Aseptic sampling device

Abstract

The invention relates to an aseptic sampling device, comprising: - a sampling means (1) arranged to aseptically sample a raw material (2) contained in a first container (3) of a predetermined volume, and - a receiving chamber (4) which has a confinable space (5) and is arranged to enable decontamination of said receiving chamber by passing at least one fluid into said confinable space (5), said receiving chamber (4) being provided with a sealable opening (6) and an accommodating means (7) that can be oriented in the confinable space (5).

Description

[0001]ASEPTIC SAMPLING DEVICE The present invention relates to an aseptic sampling device arranged to allow proliferation of a raw material (in a culture medium) or to allow cell or microbial culture. Generally, sampling devices are used in the pharmaceutical industry or in the field of biotechnologies to collect and transfer a raw material that can proliferate in a culture medium. This raw material is often in solution, suspension, emulsion or even in the form of a supernatant or plasma. It is thus collected from a container, for example by means of a syringe or a pipette, and possibly transferred to another container in order to allow proliferation in a culture medium. Thus, the raw material can be collected and transferred from one container to another depending on the intended purpose in the technical field considered. InIn certain fields of application such as those mentioned above, it is necessary that the raw material can be removed from one container aseptically and possibly transferred aseptically to another container, particularly when a culture (cellular or bacterial) is planned. These means of removal represent one of the keystones of these pharmaceutical and biotechnology industries since they are part of the first step of the process. This step is crucial since it requires being able to remove and transfer a raw material aseptically, which conditions the rest of the process. More precisely, the aseptic removal of a raw material is crucial in different fields of application, in particular as soon as a raw material is predisposed to being able to proliferate in a culture medium. This is commonly called "cell reproduction / amplification" or "bacterial culture". Among theseIn culture, the skilled person also knows how to culture infectious agents. Another example relates to human mesenchymal stem cells (hMSCs) which are multipotent cells that can also proliferate (like undifferentiated cells). These can differentiate into different types of cells such as bone marrow, cartilage, tendon, muscle or even neuronal cells. hMSCs have numerous therapeutic benefits and are the subject of several research projects, such as cell therapy or tissue regeneration. Another example where the reproduction of a raw material can be judicious concerns the field of cellular immunotherapy, the treatment of which consists of producing CAR-T cells (in English: "Chimeric Antigenic Receptor - T") which aims to fight cancer by relying on the patient's own immune system. Once produced, the CAR-T cells are multiplied in theintended to be administered to the patient. In addition, culture can allow vaccine production or even an application in the field of gene therapy. Nowadays, cell or bacterial reproduction or the culture of infectious agents constitutes a major asset in the development of the biotechnology sector, to name just a few examples. Typically, cell or infectious agent culture can be carried out by collecting the raw material in small preservation containers. These preservation containers can be ampoules or cryotubes for cells, which are generally stored at very low temperatures (between -70 °C and -196 °C). This process, called cryopreservation, allows most biological activities and chemical reactions to be suspended and thus their contents to be preserved. It is obvious that in the case of dilution of the raw material or formulation, a temperature between -4 °C androom temperature will be sufficient. Cells or infectious agents are generally transferred to larger containers, where environmental conditions are present that are conducive to their growth and reproduction. These culture containers can be petri dishes, flasks containing culture medium or bioreactors containing culture medium. This makes it possible to obtain a large quantity of cells or infectious agents from a small volume in order to enable the production of molecules, drugs, vaccines, genetically modified organisms or the implementation of gene therapy to treat certain genetic diseases. It is conceivable that the protocol for collecting and culturing cells or infectious agents in the pharmaceutical industry or in the field of biotechnology is relatively demanding given that the collection step constitutes the very first step forallow efficient cultivation and free of unwanted germs and bacteria in the culture medium. However, currently, the raw material is extracted manually with a syringe in a chamber under laminar flow. The user disinfects the preservation container (bottle) with an alcohol wipe, for example, and can then open the glass container, for example by breaking the head, to manually collect the suspension using a syringe, which is then transferred to another container, for example for cultivation. With this type of handling, it cannot be excluded that the user contaminates the environment around the solution to be collected, especially when it is in contact with this environment. The use of laminar flow cannot completely exclude the absence of specific and biological contamination due to its design. Unfortunately, each of the steps explained above(decontamination, opening, sampling and transfer) is conducive to the introduction of contaminants. Thus, a poorly decontaminated surface, a human error in handling or a failure in the laminar flow device lead to contamination. The latter result in significant delays and additional costs, the culture then becoming unusable. In a market, often with just-in-time production, it is increasingly difficult to ensure that all these steps are carried out aseptically. Also, the use of laminar flow in a suitable box is expensive for the user and does not guarantee safe and systematic aseptic sampling in the context of industrial production. In addition, these methods can present significant risks for the handler who may be exposed to highly contagious and pathogenic infectious agents during the various handling operations. For these reasons, there is a real need forto be able to ensure aseptic sampling that is reliable, efficient, simple and fast, while reducing the risks of exchange of contaminants from the user to the solution / suspension to be sampled or vice versa. There is therefore a real need to provide a device that makes it possible to sample a raw material from a first (preservation) container easily, efficiently and reliably, while limiting as much as possible the risks of contamination as mentioned above. To solve this problem, the present invention provides an aseptic sampling device for proliferation of a raw material (2) (in a culture medium) or for cellular or microbial culture, the device comprising: - A sampling means (1) of a raw material (2), preferably in solution, arranged to proliferate in a culture medium, said sampling means (1) being arranged to aseptically sample the raw material (2) which is containedin a first container (3) of a predetermined volume, and - A receiving chamber (4) which has a confinable space (5) and which is arranged to allow decontamination thereof by the passage of at least one fluid in said confinable space (5), said receiving chamber (4) being provided with: o a closable opening (6) arranged for passage of said first container (3) in said confinable space (5), and when it is closed, is arranged to confine the receiving chamber (4), o a receiving means (7) orientable in the confinable space (5) and being arranged to receive said first container (3) and position it in the direction of said sampling means (1), the latter being arranged to aseptically collect said solution (2) contained in said first container (3) and arranged to transfer it aseptically to a second container (8) having a volume greater than the volume of said first container (3). THEDevice according to the present invention makes it possible to collect a raw material (2), preferably in solution, from a first container (3) (preferably for preservation) of a predetermined volume, in an aseptic manner. This makes it possible to minimize as much as possible the risks of contamination of both the raw material (2) (in solution) to be collected and the user of the device, with attractive production yields. The device has the advantage of being a single-use device, simple to use and less expensive than current solutions, in particular those requiring the use of a box under laminar flow. The device according to the invention is portable, which facilitates its implementation on site (industrial). Also, the device according to the invention is configured so as to be selectively confinable. Indeed, the receiving chamber (4) can be confined by closing the closable opening (6), by a closing element, byexample using a stopper, a membrane, a septum, a valve, etc. This makes it possible to choose when the device must be confined or not depending on the handling step. When the receiving chamber (4) has a confined space (5), it is also in an aseptic environment. According to the device of the present invention, the sampling means (1) can be located either in the confinable space (5) and therefore in the receiving chamber (4), or outside the receiving chamber (4). In the first case, the confinable space (5) extends to the sampling means (1). Thus, the receiving chamber (4) and the sampling means (1) can then be confined by closing the closable opening (6), by a closing element, for example using a stopper, a membrane, a septum, a valve. This makes it possible to choose when the device must be confined or not depending on the handling step. The sampling means (1) andthe receiving chamber (4) can thus be confined and in an aseptic environment. Alternatively, the device according to the present invention also covers the possibility of having the sampling means (1) which is located next to (adjacent to) the confinable space (5), i.e. outside the receiving chamber (4). The sampling means (1) then forms a first confined part of the device of the present invention and the receiving chamber (4) forms the second confinable part of the device according to the invention. The sampling means (1) being preferentially directly (arranged to be) connected (in fluid communication) to the receiving chamber (4) or indirectly connected thereto by means of an intermediate (fluidic) connection element. The device according to the invention may comprise several parts. This alternative option provided by the device according to the invention also makes it possible to selectively confine certain parts of the device. Thus, thesampling means (1) is located in a confined and sealed space (the first part), adjacent to that of the receiving chamber (4) which is located in the second confinable part of the device. In this embodiment, it is then possible to confine or not the receiving chamber (4), while maintaining the sampling means (1) in a confined and sealed space throughout the handling and according to the needs. Preferably, fluid communication is therefore possible between the receiving chamber (4) and the sampling means (1) according to this alternative mode. Thus, the receiving chamber (4) can be confined by closing the closable opening (6), by a closing element, for example using a plug, a membrane, a septum, a valve, etc. These embodiments, which can be combined with each other, offer flexibility to the user, which is particularly advantageous. The receiving chamber of the device according to the invention can also bedecontaminated at any time easily and efficiently. Thus, the device according to the present invention provides a closed (confined) system which allows both the collection and aseptic transfer of a raw material (2) which can proliferate in a culture medium. In view of the above, the collection device of the present invention provides an effective, simple and reliable solution for aseptically collecting (and possibly transferring) a raw material (2) which is arranged to proliferate in a culture medium. In a preferred embodiment according to the present invention, said collection means (1) is adjacent to said confinable space (5) of said receiving chamber (4) before collection, and is preferably in a confined and sealed environment. This mode makes it possible to facilitate the collection of the raw material (2) and effectively ensure aseptic collection. The collection means is preferably locatedoutside the receiving chamber (4) before sampling. The sampling means (1) then advantageously forms a first confined part of the device of the present invention and the receiving chamber (4) forms the second confinable part of the device according to the invention. The sampling means (1) being preferably directly (arranged to be) connected to the receiving chamber (4) or (arranged to) be indirectly connected to the latter by means of an intermediate (fluidic) connection element. The device according to the invention may comprise several parts. This alternative option provided by the device according to the invention makes it possible to more selectively confine certain parts of the device. Thus, the sampling means (1) is located in a confined and sealed space (the first part) relative to the receiving chamber (4) and adjacent to it (second part of the device). In this embodiment, it is then possible to confine or not thereceiving chamber (4), while maintaining the sampling means (1) in a confined and sealed space throughout the handling and as required. Preferably, fluid communication is established between the receiving chamber (4) and the sampling means (1) according to this advantageous mode. Thus, the sampling means (1) can be confined independently of the confinable space (5) of the receiving chamber (4). This makes it possible to reduce the possible risks of contamination and to allow careful control of the sampling means (1) and the confinable space (5) of the receiving chamber (4). Also, the sampling means (1) is in an aseptic environment. Thus, the receiving chamber (4) can be confined by closing the closable opening (6), by a closing element, for example using a plug, a membrane, a septum, a valve, etc. This flexibility offered to the user is particularly advantageous. In a mode ofpreferred embodiment according to the present invention, said sampling means (1) is separated from the receiving chamber (4), preferably by a reclosable element (9) chosen from the group comprising a septum, a membrane and any other equivalent element which allows opening and closing in a sealed manner, while ensuring aseptic sampling. A solenoid valve could also be used under these preferred conditions. A reclosable element (9) makes it possible to isolate the receiving chamber (4) from the sampling device (1) and at the same time facilitates access to the confinable space (5). This makes it possible to further reduce the risks of contamination. It is also possible to carry out several rinses and / or decontaminations of the space (5) when it is confined. A fluid communication between the sampling means (1) and the receiving chamber (4) is preferably established in order to facilitate the sampling of the raw material (2). The preceding paragraphs andThe related description relating to the embodiment in which the sampling means (1) is adjacent to the receiving chamber (4) are also applicable here. Preferably, during said sampling, a part of said sampling means (1) is located in the confinable space (5) of the receiving chamber (4). This makes it possible to sample the raw material (2) from the first container (3), while limiting the time and the degree of exposure of the sampling means (1) in the confinable space (5). More specifically, this embodiment is carried out when the space (5) of the receiving chamber (4) is confined and sealed with respect to the external surrounding environment. It is preferable to avoid any introduction of the sampling means (1) into the confinable space (5) of the receiving chamber when the latter is open to the surrounding environment. More preferably, the sampling means (1) is located in a sampling chamber (11) which has a guide means (12)of said sampling means (1). This makes it easier to guide the sampling device (1) in order to facilitate handling during sampling. Advantageously, said guide means (12) is arranged to move said sampling means (1), preferably, along a median axis of said sampling chamber (11) towards said receiving chamber (4). This makes it even easier to guide the sampling device (1) in a predetermined sampling direction. According to a particularly preferred embodiment, the sampling chamber (11) has a flexible body (11a) which has a rest position and a sampling position. Thus, when the flexible body (11a) is in the rest position, the entire sampling means (1) is located in the sampling chamber (11). When the flexible body (11a) is in the sampling position, the sampling means (1) is moved into the confined space (5) of the receiving chamber (4) tobe in contact with the raw material (2) to be sampled (in solution). When the sample is taken, the flexible body (11a) is arranged to return to the rest position. By a pumping or suction or piston system or any other sampling system which guarantees aseptic sampling, the raw material (2) can preferably be sampled and transferred to the second container (8). The latter may comprise a culture medium which will be mixed with the raw material (2) so as to allow amplification of the raw material (2). Alternatively, this flexible body (11a) can also be a piston which also makes it possible to provide a confined environment in which the sampling means is located. The operation indicated above is then similar with regard to the rest and sampling positions. Advantageously, the guide means (12) has a groove (12a) which extends longitudinally on an outer surface (12b) of saidguide means (12a) for sliding said sampling means (1) so that one of the ends (1a) of said sampling means (1) is introduced into said receiving chamber (4). Even more advantageously, said sampling means (1) has a body (13), preferably a pump body (13), arranged to allow the passage of said raw material (2) and which is provided at one of its ends with a needle (14) or a conduit. The presence of a needle (14) or a conduit allows the sampling means (1) to be easily inserted inside the first container (3), and therefore constitutes a means which allows a fluid to pass, for example by suction. The needle will be preferred for its efficiency because it ensures simple aseptic sampling. Preferably, therefore, the needle (14) can be replaced by a conduit which would allow efficient sampling and transfer. Indeed, the needle or the conduit has a rather passive rolein the device since it does not ensure the removal of the raw material (2) but rather allows easy and efficient access to the bottom of the first container (3) (vial). Any other equivalent means would also be suitable. Note that the needle will be preferred for its efficiency. This type of handling can thus be used to allow sampling in an aseptic manner in a closed / confined system (provided by the device according to the invention). Alternatively, the sampling means (1) is located in a confined and sealed environment and the receiving chamber (4) in a separate confinable space (5). In a preferred embodiment according to the present invention, said sampling chamber (11) is confined and sealed. This embodiment makes it possible to provide the sampling means (1) with an environment isolated from that of the confinable space (5) of the receiving chamber (4). Thus, when the receiving chamber (4) is open, the receiving chamber (4)sampling (11) (and the sampling means (1)) remains confined and sealed, which provides freedom of action when handling the device, while avoiding any contamination of the sampling means (1). In addition and preferably, the receiving chamber (4) has at least part of its surface made of flexible material (15), said part possibly being adjacent to said receiving means (7), which is arranged to pass through said at least one part (15) of the surface of the receiving chamber (4) made of flexible material. The flexible part (15) makes it possible to ensure that the receiving means (7) can be oriented following easy handling and, preferably throughout the confinable space (5). This part made of flexible material (15) advantageously allows a rotational movement, pivoting and / or a longitudinal movement of the receiving means (7). This means that it is not excluded that the receiving chamber (4) has part of its surface made of flexible materialrigid which is slightly flexible relative to the part made of flexible material. It is preferred to have a receiving chamber (4) which has a part of its surface which is deformable in space (part made of flexible material) and another part which is less so (part made of rigid material) in order to be able to offer a certain support for a part of the elements of the receiving chamber (4). According to an advantageous embodiment, the device according to the invention comprises a second container (8) adjacent to said receiving chamber (4) and which is connected by said sampling means (1) to said receiving chamber (4). Thus, the second container (8) is in fluid communication with the sampling means (1), which makes it possible to transfer the raw material (2) to this second container (8) which contains a culture medium suitable for cellular reproduction or any other type of amplification of a raw material (2). Advantageously, a fluid communication canbe established between the second container (8) and the sampling means (1) and the receiving chamber (4) selectively to minimize the presence of contaminants during handling. Preferably, said second container (8) has a volume greater than that of the first container (3), said second container (8) being arranged to allow culturing (amplification of a raw material (2)), when said sampled solution (2) from said first container (3) is transferred into said second container (8). This makes it possible, from a small container (3), to inoculate a larger container (8), to allow amplification of the raw material (2), in particular cellular reproduction. In a preferred embodiment according to the present invention, the receiving means (7) has a first part (7a) which extends into said confinable space (5) and a second part (7b) which extends outside said receiving chamber (4) under theform of a guide means (10), preferably along a median axis which passes through said receiving chamber (4). This allows the user to easily manually or automatically guide the receiving means by orienting this second part which is in the form of a guide means (10) outside the receiving chamber (4), without risk of contamination. Even more preferably, the part in the form of a guide means (10) is in fluid communication with said receiving chamber (4). This makes it possible to connect a fluid evacuation means (18), for example by connecting a conduit to one of the ends of this second part in the form of a guide means (10). Access to the receiving chamber (4) is thus facilitated. This access is located along a median axis of the receiving chamber (4), preferably opposite the closable opening (6). The receiving chamber (4) is advantageously arranged to be (or is) in fluid communicationwith at least one of the following elements or taken in combination: - A means for supplying at least one decontamination fluid (16) - A means for supplying at least one rinsing fluid (17), - A means for supplying at least one drying fluid (19), - A first means for discharging at least one fluid (18), said discharge means (18) being optionally directly connected to one of the ends (7c) of said receiving means (7), - And a second means for discharging drying fluid (20). In this way, the receiving chamber (4) can be prepared before receiving the first container (3) in order to ensure that the confinable space (5) can allow aseptic sampling when the opening (6) is closed after introduction of the first container (3) into the confinable space. This preferred embodiment implies that the receiving chamber (4) can be in fluid communication with at least one of the aforementioned elements (16, 17, 18, 19, 20). Preferably, the chamberreceiving chamber (4) comprises an opening means (22) for opening the first container (3), the opening means is preferably located in the confinable space (5). The opening means (22) is arranged to allow access to the raw material (2) of the first container (3). The opening means (22) can for example break one of the ends of the first container (3) (container which can be made of glass) or unlock / unscrew easily a cap, or even uncap the first container (3). This additional option linked to the presence of said opening means (22) thus allows access to the raw material (2) contained in any type of container (3), in particular when the first container (3) is housed in the receiving chamber (4). In a particularly preferred manner, said receiving means (7) is molded in a single piece. Also, the receiving means can be machined from a block of plastic or metal material. The device according to the invention can for examplebe manufactured by a 3D printing process or by molding involving the use of a series of molds. In a preferred embodiment according to the present invention, the device is a single-use device, preferably portable. In a preferred embodiment according to the present invention, the first container (3) has a volume of less than 20 ml, preferably less than 15 ml or greater than 2 ml. The first container (3) is preferably chosen from the group consisting of an ampoule, a cryotube, a vial (which may come from the company Aseptic Technologies). The material of the first container may be made of glass, plastic. Even more advantageously, the device according to the invention may operate using an automated or even robotic system. Other embodiments of the device according to the invention are indicated in the appended claims. Definitions The term "aseptic" refers to the conditions under whichsampling and transfer actions are performed. In the context of the present invention, a sampling device is provided which makes it possible to sample a raw material aseptically. In other words, each action which can be carried out using the device according to the invention is done aseptically, which makes it possible to keep the environment (for example the confined space) aseptic. This also applies to the sampling means which is arranged to sample and transfer the raw material aseptically. In the context of the present invention, the expression "raw material" includes the term strain or any other biological material which can proliferate in a culture medium. The "raw material" is preferably a solution, a suspension, an emulsion or in the form of a supernatant. The raw material is preferably chosen from the group comprising (consisting of) cells (of human or animal origin), bacteria,infectious agents, viruses, (living) (micro)organisms, yeasts, algae, prions, and mixtures thereof. Preferably, an ingredient or excipient that can be used in the composition of sterile solutions may also constitute the raw material. Preferably, the raw material may be in solid form and then dissolved before introduction into the device according to the invention or this dissolution is carried out when the container is introduced into the device according to the invention. All the characteristics of this paragraph may be combined with each other. By "(micro)organism" is meant all organisms invisible to the naked eye. This term includes bacteria, protozoa, microscopic algae, microscopic fungi. This definition also includes eukaryotic plant, animal or human cells, derived from tissues, cancerous or non-cancerous cell lines. Must also be included inthis definition all infectious agents, living or inert, such as viruses or prions. The aforementioned categories may be genetically modified. By "tight" we mean the ability to not allow fluids (liquids, gases), dust or even humidity to pass through. The expression "confinable space" must be understood to mean that the space can be confined, in relation to the external environment, in particular outside that of the receiving chamber or in relation to other surrounding compartments. This characteristic can be linked to the closable opening. Thus, when this opening is closed, the confinable space becomes confined and, preferably also watertight. It is therefore possible to have access to the confinable space by means of the closable opening which leaves a certain latitude to the user at the time of manipulations (manual or automatic). This confinable space is arranged to be decontaminated, in particular beforesampling or before introduction of the first container into the receiving chamber. The expression "first container" can be interpreted in the context of the present invention as "the (preservation) container" which contains the raw material to be sampled. Thus, this type of first container can be present in large quantity (in series). A plurality of first containers can therefore be the subject of the present invention in view of the disclosed embodiments. Thus, several containers can be present in the receiving chamber in order to operate the device in series or several first containers can be added individually, one after the other, in series. The expression "second container" relates to a type of amplification container. In other words, this type of container can also be present in large quantity (in series). This allows an amplification of the raw material, in particular a reproductioncellular. For example, a bioreactor can act as a second container and include a culture medium. As explained above, the pharmaceutical or biotechnology industry will use the sampling device according to the invention to sample and, possibly, transfer a raw material (2). The latter can proliferate in a culture medium. This raw material (2) can be in solution, or in suspension or even in the form of a supernatant. It is thus sampled from the first container (3) with the sampling means (1), and possibly transferred to a second container (8) in order to allow proliferation in a culture medium. This is commonly called "cell reproduction" or "bacterial culture". Among these cultures, those skilled in the art also know the culture of infectious agents, human mesenchymal stem cells (hMSC), CAR-T cells (in English: "Chimeric Antigenic Receptor – T") which are multiplied for the purpose of being administered to the patient. Furthermore, culturing can be used in the production of vaccines, in the field of gene therapy. According to the present invention, it is preferably possible to use a decontamination fluid chosen from the group comprising water, hydrogen peroxide, peracetic acid, and their mixtures. Advantageously, the drying fluid can be compressed air. Preferably, the rinsing fluid can be water. Thus, the device according to the invention is suitable for use in the context of cellular or bacterial reproduction or the culture of infectious agents, to name but a few examples. According to a preferred embodiment of the present invention, a first container (3) comprising at least one cell in solution (2) is introduced into the closable opening (6). The container is closed. Then, the receiving means (7) which is positioned along an axismiddle of the receiving chamber (4) is oriented towards the opening (6) and receives the first container (3) which is held stably in the receiving means (7). The opening (6) is closed using a closing element, such as a cap. Thus, the receiving chamber (4) is sealed, when the opening (6) is hermetically closed, which forms a confinable space (5) in the receiving chamber (4). The receiving chamber (4) is then decontaminated using a fluid. When the receiving chamber (4) is decontaminated, the first container (3) is oriented with the receiving means (7) towards the sampling means (1). The sampling means (1) is positioned inside the confinable space (5) until it reaches the bottom of the first container (3). It should be noted that the sampling means (1) is located in a confined environment before sampling. By a pumping system, the solution (2) is taken and transferred to a secondcontainer (8) which contains a culture medium. Advantageously, the material taken in solution is transferred aseptically to a second container (8) which has a volume greater than that of the first container (3). These steps can be carried out several times, that is to say by introducing several containers of the same type as the first container (3) in series into the receiving chamber (4). It should be noted that the first container (3) is intended to comprise a raw material (2) arranged to proliferate in a culture medium. The second container (8) is intended to contain culture medium and the raw material (2) contained in the first container (3). The volume of the second container (8) in the case of cell reproduction will preferably increase according to a complete amplification process (commonly called the "end to end" process) so as to increase the quantity of amplified material to the desired final volume. The aim beingto advantageously and ultimately provide an injectable solution, preferably in the pharmaceutical field or for biotechnological applications. According to a preferred embodiment, the device according to the invention is therefore arranged to allow the aseptic production of an injectable solution in the pharmaceutical field or for biotechnological applications. Alternatively, it is also possible to have a receiving chamber (4) which has several receiving means (7) so as to be able to take raw material (2) from several containers (3). The sampling device of the present invention allows sampling and possibly transfer of a raw material (2) which is arranged to proliferate in a culture medium in an aseptic manner. The aseptic sampling makes it possible to avoid any contamination of the contents of the first container by unwanted contaminants, such as germs of the microorganism type. This has the effectadvantage of being able to increase production yields, thanks to the limitation of waste of raw material (2) resulting from possible contamination. The device according to the present invention comprises a receiving chamber (4) which is sealed when the closable opening (6) is closed. The sealing prevents fluids (liquids or gases), dust and humidity from passing through. This thus aims to create a confined space (5) relative to the surrounding environment, external to the receiving chamber (4), and possibly external to the sampling means (1). It should be noted that the user can be replaced by an automatic, robotic system which makes it possible to dispense with the presence of the latter. Also, said receiving means (7) is orientable in the confinable space (5), which allows it to be oriented as desired in the confinable space (5). This thus advantageously makes it possible to position the receiving means (7) facing the closable opening (6), to orient thisfirst container (3) towards the sampling device (1), or even more preferably to allow this first container (3) to be oriented in a location of the receiving chamber (4) to possibly break one of the ends of a container (made of glass) in order to have access to its contents. Advantageously, the device according to the invention is sterilized by gamma irradiation, preferably before any sampling manipulation, or even before any introduction of the first container (3) into the device. The device according to the invention allows an amplification or proliferation of the raw material. Preferably, it is also possible to use the device according to the invention to dilute the raw material or even to carry out formulation or sterility tests. Other characteristics, details and advantages of the invention will emerge from the description given below, without limitation and with reference to the drawings and examples.The references of each element included in the present invention are as follows: Sampling means (1) End of the sampling means (1a) Raw material to be sampled (2) First container (3) Proximal end of the first container (3a) Receiving chamber (4) Confinable space (5) Closable opening (6) Receiving means (7) First part of the receiving means (7a) Second part of the receiving means (7b) Distal end of the receiving means (7c) Second container (8) Resealable element (9) – ensuring sealing Guiding means (10) – second part of the receiving means (7b) Sampling chamber (11) Flexible part (11a) of the sampling chamber (11) Guiding means (12) of the sampling means (1) Groove (12a) of the guiding means (12) Outer surface (12b) of the guiding means (12) Body (13) of the sampling means (1) Needle (14) of the sampling means (1) Flexible part (15) of the receiving chamber (4) Means for supplying at least one fluid ofdecontamination (16) Fluid connection of at least one decontamination fluid (16a) Means for supplying at least one rinsing fluid (17, 27) Fluid connection of at least one rinsing fluid (17a) First fluid discharge means (18) Means for supplying a drying fluid provided with a filter membrane and a hydrophobic filter (19) Fluid connection of at least one drying fluid (19a) Fluid connection for decontamination of the fluid connection of at least one drying fluid (19b) Second fluid discharge means (20) Rigid part 21 (rigidity defined relative to the flexible part (15)) of the receiving chamber (4) Opening means (22) of the first container (3) Means for receiving at least one filter purge fluid (24) Fluid connection of at least one filter purge fluid (24a) Means for storing used fluids (25) Filtration means (26) with a hydrophilic filter Means for supplying at least one rinsing fluid (27) for thesampling means (1) Fluid connection of at least one rinsing fluid (27a) for the sampling means (1) Sampling conduit (27b, 27c) Means for venting the container (8) and for sucking up the raw material (2) Pumping means, pumps (A) Hydrophobic or hydrophilic filter (F) depending on the intended use Figure 1 is a schematic view of an embodiment of the device according to the present invention. Figure 2 is a schematic view of a preferred embodiment of the device according to the present invention. Figures 3 to 10 are illustrations of the device of Figure 2 according to different handling steps. Figure 11 is a schematic view of an embodiment of the device according to the present invention. In the figures, identical or similar elements bear the same references. Other characteristics and advantages of the present invention will be drawn from the non-limiting description which follows, and with reference to thedrawings and examples. Figure 1 illustrates an aseptic sampling device according to an embodiment of the invention which is arranged to allow the sampling of a raw material (2). This raw material (2) may be a cell or a (micro)organism in suspension. The device of Figure 1 comprises a sampling means (1) for a raw material in solution and a sealed receiving chamber (4) which has a confined space (5). The sampling means (1) is adjacent to the receiving chamber (4) which is provided with an opening (6) closed by a plug and a receiving means (7). In addition, it appears that the sampling means (1) is separated from the receiving chamber (4) by a closable element, in this case by a septum (9). Also, the sampling means (1) is located in a sampling chamber (11) which has a guide means (12). This guide means (12) is in the form of a cone which is connected to the sampling means (1)at the body (13), for example a tip (14), which is provided at one of its ends with a needle (14) and, possibly at the other end with a pump body (or a conduit). The sampling means (1) thus has a sealed body (13) provided at one of its ends with a needle (or any other means capable of allowing the raw material present in the first container (3) to pass through. The body (13) is also provided at the other end, opposite the needle, with a conduit (27b). Thus, the body (13), the needle (14) and the conduit (27b) are in fluid communication. The sampling chamber (11) is confined and sealed, which is therefore also the case for the sampling means (1) which is located in a confined environment and separated from the confined space (5) of the receiving chamber (4). Also, the sampling chamber (11) comprises a flexible body (11a), which preferably functions like an accordion, which has a rest position (stretched shape of aaccordion) and a sampling position (contracted shape of an accordion). Thus, when the flexible body (11a) is in the rest position, the entire sampling means (1) is located in the sampling chamber (11) as illustrated in Figure 1. When the flexible body (11a) is in the sampling position, it is in a position where it is folded back on itself (like an accordion in the contracted position) and the sampling means (1) is then located in the confined space (5) of the receiving chamber (4). When the sampling is carried out, the flexible body (11a) is arranged to move back into the rest position (with the accordion in the stretched position). Alternatively, this flexible body (11a) can also be a piston which also makes it possible to provide a confined environment in which the sampling means is located. The operation indicated above is then similar with regard to the rest and sampling positions. Such an embodiment is illustrated inFigure 11. The receiving chamber (4) has at least a part of its surface made of flexible material (15), said part being possibly adjacent to said receiving means (7), which passes through this part (15) in a sealed manner, preferably along a median axis of the receiving chamber (4). Figure 1 shows a receiving chamber (4) which has a part of its surface made of flexible material (15) and another part made of rigid material (21) (this rigidity being defined with respect to the flexible material). Thus, the surface made of flexible material (15) can be made of a malleable plastic and the more rigid material (15) of elastomer, preferably rubber (less malleable). The receiving means (7) of the receiving chamber (4) comprises a first part (7a) located in the confineable space (5) which holds (without manual intervention) in a stable manner the first container (3) which contains a raw material (2) to be sampled, for example cells in suspension(2). The first container (3) has a proximal part 3a (made of glass) and is closed when it is in the confined space (5). This first part (7a) is connected to a second part (7b) which is located outside the receiving chamber (4). This second part (7b) extends outside said receiving chamber (4) in the form of a guide means (10), which can be oriented relative to a median axis which passes through said receiving chamber (4). In addition, the second part (7b) of the receiving means (7) has a distal end (7c) connected to a first means for discharging at least one fluid (18). Thus, the receiving means (7) is in fluid communication with the confined space (5) of the receiving chamber (4). Alternatively, the distal end (7c) is closed, without being connected to the first means for discharging at least one fluid (18). In this embodiment, the means for discharging at least one fluid (18) is located elsewhere on thereceiving chamber (4), so as to be separated from the distal end (7c) of the receiving means (7). Also, the receiving means (7) is located on the part of the receiving chamber (4) which is made of flexible material (15). The receiving chamber (4) further comprises, and preferably on its part made of rigid material, the closed opening (6), a means for opening (22) the first container (3) and a fluid connection (23) of a fluid. The opening means (22) is capable of receiving the proximal part (3a) of the first container (3) and is arranged to break the proximal part (3a) of the first container (3) by a pivoting movement. Depending on the type of closing means of the first container (3), the opening means (22) will have a shape and a function which will allow access to the first container (3) in an aseptic manner. This type of closing means can be a stopper, a membrane, a capsule, etc. It is obvious that when the first container (3) is provided with a septum atthe proximal end (3a) of the first container (3), the opening means (22) is not used (or even present) in the receiving chamber (4). As illustrated in Figure 1, the opening means (22) can also be connected to a fluid connection which is connected to a filtration means (26). This filtration means (26) makes it possible to filter the fluids, here the rinsing and / or decontamination fluids to limit contamination and fouling of the receiving chamber (4). This filtration means (26) is connected to a fluid connection of at least one filter purge fluid (24a) which is in the form of a conduit (24a) which lands in a container (24) acting as a means for receiving at least one filter purge fluid (24). The filtration means (26) is also connected to a means for supplying a decontamination fluid (hydrogen peroxide) (16) via a decontamination fluid connection (16a). In addition, the filtration means (26) is connectedto a rinsing fluid (water) supply means (17) via a rinsing fluid connection (17a). Alternatively, when the opening means (22) is not present, the supply connections (16, 17), the filtration means (26) and their respective conduits (16a, 17a, 24a) are arranged to be in fluid communication with the receiving chamber (4). In the embodiment illustrated in FIG. 1, the receiving chamber (4) is also fluidically connected to a drying fluid (air) supply means (19). Thus the nozzle (23) of the receiving chamber (4) is connected by a conduit (19a) to the drying fluid (air) supply means (19). Then, the drying fluid supply means (19) is also connected to a conduit (19b) which allows, via a pump (A), the fluids to be evacuated from the receiving chamber (4) following drying to a receiving container (by disposal, container (25)). The deviceillustrated also comprises a fluid (here air) evacuation means (20) which may for example be located in the container (25) or elsewhere depending on the arrangement of all the elements forming the device according to the invention. Additionally, the body (13), the needle (14) and the conduit (27b) are in fluid communication. The sampling conduit (27b, 27c) makes it possible to transfer the raw material (2) in solution (cell in suspension) to a second container (8). It is also possible to rinse the sampling means (1) using a means for supplying a rinsing fluid (27). The device may also include an evacuation means (28). In practice, the second container may contain a culture medium (not illustrated). The second container (8), adjacent to said receiving chamber (4), is connected by said sampling means (1) to said receiving chamber (4), through which the raw material (2) of interest is transferred. The second container(8) has a volume greater than that of the first container (3) and is arranged to allow cultivation, when said raw material (2) taken from said first container (3) is transferred into said second container (8). Figure 1 thus comprises several conduits provided to allow at least one fluid to pass (16a, 17a, 18, 19a, 19b, 24a, 27a, 27b, 27c, 28), several pumps (A), as well as elements (19, 20, 24, 25, 26, 27) commonly used in the technical field of the present invention and which can be connected to the device of the invention in several ways. In operation, a decontamination liquid (hydrogen peroxide) is supplied by the fluid supply means (16), until it partially fills the receiving chamber (4). Then, the cap of the opening (6) is removed and an aseptic bottle (3) (supplied by the company Aseptic Technologies) containing suspended cells (2) is introduced into the receiving chamber (4),in which the receiving means (7) is oriented at its second part (7b) towards the opening (6). Thus, the bottle (3) is housed in the receiving means (7) in a stable manner. When the receiving means (7) is oriented, the flexible surface (15) of the receiving chamber (4) deforms to allow adequate orientation. When the bottle (3) is held in the receiving means (7), the latter is positioned vertically along a median axis of the receiving chamber (4). A decontamination step is then carried out by supplying the receiving chamber (4) with decontamination fluid (hydrogen peroxide) until it is completely filled with decontamination fluid. As soon as the decontamination is finished, emptying is carried out in order to eliminate the decontamination fluid (conduit (18) in the disposal container (25). After the decontamination step, a complete filling of the receiving chamber (4) is carried out with a rinsing fluid(water) using the rinsing fluid supply means (17) in order to remove all traces of decontamination fluid. This is then followed by a draining step towards the disposal container (25). Preferably, this rinsing step is dynamic in that it removes the decontamination liquid and is therefore not limited to diluting it. A drying step then takes place by the drying fluid supply means (19), preferably by introducing compressed air. When the bottle (3) is to be broken at its proximal end (3a), it is oriented in the opening means (22) which will allow, following a rotational / pivoting movement, to break this end in order to allow access to the suspended cells (2) to be collected. This step is optional and not necessary when access to the raw material (2) to be collected does not require breaking a part of the container (3). For example, when the container is provided with a septum or any otherresealable element which allows access to the contents of the bottle without breakage. Then, the receiving means (7) housing the open bottle is oriented towards the sampling means (1), preferably along a median axis of the sampling chamber. Thus, the opening of the bottle is located opposite the septum (9). As explained above, the flexible body (11a) of the sampling chamber will allow the needle (14) of the sampling means (1) to be introduced into the confined space (5) of the receiving chamber (4) by passing from a rest position (tense accordion shape, as illustrated in Figure 1) to a sampling position (contracted accordion shape). When the flexible body (11a) is in the sampling position, it is in a position where it is folded back on itself (like an accordion in the contracted position) and the sampling means (1) is then located in the confined space (5) of the receiving chamber (4), more precisely at the bottom of the bottle (3) ready tocollect the suspended cells. By a pumping or suction or piston system or any other collection system which guarantees aseptic collection, the suspended cells are thus collected and transferred to the second container (8). The latter comprises a culture medium which will be mixed with the suspended cells so as to allow cell reproduction. When the collection is carried out, the flexible body (11a) is arranged to return to the rest position (with the accordion in the stretched position). Thus, the needle (14) can be replaced by a conduit which would allow efficient collection and transfer. Indeed, the needle has a rather passive role in the device since it does not ensure the removal of the suspended cells but rather allows easy and efficient access to the bottom of the bottle. Any other equivalent means would also be suitable. This type of manipulation can thus be used to allowgeneral in a closed system (provided by the device according to the invention) of an aseptic sampling means. The “end-to-end” type processes can also integrate the device according to the invention and consist of integrating all the stages of a production process from the raw material to the finished product. Thus, the device according to the invention makes it possible to integrate the first stage of a process called “end-to-end”. Figure 2 is similar to Figure 1 and illustrates another embodiment of the device according to the invention by taking up part of the references of Figure 1, except that the sampling means (1) is different. The sampling means 1 is located in a sampling chamber (11) which has a guide means (12) which makes it possible to move said sampling means (1), preferably along a median axis of said sampling chamber (11) towards said receiving chamber (4). The guide means (12) has a groove (12a)which extends longitudinally on an outer surface (12b) of said guide means (12) to slide said sampling means (1) so that one of the ends (1a) of said sampling means (1) is introduced into said receiving chamber (4). In this case, the needle can thus be introduced into the confinable space (5) of the receiving chamber (4). As illustrated, the body (13) is provided with a guide means (12), in the form of a projection, which extends to outside the sampling chamber (11). In this embodiment, a flexible body (11a) is not necessary, which makes it possible to have a partly rigid sampling chamber (11). The operation of the device illustrated in Figure 1 described above is also applicable here. It should be noted that concerning the different handling steps related to decontamination, rinsing and drying. Those skilled in the art can combine these steps as desired depending on the needs during themanipulation. Figures 3-10 illustrate how the device can be used, in particular when rinsing and / or decontamination and / or drying takes place. These figures 2-10 can also be understood as sequentially illustrating how the device is implemented. Figure 3 illustrates the device according to a preferred mode when a decontamination fluid (such as hydrogen peroxide) is introduced into the receiving chamber (4) which is partially filled with decontamination liquid. This fluid can also be a rinsing fluid, such as water. Figure 4 illustrates the device according to an advantageous mode, in which a step of positioning the first container (3) in the receiving chamber (4) is carried out by said receiving means (7) which is oriented towards the closable opening (6). According to a particularly advantageous mode (not illustrated), in which the first container (3) is positioned along a median axis of thereceiving chamber (4), in a vertical position, when a decontamination fluid (such as hydrogen peroxide) partially or completely fills the receiving chamber (4). This fluid may be a rinsing fluid (such as water). This step may be located after that illustrated in Figure 4. Figure 5 illustrates a complete decontamination step by filling the entire receiving chamber (4) with a decontamination fluid. Figure 6 illustrates an advantageous embodiment, in which a step of emptying the decontamination (or rinsing) fluid from the receiving chamber (4) is carried out. Figure 7 illustrates a complete rinsing step by filling the entire receiving chamber (4) with a rinsing fluid. Figure 8 illustrates an embodiment in which the flexibility of a part of the receiving chamber (4) is illustrated. A step of opening the first container (3) is carried out after positioning the first container(3) in the opening means (22). Figure 9 illustrates a particular embodiment, in which a step of positioning the opening of the first container (3) opposite the sampling means (1) is carried out by pivoting the receiving means (7). Figure 10 illustrates a preferred embodiment in which the sampling means (1) is placed inside the first container (3) to allow sampling. Figure 11 illustrates an additional embodiment of the device according to the invention which includes the elements described in Figure 1, except for the sampling chamber which comprises a rigid body (11b) which has a rest position and a sampling position. Thus, when the rigid body (11b) is in the rest position, the entire sampling means (1) is located in the sampling chamber (11). When the rigid body (11b) is in the sampling position, the sampling means (1) is moved into the confined space (5) of the receiving chamber (4) tobe in contact with the raw material (2) to be sampled (in solution). When the sampling is carried out, the rigid body (11b) is arranged to move back into the rest position. In a preferred embodiment, the rigid body (11b) is a piston, as illustrated in Figure 11, which also provides a confined space to accommodate the sampling device. In another preferred embodiment, the sampling chamber (11) is equipped with a stop on one of its internal walls, making it possible to prevent the rigid body (11b) from accidentally leaving the sampling chamber (11) when it is in the rest position. In a more preferred embodiment, the guide means (12) comes into contact against the stop in order to prevent the rigid body (11b) from accidentally leaving the sampling chamber (11) when it is in the rest position. The embodiment illustrated in Figure 8 is not essential when the first container (3) is provided with an elementresealable, such as a septum or any equivalent element. In the figures, identical or similar elements bear the same references. Within the scope of the present invention, any singular article such as, for example, "a", "an", "the", "the", "of", "of the" may be replaced by an article which designates a plural such as, for example, "at least 2", "at least 3", "several" etc. The word "include", "contains" or any equivalent term or derivatives may be replaced by "consisting of" in order to define a list or possibilities of exclusive selection so as not to include other elements not cited in the expression used. It is understood that the present invention is in no way limited to the embodiments described above and that many modifications may be made thereto without departing from the scope of the appended claims.

Claims

CLAIMS 1. Aseptic sampling device for the proliferation of a raw material in a culture medium or for cell or microbial culture, the device comprising: - A sampling means (1) for a raw material (2), preferably in solution, arranged to proliferate in a culture medium, said sampling means (1) being arranged to aseptically sample the raw material (2) contained in a first container (3) of a predetermined volume, and - A receiving chamber (4) having a confinable space (5) and arranged to permit decontamination thereof by the passage of at least one fluid into said confinable space (5), said receiving chamber (4) being provided with: o a closable opening (6) arranged for the passage of said first container (3) into said confinable space (5) and, when closable, arranged to confine the receiving chamber (4),o of a receiving means (7) orientable in the confining space (5) and arranged to receive said first container (3) and position it in the direction of said sampling means (1), the latter being arranged to aseptically sample said solution (2) contained in said first container (3) and arranged to aseptically transfer it to a second container, (8) having a volume greater than the volume of said first container (3).

2. Device according to claim 1, wherein said sampling means (1) is adjacent to said confining space (5) of said receiving chamber (4) before sampling, and is preferably in a confined and sealed environment.

3. Device according to any one of the preceding claims, wherein said sampling means (1) is separated from said receiving chamber (4) by a resealable element (9) selected from the group comprising a septum, a membrane, and a solenoid valve.

4. Device according to any one of the preceding claims, wherein, at the time of said sampling, a portion of said sampling means (1) is located in the confining space (5) of the receiving chamber (4). 5.A device according to any one of the preceding claims, wherein said sampling means (1) is located in a sampling chamber (11) which has a guiding means (12) for said sampling means (11).

6. A device according to claim 5, wherein said guiding means (12) is arranged to move said sampling means (1) along a median axis of said sampling chamber (11) towards said receiving chamber (4).

7. A device according to claim 5, wherein said guiding means (12) has a groove (12a) extending longitudinally over an outer surface (12b) of said guiding means (12) to allow said sampling means (1) to slide so that one end (1a) of said sampling means (1) is introduced into said receiving chamber (4).

8. A device according to any one of the preceding claims, wherein said sampling means (1) has a 9. A device according to any one of the preceding claims, wherein said sampling chamber (11) is confined and sealed.

10. A device according to any one of the preceding claims, wherein said receiving chamber (4) has at least a portion of its surface made of flexible material (15), said portion being optionally adjacent to said receiving means (7), which is arranged to pass through said at least a portion (15) of the surface of the receiving chamber (4) made of flexible material.

11. A device according to any one of the preceding claims, comprising a second container (8) adjacent to said receiving chamber (4) and connected by said sampling means (1) to said receiving chamber (4). 12.A device according to claim 11, wherein said second container (8) has a larger volume than the first container (3) and is arranged to allow culturing when said raw material (2) taken from said first container (3) is transferred into said second container (8).

13. A device according to any one of the preceding claims, wherein said receiving means (7) has a first portion (7a) extending into said confining space (5) and a second portion (7b) extending outside said receiving chamber (4) in the form of a guiding means (10), preferably along a median axis that passes through said receiving chamber (4).

14. A device according to any one of the preceding claims, wherein said portion in the form of a guiding means (10) is in fluidic communication with said receiving chamber (4).

15. Device according to any one of the preceding claims, wherein said receiving chamber (4) is arranged to be in fluidic communication with at least one of the following elements or taken in combination: - A means for supplying at least one decontamination fluid (16) - A means for supplying at least one rinsing fluid, (17) - A means for supplying at least one drying fluid (19), - A first means for evacuating at least one fluid (18), said evacuation means (18) being optionally directly connected to one of the ends (7c) of said receiving means (7), - And a second means for evacuating drying fluid (20).

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