Sterile Sampling Device

Abstract

The present invention relates to a sterile sampling device comprising a sampling means (1) configured for aseptically recovering a 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 allow decontamination thereof by the passage of at least one fluid within the confinable space (5), the receiving chamber (4) comprising a closable opening (6) and a receiving means (7) oriented within the confinable space (5).

Description

[Technical field]

[0001] The present invention relates to a sterile sampling device configured to allow for the growth (in a broth) of a material or the cultivation of a cell or microorganism. [Background technology]

[0002] Typically, sampling devices are used in the pharmaceutical industry and biotechnology to collect and transfer material that can be grown in culture, often in the form of a solution, suspension, emulsion, or even supernatant or plasma, and is therefore taken from a container, for example with a syringe or pipette, and optionally transferred to another container for growth in culture.

[0003] Thus, the raw material can be collected and transferred from one container to another depending on the intended purpose in the art. In some application fields such as those mentioned above, especially when cultures (cells or bacteria) are foreseen, it is necessary to be able to aseptically collect the raw material from a container and optionally transfer it aseptically to another container. These sampling means are the linchpin of these pharmaceutical and biotechnological industries, since they are part of the first stage of the process. This step is very important and affects the subsequent steps, since the raw material needs to be collected and transferred aseptically.

[0004] More specifically, the aseptic sampling of raw materials is essential in various application fields, especially whenever the raw material is predisposed to grow in a culture medium. This is commonly called "cell reproduction / amplification" or "bacterial culture". Among these culture techniques, the skilled person is also familiar with the culture of infectious substances.

[0005] Another example is human mesenchymal stem cells (hMSCs). hMSCs are pluripotent cells that can also proliferate (like undifferentiated cells) and differentiate into many different cell types, including bone marrow, cartilage, tendon, muscle, and nerve cells. hMSCs have many therapeutic benefits, including cell therapy and tissue regeneration, and have been widely studied.

[0006] In the field of cellular immunotherapy, treatments consist of the production of CAR-T cells ("chimeric antigen receptor-T"), with the aim of relying on the patient's own immune system to fight cancer. Once produced, the CAR-T cells are expanded with the aim of being administered to the patient.

[0007] Furthermore, culturing the cells will enable applications in the fields of vaccine production and gene therapy.

[0008] Currently, the propagation of cells or bacteria or the cultivation of infectious agents is a great asset in the development of the biotechnology field.

[0009] Typically, culturing of cells or infectious agents can be done by collecting the raw material in small storage containers. These storage containers can be ampoules or cryotubes for cells, which are generally stored at ultra-low temperatures (-70°C to -196°C). This process, called cryopreservation, stops most biological activity and chemical reactions, thus preserving the contents. Obviously, temperatures between -4°C and room temperature are sufficient for diluting raw materials or preparations.

[0010] Cells or infectious agents are typically transferred to larger containers where the environmental conditions are suitable for their growth and reproduction. These culture containers can be petri dishes, flasks containing culture medium, or bioreactors containing culture medium. This allows obtaining small to large quantities of cells or infectious agents to allow the production of molecules, drugs, vaccines, genetically modified organisms, or to carry out gene therapy to treat certain genetic disorders.

[0011] It can be assumed that the protocols for sampling and culturing cells and infectious materials in the pharmaceutical and biotechnology industries are relatively stringent, considering that the sampling step is the first step to enable effective culturing of bacteria and unwanted bacteria in the culture medium.

[0012] However, currently, extraction of raw materials is done manually with a syringe in a laminar flow enclosure: the user disinfects the storage container (vial), for example with an alcohol wipe, opens the glass container (e.g. by cracking the top), manually extracts the suspension with a syringe, and transfers it to another container, for example for cultivation.

[0013] With this type of handling, the user cannot exclude the possibility of contaminating the environment surrounding the solution being collected, especially if they are in contact with this environment. The use of laminar flow, by its design, cannot completely exclude the absence of specific and biological contamination.

[0014] Unfortunately, each of the steps described above (decontamination, opening, sampling, transfer) can lead to the introduction of contaminants. Thus, poorly decontaminated surfaces, human mishandling, and failure of laminar flow equipment lead to contamination. The result is unusable cultures, causing significant delays and additional costs. In markets where flows are often tight, it is increasingly difficult to carry out all these steps aseptically. Also, the use of laminar flow in special enclosures is expensive for users and does not guarantee sterile sampling in a safe and systematic way in the context of industrial production.

[0015] In addition, these methods may pose significant risks to handling personnel who may be exposed to highly contagious pathogenic infectious agents during various handling operations. Summary of the Invention [Problem to be solved by the invention]

[0016] For these reasons, there is a recognized need to ensure reliable, efficient, simple and rapid sterile sampling whilst reducing the risk of exchange of contaminants into the solution / suspension taken from the user and vice versa.

[0017] Therefore, a need has been identified to provide an apparatus that allows easy, efficient and reliable recovery of raw material from the first (storage) container while minimizing as much as possible the risk of such contamination. [Means for solving the problem]

[0018] To solve this problem, the present invention provides a sterile sampling device for the growth of a source material (2) (culture medium) or for the cultivation of cells or microorganisms, the device comprising: a sampling means (1) for a material (2) adapted to grow in a culture medium, preferably in a solution, adapted to aseptically collect the material (2) contained in a first container (3) of a predetermined volume; a receiving chamber (4) having a containable volume (5) and configured to allow the passage of at least one fluid within the containable volume (5) to enable decontamination thereof, The reception room (4) is a closable opening (6) configured for passage of the first container (3) within the confinable space (5) and configured, when closed, to confine the receiving chamber (4); and a receiving means (7) orientable within the confinable space (5) and configured to receive the first container (3) and position it in the direction of the sampling means (1), the receiving means (7) configured to aseptically collect the solution (2) contained in the first container (3) and aseptically transfer it to a second container (8) having a volume larger than the volume of the first container (3).

[0019] The device according to the invention allows for the aseptic recovery of a raw material (2) (preferably a solution) from a first container (3) of a defined volume (preferably for storage), thereby minimizing as much as possible the risk of contamination of both the recovered raw material (2) (solution) and the user of the device, and achieving attractive production yields.

[0020] The device has the advantage that it can be a single-use device, is simple to use and is less expensive than current solutions, particularly those which require the use of laminar flow enclosures. The device according to the invention is portable and easy to implement in the field (industrially).

[0021] The device according to the present invention is also constructed to allow for selective containment.

[0022] Indeed, the receiving chamber (4) can be confined by closing the closable opening (6) via a closure element, e.g. a stopper, a membrane, a septum, a valve, etc. This makes it possible to choose whether the device is confined or not, depending on the handling steps.

[0023] If the receiving room (4) has a confined space (5), it is also a sterile environment.

[0024] According to the device according to the invention, the sampling means (1) can be located either within the confinable space (5) and thus within the receiving chamber (4) or outside the receiving chamber (4).

[0025] In the first case, the confinable space (5) extends to the sampling means (1). The receiving chamber (4) and the sampling means (1) can thus be closed via a closure element, e.g. a stopper, a membrane, a septum, a valve, etc., by closing the closable opening (6). This makes it possible to choose when to close or not to close the device depending on the process handling. The sampling means (1) and the receiving chamber (4) can thus be confined in a sterile environment.

[0026] Alternatively, the device according to the invention also covers the option of the sampling means (1) being placed next to (adjacent to) the confinable space (5), i.e. outside the receiving chamber (4). In this case, the sampling means (1) forms a first closable part of the device according to the invention, and the receiving chamber (4) forms a second closable part of the device according to the invention. The sampling means (1) is preferably (configured to be) directly (fluidically) connected to the receiving chamber (4) or indirectly connected by an intermediate (fluid) connecting element. The device according to the invention can be composed of several parts.

[0027] This alternative option offered by the device according to the invention also allows selective confinement of certain parts of the device. Thus, the sampling means (1) is located in a confined and sealed space (first part) adjacent to that of the receiving chamber (4) located in the second closable part of the device. In this embodiment, it is possible to confine (or not confine) the receiving chamber (4) while keeping the sampling means (1) in a limited and sealed space during handling and on demand. Preferably, therefore, according to this alternative, fluid communication is possible between the receiving chamber (4) and the sampling means (1).

[0028] Thus, the receiving chamber (4) can be enclosed by closing the closable opening (6) via a closure element, such as, for example, a stopper, a membrane, a septum, a (solenoid) valve or the like.

[0029] These embodiments, which can be combined with one another, offer the user flexibility, which is particularly advantageous.

[0030] Furthermore, the receiving chamber of the device according to the invention can be decontaminated easily and efficiently at any time.

[0031] Thus, the device according to the invention makes it possible to have a closed (containment) system that allows the aseptic collection and transport of the raw material (2) that can be grown in a culture medium.

[0032] In view of the above, the sampling device of the present invention provides an effective, simple and reliable solution for aseptically collecting (and optionally transporting) a source material (2) adapted for growth in a culture medium.

[0033] In a preferred embodiment according to the invention, the sampling means (1) is adjacent to the confinable space (5) of the receiving chamber (4) before sampling, preferably in a confined and sealed medium. This embodiment makes it possible to facilitate the sampling of the raw material (2) and to effectively ensure a sterile sampling. The sampling means is preferably arranged outside the receiving chamber (4) before sampling. The sampling means (1) then advantageously forms a first confinable part of the device according to the invention, and the receiving chamber (4) forms a second confinable part of the device according to the invention. The sampling means (1) is preferably (configured to be) directly connected to the receiving chamber (4) or (configured to be) indirectly connected to the latter by means of an intermediate (fluid) connection element. The device according to the invention can be composed of several parts.

[0034] This alternative option offered by the device according to the invention allows a more selective containment of certain parts of the device. Thus, the sampling means (1) is placed in a confined and sealed space (first part) opposite and adjacent to the receiving chamber (4) (second part of the device). In this embodiment, it is possible to confine (or not) the receiving chamber (4) while keeping the sampling means (1) in a limited sealed space during handling and on demand. Preferably, according to this advantageous embodiment, a fluid communication is established between the receiving chamber (4) and the sampling means (1).

[0035] The sampling means (1) can therefore be contained independently from the containable volume (5) of the receiving room (4), reducing possible contamination risks and allowing careful control of the sampling means (1) and the containable volume (5) of the receiving room (4).

[0036] Additionally, the sampling means (1) is in a sterile environment.

[0037] Thus, the receiving chamber (4) can be enclosed by closing the closable opening (6) via a closure element, for example a stopper, a membrane, a septum, a (solenoid) valve or the like.

[0038] This flexibility offered to the user is particularly advantageous.

[0039] In a preferred embodiment according to the invention, the sampling means (1) is separated from the receiving chamber (4) via a closable element (9), preferably selected from the group consisting of a septum, a membrane and any other equivalent element allowing it to be opened and closed in a sealed manner while ensuring a sterile sampling. Under such preferred conditions, a solenoid valve may also be used.

[0040] The closable element (9) allows for isolating the receiving chamber (4) from the sampling device (1) and at the same time facilitating access to the containable space (5), which allows for a further reduction in the risk of contamination. It also allows for multiple cleaning and / or decontamination of the space (5) when it is confined. To facilitate sampling of the raw material (2), it is preferable to provide a fluid communication between the sampling means (1) and the receiving chamber (4).

[0041] The above paragraph and related explanations regarding the embodiment in which the sampling means (1) is adjacent to the receiving chamber (4) also apply here.

[0042] Preferably, during said sampling, a part of the sampling means (1) is located within the confinable space (5) of the receiving chamber (4), which allows to collect the raw material (2) from the first container (3) while limiting the residence time and degree of exposure of the sampling means (1) in the confinable space (5). More precisely, this embodiment is implemented when the space (5) of the receiving chamber (4) is confined and sealed against the external surrounding environment.

[0043] If the sampling means (1) is open to the surrounding environment, it is preferable to avoid introducing the sampling means (1) into the containable volume (5) of the receiving room.

[0044] More preferably, the sampling means (1) is arranged in a sampling chamber (11) having guide means (12) for the sampling means (1), which allows the sampling device (1) to be more easily guided in order to facilitate handling during sampling.

[0045] Advantageously, the guide means (12) are arranged to move the sampling means (1), preferably along the central axis of the sampling chamber (11) towards the receiving chamber (4), which further facilitates guiding the sampling device (1) in a predefined sampling direction.

[0046] According to a particularly preferred embodiment, the sampling chamber (11) has a flexible body (11a) having a rest position and a sampling position. Thus, when the flexible body (11a) is in the rest position, the sampling means (1) is entirely located within the sampling chamber (11). When the flexible body (11a) is in the sampling position, the sampling means (1) is moved into the confinable space (5) of the receiving chamber (4) and into contact (in solution) with the material (2) to be collected. Once sampling has been performed, the flexible body (11a) is arranged to return to the rest position.

[0047] The source material (2) is preferably collected and transferred to a second container (8) by means of a pump, suction, piston system or other sampling system that ensures sterile sampling, the latter may contain a culture medium that is mixed with the source material (2) to allow amplification of the source material (2).

[0048] Alternatively, this flexible body (11a) may be a piston, making it possible to provide a narrow environment in which the sampling means is placed. The above operation is similar for the rest position and the sampling position.

[0049] Advantageously, the guide means (12) has a longitudinally extending groove (12a) on its outer surface (12b) for sliding the sampling means (1) so that one of its ends (1a) is introduced into the receiving chamber (4).

[0050] More advantageously, the sampling means (1) comprises a body (13), preferably a pump body (13), configured to allow the passage of the source material (2) and provided at one of its ends with a needle (14) or a line. The presence of the needle (14) or a line allows the sampling means (1) to be easily inserted into the first container (3) and thus a means for passing a fluid, for example by suction. A needle is preferred in terms of efficiency, as it ensures easy and sterile sampling.

[0051] Preferably, the needle (14) can therefore be replaced by a line allowing efficient sampling and transfer. In fact, the needle or line plays a rather passive role in the device, since it does not ensure the removal of the raw material (2) but provides an easy and efficient access to the bottom of the first container (3) (vial). Other equivalent means are also suitable.

[0052] It should be noted that needles are more efficient.

[0053] This type of handling can therefore be used to enable sterile sampling in a closed / contained system (provided by a device according to the invention).

[0054] Alternatively, the sampling means (1) is placed in a confined, sealed environment and the receiving chamber (4) is placed in a separate, containable space (5).

[0055] In a preferred embodiment according to the invention, the sampling chamber (11) is enclosed and sealed. This embodiment makes it possible to provide the sampling means (1) with an environment isolated from that of the confined space (5) of the receiving chamber (4). Thus, when the receiving chamber (4) is open, the sampling chamber (11) (and the sampling means (1)) remains enclosed and sealed, providing freedom of movement when handling the device while avoiding contamination of the sampling means (1).

[0056] In addition, the receiving chamber (4) preferably has at least a part (15) of its surface made of a flexible material, which part is optionally adjacent to the receiving means (7) that is configured to pass through said at least a part (15) of the surface of the receiving chamber (4) made of a flexible material. This flexible part (15) allows the receiving means (7) to be reliably oriented according to easy handling, preferably throughout the entire confinable space (5). This part (15) made of flexible material advantageously allows a rotational, oscillating and / or longitudinal movement of the receiving means (7). This does not mean that it is excluded that the receiving chamber (4) has a part of its surface made of a rigid material that is slightly flexible with respect to the part made of flexible material. Preferably, the receiving chamber (4) has some of its surfaces which are deformable in space (parts made of flexible material) and some which are not (parts made of rigid material) so as to provide some support to some of the elements of the receiving chamber (4).

[0057] According to an advantageous embodiment, the device according to the invention comprises a second container (8) adjacent to the receiving chamber (4) and connected to it by means of sampling means (1), which are thus in fluid communication with the sampling means (1), making it possible to transfer the raw material (2) into this second container (8) containing a culture medium suitable for cell regeneration or any other type of amplification of the raw material (2).

[0058] Advantageously, selective fluid communication can be established between the second container (8) and the sampling means (1) and the receiving chamber (4) to minimize the presence of contaminants during handling.

[0059] Preferably, the second container (8) has a volume larger than that of the first container (3), and the second container (8) is arranged to allow culturing (amplification of the source material (2)) when the harvest solution (2) from the first container (3) is transferred to the second container (8), thereby allowing seeding of the larger container (8) from the smaller container (3) and thus allowing amplification of the source material (2), in particular cell regeneration.

[0060] In a preferred embodiment according to the invention, the receiving means (7) has a first portion (7a) which extends into the confinable space (5) and a second portion (7b) in the form of a guide means (10) which extends outside the receiving chamber (4), preferably along a central axis passing through the receiving chamber (4), so that the user can easily guide the receiving means, either manually or automatically, without risk of contamination, by orienting the second portion in the form of the guide means (10) outside the receiving chamber (4).

[0061] More preferably, the part in the form of a guide means (10) is in fluid communication with the receiving chamber (4). This makes it possible to connect a fluid removal means (18), for example by connecting a line to one of the ends of this second part in the form of a guide means (10). Thus, access to the receiving chamber (4) is facilitated. This access is located along the central axis of the receiving chamber (4), preferably opposite the closable opening (6).

[0062] The receiving chamber (4) advantageously comprises: a means (16) for supplying at least one decontamination fluid; a means (17) for supplying at least one rinsing fluid; at least one means (19) for supplying a drying fluid; a first means (18) for removing at least one fluid, optionally connected directly to one of the ends (7c) of the receiving means (7); and a second means for removing (drying) the fluid (20).

[0063] In this way, the receiving chamber (4) can be prepared before receiving the first container (3) so that when the opening (6) is closed after introduction of the first container (3) into the accommodation space, the confinable space (5) ensures sterile sampling.

[0064] This preferred embodiment means that the receiving chamber (4) is in fluid communication with at least one of the above elements (16, 17, 18, 19, 20).

[0065] Preferably, the receiving chamber (4) comprises a means (22) for opening the first container (3), the opening means being preferably arranged in the confinable space (5). The opening means (22) is configured to allow access to the ingredient (2) in the first container (3). The opening means (22) can for example be able to break one of the ends of the first container (3) (which may be made of glass), to simply unlock / unscrew a stopper or even to remove the cap of the first container (3). This additional option associated with the presence of the opening means (22) therefore allows access to the ingredient (2) contained in any type of container (3), especially when the first container (3) is contained in the receiving chamber (4).

[0066] In a particularly preferred embodiment, the receiving means (7) is integrally moulded. It may also be machined from a block of plastic or metal material.

[0067] A device according to the invention can be manufactured, for example, by a 3D printing process or by molding involving the use of a series of molds.

[0068] In a preferred embodiment according to the present invention, the device is a single use device, and is preferably portable.

[0069] 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 or equal to 2 ml.

[0070] The first container (3) is preferably selected from the group consisting of an ampoule, a cryotube, and a vial (manufactured by Aseptic Technologies). The material of the first container is made of glass or plastic.

[0071] Further advantageously, the apparatus according to the present invention can be operated using an automated or robotic system.

[0072] Further embodiments of the method according to the invention are set forth in the accompanying claims.

[0073] definition The term "sterility" refers to the conditions under which sampling and transfer operations are performed. In the context of the present invention, a sampling device is provided that allows for the aseptic collection of material. In other words, each operation that can be performed using the device according to the invention is performed aseptically, which allows the environment (e.g. closed space) to be kept sterile. This also applies to sampling means that are configured for aseptically collecting and transferring material.

[0074] In the context of the present invention, the expression "raw material" includes strains or other biological material capable of growing in a culture medium. The "raw material" is preferably in the form of a solution, suspension, emulsion or supernatant. The raw material is preferably selected from the group consisting of (consisting of) cells (of human or animal origin), bacteria, infectious agents, viruses, (living) (microbial) organisms, yeasts, algae, prions and mixtures thereof. Preferably, ingredients or excipients that can be used in the composition of a sterile solution may also constitute a raw material. Preferably, the raw material may be in solid form and then dissolved before being introduced 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 features of this paragraph may be combined with each other.

[0075] "(Micro)organisms" refers to all living organisms that are not visible to the naked eye. The term includes bacteria, protozoa, microalgae, and microfungi. The definition also includes plant, animal, and human eukaryotic cells, cells of tissue origin, cancer cells, and non-cancerous cell lines. The definition must also include all infectious agents, whether live or inactive, such as viruses and prions. The aforementioned classifications may be genetically modified.

[0076] "Sealed" means that it is impermeable to liquids (liquids and gases), dust, and moisture.

[0077] The expression "confinable space" should be understood to mean that the space can be confined with respect to the external environment, in particular with respect to the outside of the receiving room or with respect to other surrounding compartments. This feature may be coupled with a closable opening. When this opening is closed, the confinable space is thus confined and preferably sealed. The closable opening thus allows access to the confinable space and leaves the user with some flexibility when handling (manual or automatic).

[0078] This containable space is arranged to be decontaminated, in particular before sampling or before introducing the first container into the containment chamber.

[0079] The expression "first container" can be interpreted in the context of the present invention as a "(storage) container" that contains the recovered raw material. Thus, first containers of this kind can be present in large quantities (in series). Thus, multiple first containers can be addressed by the present invention in view of the disclosed embodiments. Thus, multiple containers can be present in the receiving chamber or multiple first containers can be added individually, one after the other, in series, in order to operate the device in series.

[0080] The expression "second vessel" relates to a type of amplification vessel. In other words, vessels of this type may be present in large quantities (in series). This allows the amplification of the raw material, in particular the cell regeneration. For example, a bioreactor can serve as the second vessel and constitute the culture medium.

[0081] As explained above, in the pharmaceutical or biotechnological industry, the sampling device according to the invention is used to take and, optionally, transfer a raw material (2). The latter can be grown in a culture medium. This raw material (2) can be in the form of a solution, a suspension or a supernatant. It is therefore taken from a first container (3) with the sampling means (1) and is optionally transferred to a second container (8) so that it can grow in a culture medium. This is commonly called "cell growth" or "bacterial culture". Among these cultures, the skilled person is also aware of the culture of infectious agents, human mesenchymal stem cells (hMSCs) and CAR-T cells (Chimeric Antigenic Receptor-T) grown for the purpose of administering them to patients. Furthermore, the culture can also be used in the fields of vaccine production and gene therapy.

[0082] According to the invention, it is possible to use a decontamination fluid preferably selected from the group consisting of water, hydrogen peroxide, peracetic acid and mixtures thereof.

[0083] Advantageously, the drying fluid may be compressed air.

[0084] Preferably, the rinse liquid is water.

[0085] The device according to the invention is therefore suitable for use in the context of cell or bacterial propagation or the cultivation of infectious agents, to name just a few examples.

[0086] According to a preferred embodiment of the invention, a first container (3) containing at least one cell in a solution (2) is introduced into the closable opening (6). The container is closed. Then, a receiving means (7) arranged along the central axis of the receiving chamber (4) is directed towards the opening (6) to receive the first container (3) stably held in the receiving means (7). The opening (6) is closed using a closing element such as a stopper. Thus, when the opening (6) is hermetically closed, the receiving chamber (4) is sealed and a confinable space (5) is formed in the receiving chamber (4). The receiving chamber (4) is then decontaminated using a fluid. Once the receiving chamber (4) is decontaminated, the first container (3) directs the receiving means (7) towards the sampling means (1). The sampling means (1) is placed in the confinable space (5) until it reaches the bottom of the first container (3). It should be noted that the sampling means (1) is placed in a closed environment before sampling. By means of a pump system, the solution (2) is withdrawn and transferred to a second container (8) containing the culture medium.

[0087] Advantageously, the recovered material in solution is aseptically transferred to a second container (8) having a volume greater than that of the first container (3). These steps can be carried out several times, i.e. by introducing several containers of the same type as the first container (3) in series into the receiving chamber (4).

[0088] It should be noted that the first container (3) is intended to contain the ingredient (2) configured to grow in a culture medium, and the second container (8) is itself intended to contain the culture medium and the ingredient (2) contained in the first container (3).

[0089] The volume of the second container (8) in case of cell replication is preferably increased following the complete amplification process (commonly called an "end-to-end" process) so as to increase the amount of amplified material to the desired final volume, the purpose of which is advantageously to eventually provide an injectable solution, preferably for pharmaceutical or biotechnological applications.

[0090] According to a preferred embodiment, the device according to the invention is therefore arranged for the sterile production of injectable solutions for pharmaceutical or biotechnological applications.

[0091] Alternatively, the receiving chamber (4) may be provided with a plurality of receiving means (7) so that the raw material (2) can be collected from a plurality of containers (3).

[0092] The sampling device of the invention allows the raw material (2) arranged to grow in a culture medium to be sampled aseptically and optionally transferred. Aseptic sampling makes it possible to avoid contamination of the contents of the first container with unwanted contaminants such as bacteria of the microbial type. This has the advantage of increasing the production yield by limiting the waste of raw material (2) due to potential contamination.

[0093] The device according to the invention comprises a receiving chamber (4) which is sealed when the closable opening (6) is closed. The sealing prevents the passage of fluids (liquid or gas), dust and moisture and thus aims to create a closed space (5) outside the receiving chamber (4) and optionally outside the sampling means (1) with respect to the surrounding environment.

[0094] It should be noted that the presence of a human can be made unnecessary by replacing the human with an automated robotic system.

[0095] The receiving means (7) is also orientable within the confinable space (5) and can thereby be oriented as desired within the confinable space (5), thus advantageously allowing to position the receiving means (7) facing the closable opening (6), orienting this first container (3) towards the sampling device (1), or even more preferably orienting this first container (3) to a location within the receiving chamber (4) and optionally breaking one of the ends of the container (made of glass) to access its contents.

[0096] Advantageously, the device according to the invention is sterilized by gamma irradiation, preferably before handling the sample or before introducing the first container (3) into the device.

[0097] The device according to the invention allows the amplification or multiplication of raw materials. Preferably, the device according to the invention can also be used to dilute raw materials, perform formulation tests and sterility tests.

[0098] Other characteristics, details and advantages of the invention are explained in the following description, in a non-limiting manner, with reference to the drawings and examples. [Brief description of the drawings]

[0099] [Figure 1] FIG. 1 is a schematic diagram showing one embodiment of an apparatus according to the present invention. [Diagram 2] FIG. 2 is a schematic diagram of a preferred embodiment of the device according to the invention. [Diagram 3] FIG. 3 is a diagram of the apparatus of FIG. 2 at different process steps. [Figure 4] FIG. 4 is a diagram of the apparatus of FIG. 2 at different process steps. [Diagram 5] FIG. 5 is a diagram of the apparatus of FIG. 2 at different process steps. [Figure 6] FIG. 6 is a diagram of the apparatus of FIG. 2 at different process steps. [Figure 7] FIG. 7 is a diagram of the apparatus of FIG. 2 at different process steps. [Figure 8] FIG. 8 is a diagram of the apparatus of FIG. 2 at different process steps. [Figure 9] FIG. 9 is a diagram of the apparatus of FIG. 2 at different process steps. [Figure 10] FIG. 10 is a diagram of the apparatus of FIG. 2 at different process steps. [Figure 11] FIG. 11 is a schematic diagram illustrating one embodiment of an apparatus according to the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0100] In the drawings, the same reference numbers are used to refer to the same or similar elements.

[0101] Other characteristics and advantages of the invention are explained in the following non-limiting description, with reference to the figures and examples.

[0102] Figure 1 shows a sterile sampling device according to an embodiment of the invention arranged to allow sampling of a raw material (2), which may be a planktonic cell or a (microbial) organism.

[0103] The device of Fig. 1 comprises a means (1) for sampling a material in a solution and a sealed receiving chamber (4) with a confinable space (5). The sampling means (1) is adjacent to the receiving chamber (4) with an opening (6) closed by a stopper and a receiving means (7). Furthermore, the sampling means (1) is separated from the receiving chamber (4) via a closable element, in this case a partition (9). The sampling means (1) is also arranged in a sampling chamber (11) with a guide means (12). The guide means (12) has a body (13), e.g. a cone shape, connected to the sampling means (1) at a tip (14), at one end of which a needle (14) is provided and, optionally, at the other end, a pump body (or line).

[0104] The sampling means (1) thus comprises a closed body (13) provided at one end with a needle (or any other means through which material present in the first container (3) can be passed). The body (13) is also provided at its other end opposite the needle with a line (27b). The body (13), the needle (14) and the line (27b) are thus in fluid communication.

[0105] The sampling chamber (11) is enclosed and sealed, so that the sampling means (1) is also in a sealed environment and is separated from the containment space (5) of the receiving chamber (4).

[0106] Also, the sampling chamber (11) preferably consists of a flexible body (11a) that functions like an accordion, which has a rest position (expanded accordion shape) and a sampling position (compressed accordion shape). Thus, when the flexible body (11a) is in the rest position, the entire sampling means (1) is located within the sampling chamber (11), as shown in FIG. 1. When the flexible body (11a) is in the sampling position, it is in a position folded back on itself (like an accordion in a compressed position), and the sampling means (1) is located in the confined space (5) of the receiving chamber (4). Once the sample has been taken, the flexible body (11a) is arranged to return to the rest position (the accordion is in the expanded position).

[0107] Alternatively, this flexible body (11a) may be a piston, making it possible to provide a contained environment in which the sampling means is placed. In this case, the operation described above is similar with respect to the rest and sampling positions. Such an embodiment is shown in Figure 11.

[0108] The receiving chamber (4) has at least a part of its surface made of a flexible material (15), which is optionally adjacent to the receiving means (7) that passes through this part (15) in a sealed manner, preferably along the central axis of the receiving chamber (4). Figure 1 shows a receiving chamber (4) having a part of its surface made of a flexible material (15) and another part made of a rigid material (21) (the rigidity of which is defined relative to the flexible material). Thus, the surface made of the flexible material (15) can be made of a malleable plastic and the more rigid material (15) can be made of an elastomer, preferably rubber (which is less flexible).

[0109] The receiving means (7) of the receiving chamber (4) consists of a first part (7a) located in the confinable space (5) for stably holding (without manual manipulation) a first container (3) containing the material (2) to be recovered, e.g. suspended cells (2). The first container (3) has a proximal part 3a (made of glass) which is closed when in the confinable space (5). This first part (7a) is connected to a second part (7b) located outside the receiving chamber (4). This second part (7b) extends outside the receiving chamber (4) in the form of a guide means (10) which can be oriented relative to a central axis passing through the receiving chamber (4).

[0110] Furthermore, the second portion (7b) of the receiving means (7) has a distal end (7c) connected to a first means for removing at least one fluid (18), and thus the receiving means (7) is in fluid communication with the containment space (5) of the receiving chamber (4).

[0111] Alternatively, the distal end (7c) is closed without being connected to the first means for removing at least one fluid (18). In this embodiment, the means for removing at least one fluid (18) is located elsewhere in the receiving chamber (4) so ​​as to be separated from the distal end (7c) of the receiving means (7).

[0112] Moreover, the receiving means (7) is arranged in a portion of the receiving chamber (4) made of a flexible material (15).

[0113] The receiving chamber (4) further preferably comprises in its rigid material part a closable opening (6), a means (22) for opening the first container (3) and a fluid connection (23) for the fluid.

[0114] The opening means (22) is capable of receiving the proximal portion (3a) of the first container (3) and is arranged to break the proximal portion (3a) of the first container (3) via a pivoting movement.

[0115] Depending on the type of means for closing the first container (3), the opening means (22) has a shape and function that allows aseptic access to the first container (3). This type of closure means may be a stopper, a membrane, a capsule, etc.

[0116] Obviously, if the first container (3) is provided with a partition at its proximal end (3a), the opening means (22) is not used (is not present) in the receiving chamber (4).

[0117] As shown in Fig. 1, the opening means (22) can also be connected to a fluid connection that is connected to a filtering means (26) that allows filtering a fluid, here a rinsing and / or decontamination fluid to limit contamination and dirt of the receiving chamber (4). The filtering means (26) is connected to a fluid connection of at least one filter purge fluid (24a), in the form of a line (24a) that lands in a container (24) that serves as a means for receiving at least one filter purge fluid (24).

[0118] The filtering means 26 is connected to the means 16 for supplying a decontamination fluid (hydrogen peroxide) via a decontamination fluid connection 16a, and is connected to the means 17 for supplying a rinsing fluid (water) via a rinsing fluid connection 17a.

[0119] Alternatively, if the opening means (22) is not present, the supply connections (16, 17), the filtering means (26) and the respective lines (16a, 17a, 24a) are configured to be in fluid communication with the receiving chamber (4).

[0120] In the embodiment shown in Fig. 1, the receiving chamber (4) is also in fluid communication with drying fluid (air) supply means (19). Thus, the tip (23) of the receiving chamber (4) is connected to the drying fluid (air) supply means (19) by a line (19a). The means (19) for supplying drying fluid is then also connected to a line (19b) allowing the removal of the dried fluid from the receiving chamber (4) to a receiving container (container (25) by disposal) via a pump (A).

[0121] The illustrated device also comprises fluid (here air) removal means (20), which can be arranged, for example, in the container (25) or elsewhere, depending on the arrangement of all the elements forming the device according to the invention.

[0122] Furthermore, the body (13), the needle (14) and the line (27b) are in fluid communication. The sample lines (27b, 27c) allow the material (2) in solution (suspended cells) to be transferred to the second container (8). It is also possible to rinse the sampling means (1) using a rinsing liquid supply means (27). The device may also include a removal means (28).

[0123] In practice, the second container may contain a culture medium (not shown).

[0124] A second container (8) adjacent to the receiving chamber (4) is connected to the receiving chamber (4) by a sampling means (1), through which the target material (2) is transferred.

[0125] The second container (8) has a volume larger than the volume of the first container (3) and is configured so that the raw material (2) collected from the first container (3) can be cultured when transferred to the second container (8).

[0126] Thus, FIG. 1 comprises a number of lines (16a, 17a, 18, 19a, 19b, 24a, 27a, 27b, 27c, 28) provided for the passage of at least one fluid, a number of pumps (A), and elements (19, 20, 24, 25, 26, 27) commonly used in the technical field of the invention and which can be connected in several ways to the device of the invention.

[0127] In operation, the fluid supply means (16) supplies decontamination liquid (hydrogen peroxide) to the receiving chamber (4) until it is partially filled.

[0128] The stopper of the opening (6) is then removed and a sterile vial (3) (Aseptic Technologies) containing the suspended cells (2) is introduced into the receiving chamber (4) in which the receiving means (7) is arranged with its second portion (7b) facing the opening (6). The vial (3) is thus stably accommodated within the receiving means (7). When the receiving means (7) is oriented, the flexible surface (15) of the receiving chamber (4) deforms to allow for the proper orientation. When the vial (3) is held in the receiving means (7), the latter is vertically positioned along the central axis of the receiving chamber (4).

[0129] Afterwards, the decontamination process is carried out by supplying the decontamination liquid (hydrogen peroxide) until the receiving chamber (4) is completely filled with the decontamination liquid. Once the decontamination is completed, the decontamination liquid (line (18)) in the waste container (25) is emptied for removal.

[0130] After the decontamination step, a complete filling of the receiving chamber (4) is performed with rinsing liquid (water) using the rinsing liquid supply means (17) in order to remove all traces of the decontamination liquid, followed by an emptying step towards a waste container (25). Preferably, this rinsing step is dynamic in that it removes the decontamination liquid and is therefore not limited to merely diluting it.

[0131] A drying step is then carried out, preferably by introducing compressed air via drying fluid supply means (19).

[0132] If the vial (3) needs to be broken at its proximal end (3a), it is oriented in the opening means (22) to allow a rotational / pivotal movement that breaks this end to allow access to the suspended cells (2) to be collected afterwards. This step is optional and is not required if access to the material (2) to be harvested does not require breaking any part of the container (3), for example if the container has a septum or other resealable element that allows access to the contents without breaking the vial.

[0133] The receiving means (7) for receiving the open vial is then oriented towards the sampling means (1), preferably along the central axis of the sampling chamber, so that the opening of the vial is located on the opposite side of the septum (9).

[0134] As explained above, the flexible body (11a) of the sampling chamber allows the needle (14) of the sampling means (1) to be inserted into the confined space (5) of the receiving chamber (4) by moving from a rest position (expanded accordion shape, as illustrated in FIG. 1) to a sampling position (compressed accordion shape). When the flexible body (11a) is in the sampling position, it is in a folded-back position on itself (like an accordion in a compressed 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 vial (3), ready to collect suspended cells.

[0135] By means of a pump, suction, piston system or any other sampling system that ensures sterile sampling, the suspended cells are collected and transferred to a second container (8) that contains a culture medium that is mixed with the suspended cells and allows the cells to grow. Once the sample has been taken, the flexible body (11a) is positioned to return to its rest position (with the accordion in the deployed position).

[0136] The needle (14) can therefore be replaced by a conduit that allows efficient sampling and transfer. In fact, the needle plays a rather passive role in this device, since it does not ensure the removal of floating cells, but rather allows easy and efficient access to the bottom of the vial. Other equivalent means are also suitable.

[0137] This type of handling can therefore generally be used to enable a sterile sampling procedure in a closed system (provided by the device according to the invention).

[0138] Processes of the "end-to-end" type can also be integrated with the device according to the invention and consist in integrating all the steps of the production process from raw materials to the finished product. The device according to the invention therefore makes it possible to integrate the first steps of a process known as "end-to-end".

[0139] Figure 2 shows another embodiment of the device according to the invention, similar to Figure 1 and using some of the references of Figure 1, except that the sampling means (1) is different. The sampling means (1) is arranged in a sampling chamber (11) having a guide means (12) that allows the sampling means (1) to be moved towards the receiving chamber (4), preferably along the central axis of the sampling chamber (11). The guide means (12) has a longitudinally extending groove (12a) on the outer surface (12b) of the guide means (12) for sliding the sampling means (1) so that one of the ends (1a) of the sampling means (1) is introduced into the receiving chamber (4). In this case, the needle can thus be introduced into the confinable space (5) of the receiving chamber (4).

[0140] As shown, the body (13) is provided with guide means (12) in the form of a protrusion which extends outside the sampling chamber (11).

[0141] In this embodiment, a flexible body (11a) is not required, so that part of the sampling chamber (11) can be made rigid.

[0142] The operation of the apparatus of FIG. 1 described above is also applicable here.

[0143] It should be noted that various handling steps related to decontamination, rinsing and drying may be performed by one skilled in the art in any combination of these steps depending on the handling requirements.

[0144] Figures 3 to 10 show the use of the device, particularly when rinsing and / or decontamination and / or drying are performed.

[0145] 2 to 10 can also be understood as sequentially showing how the device is implemented.

[0146] 3 shows the device according to the preferred embodiment when a decontamination liquid (such as hydrogen peroxide) is introduced into the receiving chamber (4) which is partially filled with the decontamination liquid, which may also be a rinsing liquid such as water.

[0147] FIG. 4 shows a device according to an advantageous embodiment, in which the step of positioning the first container (3) in the receiving chamber (4) is carried out by means of receiving means (7) directed towards a closable opening (6).

[0148] According to a particularly advantageous embodiment (not shown), the first container (3) is placed in a vertical position along the central axis of the receiving chamber (4) 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 the step shown in FIG. 4.

[0149] FIG. 5 shows the complete decontamination process by filling the entire receiving chamber (4) with the decontamination liquid.

[0150] FIG. 6 shows an advantageous embodiment in which a step of emptying the decontamination (or rinsing) liquid from the receiving chamber (4) is carried out.

[0151] FIG. 7 shows a complete rinsing process by filling the entire receiving chamber (4) with rinsing liquid.

[0152] Figure 8 shows an embodiment illustrating the flexibility of a portion of the receiving chamber (4). The step of opening the first container (3) is carried out after positioning the first container (3) in the opening means (22).

[0153] FIG. 9 shows a particular embodiment in which the step of positioning the opening of the first container (3) opposite the sampling means (1) is performed by rotating the receiving means (7).

[0154] FIG. 10 shows a preferred embodiment in which a sampling means (1) is placed within a first container (3) to allow sampling.

[0155] Figure 11 shows a further embodiment of the device according to the invention, including the elements described in figure 1, except for the sampling chamber consisting of a rigid body (11b) having a rest position and a sampling position. Thus, when the rigid body (11b) is in the rest position, the sampling means (1) is entirely located in the sampling chamber (11). When the rigid body (11b) is in the sampling position, the sampling means (1) is moved into the confinable space (5) of the receiving chamber (4) and comes into contact with the material (2) to be collected (in solution). Once sampling has been performed, the rigid body (11b) is arranged to return to the rest position.

[0156] In a preferred embodiment, the rigid body (11b) is a piston, as shown in Figure 11, which also provides a confined space for receiving a sampling device.

[0157] In another preferred embodiment, the sampling chamber (11) may be provided with a stopper on one of its inner walls to prevent the rigid body (11b) from accidentally exiting the sampling chamber (11) when it is in the rest position.

[0158] In a more preferred embodiment, the guide means (12) contacts a stopper to prevent the body (11b) from accidentally emerging from the sampling chamber (11) when the body (11b) is in the rest position.

[0159] The embodiment shown in FIG. 8 is not necessary if the first container (3) is provided with a resealable element, such as a septum or equivalent element.

[0160] In the drawings, the same reference numbers are used to refer to the same or similar elements.

[0161] In the context of the present invention, singular articles such as, for example, "one", "single" may be replaced by plural articles such as, for example, "at least two", "at least three", "several".

[0162] The terms "comprises", "includes" or equivalent terms and derivatives may be replaced with "consisting of".

[0163] It will be understood that the invention is in no way limited to the embodiments described above, but that many modifications can be made without departing from the scope of the appended claims.

[0164] 1. Sampling method 1a End of sampling procedure 2 Recovered raw materials 3. First Container 3a Proximal end of first container 4 Reception room 5 Confinable space 6 Closable opening 7 Acceptance means 7a First part of the receiving means 7b Second part of the receiving means 7c Distal end of receiving means 8 Second Container 9 Resealable elements, providing a seal 10 Guide means, second part of receiving means (7b) 11 Sampling Room 11a Flexible part of sampling chamber (11) 12 Guide means for sampling means (1) 12a Groove of guide means (12) 12b Outer surface of guide means (12) 13. Main body of sampling means (1) 14 Needle of sampling means (1) 15 Flexible part of receiving chamber (4) 16 Means for supplying at least one decontamination fluid 16a at least one fluid connection for decontamination fluid 17, 27 Means for supplying at least one rinsing liquid 17a At least one rinse fluid connection 18 First fluid removal means 19 Means for supplying dry fluid with a filter membrane and a hydrophobic filter 19a at least one dry fluid connection 19b Fluid connection for decontaminating at least one dry fluid fluid connection 20 Second fluid removal means 21 Rigid part 21 of the receiving chamber (4) (rigidity defined with respect to the flexible part (15)) 22 Opening means of first container (3) 24 Means for receiving at least one filter purge fluid (24) 24a at least one filter purge fluid fluid connection 25 Means for storing used fluids 26 Filtration means equipped with a hydrophilic filter 27 Means for supplying at least one rinsing liquid to the sampling means (1) 27a at least one rinsing fluid connection for the sampling means (1) 27b, 27c sample lines Means for evacuating the vessel (8) and sucking in the raw material (2) A pump means, pump F Hydrophobic or hydrophilic filters depending on the intended use

Claims

1. 1. A sterile sampling device for growing a material in a broth or for cell or microbial culture, said device comprising: a sampling means (1) for a material (2) arranged to grow in a culture medium, preferably in a solution, the sampling means (1) being adapted to aseptically collect said material (2) contained in a first container (3) of a predetermined volume; a receiving chamber (4) having a confinable volume (5) and configured to allow the passage of at least one fluid within said confinable volume (5) to decontaminate it, The receiving chamber (4) a closable opening (6) configured for the passage of the first container (3) within the confineable space (5) and configured to confine the receiving chamber (4) when closed; and receiving means (7) orientable within the confinable space (5) and configured to receive the first container (3) and position it towards the sampling means (1), the receiving means configured to aseptically collect the solution (2) contained in the first container (3) and arranged to aseptically transfer it to a second container (8) having a volume larger than the volume of the first container (3).

2. 2. The device according to claim 1, wherein the sampling means (1) is adjacent to the confinable space (5) of the receiving chamber (4) prior to sampling, and is preferably in a confined and sealed environment.

3. 3. The device according to any one of claims 1 to 2, wherein the sampling means (1) is separated from the receiving chamber (4) via a resealable element (9) selected from the group consisting of a septum, a membrane, and a solenoid valve.

4. 2. The device according to claim 1, wherein during the sampling, a part of the sampling means (1) is placed in the confinable space (5) of the receiving chamber (4).

5. 2. The device according to claim 1, wherein the sampling means (1) is arranged in a sampling chamber (11) having guiding means (12) for the sampling means (1).

6. 6. Apparatus according to claim 5, wherein the guide means (12) is arranged to move the sampling means (1) along the central axis of the sampling chamber (11) towards the receiving chamber (4).

7. 6. The apparatus according to claim 5, wherein the guide means (12) has a longitudinally extending groove (12a) on an outer surface (12b) of the guide means (12) for sliding the sampling means (1) so that one of the ends (1a) of the sampling means (1) is introduced into the receiving chamber (4).

8. 2. The device according to claim 1, wherein the sampling means (1) has a body (13) arranged to allow the passage of the raw material (2), and at one end of the body is provided a suction means (14), preferably a needle (14) or a line.

9. 2. The device according to claim 1, wherein the sampling chamber (11) is enclosed and sealed.

10. 2. The device according to claim 1, wherein the receiving chamber (4) has at least a part (15) of its surface made of flexible material, said part being adjacent to the receiving means (7) arranged to pass through said at least a part (15) of the surface of the receiving chamber (4) made of flexible material.

11. 2. The device according to claim 1, comprising a second container (8) adjacent to the receiving chamber (4) and connected to the receiving chamber (4) by the sampling means (1).

12. 12. The apparatus according to claim 11, wherein the second container (8) has a volume greater than the volume of the first container (3) and is arranged so that the raw material (2) collected from the first container (3) can be cultured when transferred to the second container (8).

13. 2. The device according to claim 1, wherein the receiving means (7) has a first part (7a) extending into the confinable space (5) and a second part (7b) in the form of a guide means (10) extending outside the receiving chamber (4), preferably along a central axis passing through the receiving chamber (4).

14. 2. The device according to claim 1, wherein said portion in the form of said guide means (10) is in fluid communication with said receiving chamber (4).

15. The receiving chamber (4) means for supplying at least one decontamination fluid (16); means for supplying at least one rinsing fluid; means (19) for supplying at least one drying fluid; a first means (18) for removing at least one fluid, optionally connected directly to one of the ends (7c) of said receiving means (7); and a second means (20) for removing drying fluid.

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