and the opening / closing means (12) remain integral with each other so as to form a biopharmaceutical packaging (1). ) sterilized enclosing the sterilized biopharmaceutical content capable of undergoing one or more differential pressure type integrity tests requiring gas tightness of the package, at any desired time after sterilization.

2. sterilizable biopharmaceutical packaging (1) according to claim 1, wherein a membrane (9) permeable to the sterilization gas is distinct from the outer wall (3) of the package (1) and attached to it, in it and secured to it sealingly, the outer wall (3) having an upstream feed port (8) of sterilization gas limited by a ferrule (1 1), a communication (10) existing between the upstream feed port ( 8) and the membrane (9).

Sterilizable biopharmaceutical packaging (1) according to claim 2, in which the membrane (9) permeable to the sterilization gas extends substantially opposite the upstream feed orifice.

The sterilizable biopharmaceutical package (1) according to claim 2, wherein the sterilization gas permeable membrane (9) extends over at least substantially the entire length of the outer wall (3) of the package (1).

5. sterilizable biopharmaceutical packaging (1) according to any one of claims 2 to 4, wherein the means (12) for opening / closing is a closure member mounted movable or removable on the shell (1 1) of the upstream feed port (8) for sterilization gas.

The sterilizable biopharmaceutical package (1) according to claim 1, wherein a membrane (9) permeable to the sterilization gas is constituted by a permeable zone of the outer wall (3) of the package (1) belonging to a deployable part. / folding of the outer wall (3) of the package (1) and forming the supply passage (7) sterilization gas, this deployable / foldable portion being adapted to be deployed so that the supply passage (7) sterilization gas is opened or folded on itself towards the inside of the package (1) so that the feed passage (7) of sterilization gas is closed.

7. sterilizable biopharmaceutical packaging (1) according to claim 6, wherein the portion of the outer wall (3) of the package (1) adapted to be in the deployed state or in the folded state on itself inwardly is a longitudinal bellows (14) of the outer wall (3).

8. sterilizable biopharmaceutical packaging (1) according to claim 6, wherein the portion of the outer wall (3) of the package (1) adapted to be in the deployed state or in the folded state on itself inwardly is a transverse end portion (22a, 22b) of the outer wall (3).

9. sterilizable biopharmaceutical packaging (1) according to any one of claims 6 to 8, wherein the means (12) for opening / closing are constituted by the outer wall (3) itself, the deployable part / foldable where the sterilization gas permeable zone is located, is interposed between two side collateral parts (19a, 19b) located on either side of the deployable / foldable part, so that when the deployable / folding part is folded on itself inwardly of the package (1), the two collateral parts (19a, 19b), then located opposite each other and close to each other, are able to be sealed. to each other at their outer periphery (20) in a sealed manner, around the zone permeable to the sterilizing gas, so as to prevent the sterilizing gas from accessing the permeable zone.

The sterilizable biopharmaceutical package (1) according to any one of claims 1 to 9, wherein the inner space (2) extends over substantially the entire length of the sheath-shaped outer wall (3), and wherein the introduction opening (6) of the biopharmaceutical content to be sterilized is located at one end of the outer wall (3) in the form of a sheath.

A sterilizable biopharmaceutical package (1) according to any one of claims 1 to 10, wherein the at least one upstream gas feed port (8) and the feed opening (6) of the biopharmaceutical content to sterilize are separated from each other.

Sterilizable biopharmaceutical packaging (1) according to any one of claims 1 to 1 1, which also comprises at least one gas inlet / outlet nozzle, mounted on the outer wall (3), in communication (10) with the interior space (2), adapted to be brought to the open state or in the closed state by actuating shutter means, so as to make it possible to enter or remove from the interior space (2 ), a functional gas.

The sterilizable biopharmaceutical package (1) according to any one of claims 1 to 12, also comprising an opening defined by an annular flange on which is mounted a mobile or removable aseptic transfer means, such as a movable or removable door of Aseptic transfer type double door.

The sterilizable biopharmaceutical package (1) according to claim 13, wherein the movable or removable aseptic transfer means cooperates with the introduction opening (6) and is adapted to ensure the closure of this introduction opening (6). tightly.

15. sterilizable biopharmaceutical packaging (1) according to claim 13, wherein the movable or removable aseptic transfer means cooperates with a portion of the outer wall (3) separate from the membrane (9) permeable to the sterilization gas so as to form a secondary opening that can be opened and sealed.

16. A method of implementing a sterilizable biopharmaceutical package (1) according to any one of claims 1 to 15, for enclosing and sterilizing a biopharmaceutical content, wherein:

^There is such a package (1), empty of biopharmaceutical contents, and whose opening opening (6) is open,

■ the biopharmaceutical content to be sterilized is available,

^■ there is a source of sterilization gas,

^■ via the introduction opening (6), the biopharmaceutical content to be sterilized is introduced directly into the receiving interior space (2),

^■ then, we close the introduction opening (6) sealingly,

And then, while the supply passage (7) of sterilization gas is open, the sterilization gas is brought from the source of sterilization gas into the receiving space (2) where the biopharmaceutical content is located. to sterilize, so as to sterilize the biopharmaceutical content,

^And then, the means (12) for opening / closing being implemented is either a closure member or the outer wall (3) folded on itself and sealed so as to close the feed passage (7) for sterilizing gas, feed passage (7) for sterilization gas and means (12) for opening / closing remaining integral with each other,

^■ and thus forms a biopharmaceutical package (1) enclosing the sterilized sterilized biopharmaceutical contents can undergo one or more of the type with applicant differential pressure integrity testing tightness to the packaging gas, at any desired time after sterilization.

The method of claim 16, wherein:

^■ one has a biopharmaceutical package (1) according to claim 2, with a membrane (9) permeable to sterilizing gas separately from the outer wall (3) and has means (12) opening / closing being a closure member,

^■ and, after the biopharmaceutical contents have been sterilized, it implements the occluding member to a shell (1 1) of the upstream supply port (8) sterilization gas so as to close the passage supply (7) of sterilization gas.

18. The method of claim 16, wherein:

^■ one has a biopharmaceutical package (1) according to claim 6, with a membrane (9) permeable to the sterilizing gas formed by a permeable region of the outer wall (3) of the package (1) belonging to a party deployable / foldable, and there are means (12) for opening / closing constituted by the outer wall (3) whose deployable / foldable portion is interposed between two collateral sealed parts,

^■ and, after the biopharmaceutical contents have been sterilized, is folded deployable / collapsible section on itself towards the inside of the package (1) so that both sides collaterals are located vis-à-vis and close to each other, and sealed to one another at their outer periphery in a sealed manner, around the zone permeable to the sterilizing gas, so as to close the feed passage ( 7) sterilization gas.

19. A method according to any one of claims 16 to 18, wherein, once the sterilization is done, the outer wall (3), the supply passage (7) of sterilization gas and the means (12) are secured to each other. ) opening / closing so as to form the sterilized biopharmaceutical package (1) enclosing the sterilized biopharmaceutical content.

20. The method of claim 19, wherein, once the sterilization is done, the biopharmaceutical package (1) is not divided into several sections.

21. A method according to any one of claims 16 to 20, wherein, at any desired time after sterilization, sterilized biopharmaceutical packaging (1) enclosing the sterilized biopharmaceutical content is subjected to one or more blood integrity tests. type requiring gas tightness of the package (1).

22. sterilized biopharmaceutical packaging (1) enclosing a sterilized biopharmaceutical content characterized in that it is obtained by the implementation of the method according to any one of the Claims 16 to 21, the package (1) also having an extraction opening from the inside to the outside of the package (1) the sterilized biopharmaceutical content, sealed and subsequently able to be opened in order to extract the biopharmaceutical content from the interior space (2).