Sterile sampling device

Abstract

The present invention relates to a sterile sampling device comprising a sampling member (1) arranged to aseptically sample a raw material (2) contained in a first container (3) of a predetermined volume, and a receiving chamber (4) having a closable space (5) and arranged to sample the raw material (2) in the closable space (5) by decontaminating the receiving chamber by at least one fluid, the receiving chamber (4) is provided with a closable opening (6) and a receiving member (7) which can be oriented in the closable space (5).

Description

Technical Field

[0001] The present invention relates to a sterile sampling device configured to propagate raw materials (in culture medium) or to perform cell or microbial cultures. Background Art

[0002] In general, sampling devices are used in the pharmaceutical industry or biotechnology to collect and transfer raw materials that can be propagated in a culture medium. Such raw materials are usually in the form of solutions, suspensions, emulsions, or supernatants or plasma. Thus, the raw material can be collected from a container, for example using a syringe or a pipette, and optionally transferred to another container to propagate it in a culture medium.

[0003] Thus, raw materials can be collected and transferred from one container to another, depending on the intended purpose in the relevant technical field. In some fields of application, such as the above, raw materials must be able to be aseptically collected from a container and optionally aseptically transferred to another container, especially if a culture (cells or bacteria) is foreseen. These sampling methods are fundamental in these pharmaceutical and biotech industries, as they are part of the first step of the process. This step is crucial because it requires the ability to aseptically collect and transfer raw materials, which will affect the rest of the process.

[0004] More specifically, aseptic sampling of raw materials is crucial in different fields of application, especially when the raw materials are prone to multiplication in culture medium. This is usually referred to as "cell propagation / expansion" or "bacterial culture". Among these culture techniques, those skilled in the art are also familiar with the culture of infectious pathogens.

[0005] Another example is human mesenchymal stem cells (hMSC), which are multipotent cells that can also proliferate (similar to undifferentiated cells). They can differentiate into different cell types, such as bone marrow, cartilage, tendon, muscle or neuronal cells. hMSC have many therapeutic effects, such as cell therapy or tissue regeneration, and are currently being widely studied.

[0006] Another example of where raw materials can be carefully multiplied is in the field of cellular immunotherapy, which includes the process of producing CAR-T cells (Chimeric Antigenic Receptor-T), the purpose of which is to fight cancer with the help of the patient's own immune system. Once produced, the CAR-T cells are multiplied with the goal of being administered to the patient.

[0007] In addition, the culture can also produce vaccines or be used in the field of gene therapy.

[0008] Currently, cell or bacterial reproduction or the cultivation of infectious pathogens are the main assets for development in the field of biotechnology, to name just a few examples.

[0009] Typically, the culture of cells or infectious agents is carried out by collecting the raw materials into small storage containers. These storage containers can be ampoules or cryopreservation tubes for cells, which are usually stored at very low temperatures (between -70°C and -196°C). This process, called cryopreservation, suspends most biological activities and chemical reactions, thereby preserving the contents to be stored. Obviously, in the case of diluted raw materials or preparations, temperatures between -4°C and room temperature are sufficient.

[0010] Cells or infectious agents are usually transferred to larger containers, where environmental conditions are favorable for their growth and reproduction. These culture vessels can be petri dishes, flasks with culture media, or even bioreactors with culture media. This allows obtaining large quantities of cells or infectious agents from a small volume in order to produce molecules, drugs, vaccines, transgenic organisms or to implement gene therapy to treat certain genetic diseases.

[0011] It can be considered that in the pharmaceutical industry or biotechnology, the sampling and cultivation procedures of cells or infectious pathogens are relatively demanding, because the sampling step is the first step to effectively cultivate the culture medium free of pathogens and harmful bacteria.

[0012] However, currently the raw material is manually extracted with a syringe in a laminar flow hood. For example, the user sterilizes the storage container (vial) with an alcohol wipe, then opens the glass container, for example by breaking the container head, manually collects the suspension with a syringe, and then transfers it to another container, for example for culturing.

[0013] In this way of handling, it cannot be excluded that the user may contaminate the environment surrounding the solution to be collected, especially when the solution comes into contact with the surrounding environment. Due to the design of the laminar flow, the use of laminar flow cannot completely exclude the possibility of no specific contamination and biological contamination.

[0014] Unfortunately, each of the above steps (decontamination, opening, sampling and transfer) can result in the introduction of contaminants. Thus, insufficient surface decontamination, human operator error or malfunction of the laminar flow unit can lead to contamination. This causes significant delays and additional costs, which in turn renders the cultures unusable. In a market where liquidity is often tight, it is increasingly difficult to ensure sterility in all these steps. In addition, the use of laminar flow in special housings is costly for the user and does not guarantee aseptic sampling in a safe and systematic manner in industrial production.

[0015] Furthermore, these methods may present significant risks to handlers as they may be exposed to highly contagious and pathogenic infectious agents during various handling operations.

[0016] For these reasons, there is a need to be able to ensure aseptic sampling that is reliable, efficient, simple and rapid while reducing the risk of contaminants being transferred from the user to the solution / suspension to be collected or from the solution / suspension to be collected to the user.

[0017] It is therefore desirable to provide a device which allows easy, efficient and reliable collection of raw material from a first (holding) container, while limiting the risk of contamination as much as possible as described above. Summary of the invention

[0018] In order to solve this problem, the present invention provides a sterile sampling device for the proliferation of raw materials (2) (in culture medium) or for the cultivation of cells or microorganisms, the device comprising:

[0019] - a sampling member (1) for a raw material (2), preferably the raw material is in solution, the sampling member (1)

[0020] configured to proliferate in a culture medium, the sampling member (1) being configured to aseptically collect a raw material (2) contained in a first container (3) of a predetermined volume, and

[0021] - a receiving chamber (4) having a closable space (5) and configured to allow the decontamination of the receiving chamber (4) by the passage of at least one fluid in the closable space (5), the receiving chamber (4) being provided with:

[0022] o a closable opening (6) configured for the first container (3) in the closable space (5)

[0023] and, when closed, is configured to close the receiving chamber (4),

[0024] o A receiving member (7) capable of being oriented within the enclosable space (5) and configured to receive the first container (3) and position the first container (3) in the direction of the sampling member (1), the sampling member (1) being configured to aseptically collect the solution (2) contained in the first container (3) and to aseptically transfer the solution (3) to a second container (8), the volume of the second container (8) being greater than the volume of the first container (3).

[0025] The device according to the invention can aseptically collect raw material (2), preferably in solution, from a first container (3) of predetermined volume (preferably for storage). This can minimize the risk of contamination of the raw material (2) to be collected (in solution) and the user of the device, while increasing production yield.

[0026] The device has the advantage of being disposable, simple to use, and cheaper than current solutions, especially those requiring the use of a laminar flow hood. The device of the invention is portable and can be easily implemented on site (industrially).

[0027] Furthermore, the device according to the invention is also configured to be selectively closable.

[0028] In fact, the receiving chamber (4) can be closed by closing the closable opening (6) using a closing element, for example a plug, a membrane, a diaphragm, a valve, etc. This makes it possible to choose when to close or not close the device depending on the operating step.

[0029] When the receiving chamber (4) has a closed space (5), it is also in a sterile environment.

[0030] According to the device of the invention, the sampling member (1) can be located either inside the closable space (5), and thus inside the receiving chamber (4), or outside the receiving chamber (4).

[0031] In the first case, the closable space (5) extends to the sampling member (1). Thus, the receiving chamber (4) and the sampling member (1) can be closed by closing the closable opening (6) using a closing element, such as a plug, a membrane, a diaphragm, a valve. This makes it possible to choose when to close or not close the device depending on the operating steps. Thus, the sampling member (1) and the receiving chamber (4) can be closed and in a sterile environment.

[0032] Alternatively, the device according to the invention may also choose to have the sampling member (1) located next to (adjacent to) the closable space (5), i.e. outside the receiving chamber (4). The sampling member (1) then forms a first closed part of the device according to the invention, while the receiving chamber (4) forms a second closed part of the device according to the invention. The sampling member (1) is preferably directly (configured to) be connected (in fluid communication) with the receiving chamber (4), or indirectly connected to the receiving chamber (4) via an intermediate (fluid) connection element. The device according to the invention may comprise several parts.

[0033] This alternative provided by the device according to the invention also allows for selective closure of certain parts of the device. Thus, the sampling member (1) is located in a closed and sealed space (first part), adjacent to a receiving chamber (4) located in a second closable part of the device. In this embodiment, the receiving chamber (4) can be closed (or not) while the sampling member (1) is kept in the closed and sealed space as required throughout the treatment process. Preferably, according to this alternative mode, the receiving chamber (4) and the sampling member (1) can therefore be in fluid communication.

[0034] Thus, the receiving chamber (4) can be closed by closing the closable opening (6) by means of a closing element, for example using a plug, a membrane, a diaphragm, a (electromagnetic) valve or the like.

[0035] These embodiments that can be combined with one another provide the user with flexibility, which is particularly advantageous.

[0036] The receiving chamber of the device according to the invention can also be decontaminated at any time in a simple and effective manner.

[0037] Thus, the device according to the invention can have a closed system which allows the aseptic collection and transfer of raw materials (2) which can be propagated in a culture medium.

[0038] In view of this, the sampling device of the present invention provides an effective, simple and reliable solution for the aseptic collection (and optionally transfer) of raw materials (2) configured to be propagated in a culture medium.

[0039] In a preferred embodiment according to the present invention, the sampling member (1) is adjacent to the closable space (5) of the receiving chamber (4) before sampling, and is preferably in a closed and sealed medium. This embodiment can facilitate the sampling of the raw material (2) and effectively ensure aseptic sampling. The sampling member is preferably located outside the receiving chamber (4) before sampling. Then, the sampling member (1) advantageously forms the first closed part of the device according to the present invention, and the receiving chamber (4) forms the second closed part of the device according to the present invention. The sampling member (1) is preferably directly (configured to) be connected to the receiving chamber (4), or (configured to) be indirectly connected to the receiving chamber (4) via an intermediate (fluid) connecting element. The device of the present invention may include several parts.

[0040] This alternative provided by the device according to the invention allows for more selective closure of certain parts of the device. Thus, the sampling member (1) is located in a closed and sealed space (first part) relative to and adjacent to the receiving chamber (4) (second part of the device). In this embodiment, the receiving chamber (4) can be closed (or not) while the sampling member (1) is kept in the closed and sealed space as required during the entire treatment process. According to this advantageous embodiment, fluid communication is established between the receiving chamber (4) and the sampling member (1).

[0041] Therefore, the sampling member (1) can be closed independently of the closable space (5) of the receiving chamber (4). This can reduce the possible risk of contamination and provide fine control over the sampling member (1) and the closable space (5) of the receiving chamber (4).

[0042] Furthermore, the sampling member (1) is in a sterile environment.

[0043] Thus, the receiving chamber (4) can be closed by closing the closable opening (6) by means of a closing element, for example using a plug, a membrane, a diaphragm, a (electromagnetic) valve or the like.

[0044] This flexibility provided to the user is particularly advantageous.

[0045] In a preferred embodiment according to the invention, the sampling member (1) is preferably separated from the receiving chamber (4) by a closable element (9) selected from the group consisting of a diaphragm, a membrane and any other equivalent element that allows opening and closing in a sealed manner while ensuring aseptic sampling. Under these preferred conditions, a solenoid valve can also be used.

[0046] The closable element (9) can isolate the receiving chamber (4) from the sampling member (1) while facilitating access to the closable space (5). This can further reduce the risk of contamination. When the space (5) is closed, it can also be rinsed and / or decontaminated multiple times. The sampling member (1) and the receiving chamber (4) are preferably fluidly connected to facilitate sampling of the raw material (2).

[0047] The preceding paragraphs and the description relating to the adjacent embodiments of the sampling member (1) and the receiving chamber (4) also apply herein.

[0048] Preferably, during the sampling process, a portion of the sampling member (1) is located within the closable space (5) of the receiving chamber (4). This allows the raw material (2) to be collected from the first container (3) while limiting the residence time and exposure of the sampling member (1) in the closable space (5). More specifically, this embodiment can be implemented when the space (5) of the receiving chamber (4) is closed and sealed relative to the external surroundings.

[0049] When the receiving chamber is open to the surroundings, any introduction of the sampling member (1) into the closable space (5) of the receiving chamber is preferably avoided.

[0050] More preferably, the sampling member (1) is located in a sampling chamber (11), and the sampling chamber (11) has a guide member (12) for the sampling member (1), so that the sampling member (1) can be guided more easily for operation during the sampling process.

[0051] Advantageously, the guide member (12) is configured to move the sampling member (1), preferably along the central axis of the sampling chamber (11) towards the receiving chamber (4), so that it is easier to guide the sampling member (1) in a predetermined sampling direction.

[0052] 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 entire sampling member (1) is located in the sampling chamber (11). When the flexible body (11a) is in the sampling position, the sampling member (1) moves into the closable space (5) of the receiving chamber (4) to come into contact with the raw material (2) to be collected (in solution). When sampling is performed, the flexible body (11a) is arranged to move back to the rest position.

[0053] The raw material (2) can preferably be collected and transferred to a second container (8) by means of a pump or suction or piston system or any other sampling system that ensures aseptic sampling. The latter can include a culture medium mixed with the raw material (2) in order to amplify the raw material (2).

[0054] Optionally, the flexible body (11a) may also be a piston, which may also provide a closed environment for the sampling member to reside in. In the static position and the sampling position, the above operations are similar.

[0055] Advantageously, the guide member (12) has a groove (12a) extending longitudinally on the outer surface (12b) of the guide member (12a) for sliding the sampling member (1) so as to introduce one end (1a) of the sampling member (1) into the receiving chamber (4).

[0056] Advantageously, the sampling member (1) has a body (13), preferably a pump body (13), configured to allow the raw material (2) to pass through, and having a needle (14) or a line at one end thereof. The presence of the needle (14) or the channel makes it easy to insert the sampling member (1) into the first container (3), thus being a member that allows the passage of fluid, for example by suction. For increased efficiency, the use of a needle is preferred, as it ensures simple aseptic sampling.

[0057] Therefore, preferably, the needle (14) can be replaced by a line, which allows 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 easy and efficient access to the bottom of the first container (3) (vial). Any other equivalent member is also suitable.

[0058] It should be noted that, in order to improve efficiency, it is preferred to use a needle.

[0059] This mode of processing can therefore be used to perform aseptic sampling in a closed / closed system (provided by the device of the present invention).

[0060] Optionally, the sampling member (1) is located in a closed and sealed environment, while the receiving chamber (4) is located in a separate closable space (5).

[0061] In a preferred embodiment according to the present invention, the sampling chamber (11) is closed and sealed. This embodiment can provide the sampling member (1) with an environment that is isolated from the closable space (5) of the receiving chamber (4). Therefore, when the receiving chamber (4) is opened, the sampling chamber (11) (and the sampling member (1)) remains closed and sealed, which provides freedom of movement for operating the device while avoiding any contamination of the sampling member (1).

[0062] Furthermore, preferably, the receiving chamber (4) has at least a portion of its surface made of a flexible material (15), said portion optionally being adjacent to the receiving member (7), the receiving member (7) being configured to pass through at least a portion (15) of the surface of the receiving chamber (4) made of a flexible material. The flexible portion (15) ensures that the receiving member (7) is oriented in a manner that is convenient to operate, and preferably oriented within the entire closable space (5). This portion made of a flexible material (15) advantageously enables the receiving member (7) to move in rotation, axially and / or longitudinally. This means that it is not excluded that the receiving chamber (4) has a portion of its surface made of a rigid material, which portion is slightly flexible relative to the portion made of a flexible material. Preferably, there is a receiving chamber (4) whose surface has a portion that is deformable in space (the portion made of a flexible material) and another portion that is less deformable (the portion made of a rigid material) in order to provide some support for some elements of the receiving chamber (4).

[0063] 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 the receiving chamber (4) via the sampling member (1). The second container (8) is thus in fluid communication with the sampling member (1), so that the raw material (2) can be transferred into the second container (8), which contains a medium suitable for cell propagation or any other type of expansion of the raw material (2).

[0064] Advantageously, fluid communication can be selectively established between the second container (8) and the sampling member (1) and the receiving chamber (4) in order to minimize the presence of contaminants during the treatment process.

[0065] Preferably, the volume of the second container (8) is greater than the volume of the first container (3), and the second container (8) is arranged to allow cultivation (amplification of the raw material (2)) when the solution (2) collected in the first container (3) is transferred to the second container (8). This can be inoculated from a small container (3) to a larger container (8) to allow amplification of the raw material (2), in particular cell propagation.

[0066] In a preferred embodiment according to the invention, the receiving member (7) has a first portion (7a) extending into the closable space (5) and a second portion (7b) extending outside the receiving chamber (4) in the form of a guide member (10), preferably along a central axis passing through the receiving chamber (4). This allows the user to easily guide the receiving member manually or automatically by orienting the second portion in the form of the guide member (10) outside the receiving chamber (4) without risk of contamination.

[0067] Even more preferably, the portion in the form of the guide member (10) is in fluid communication with the receiving chamber (4). This allows the connection of a fluid removal member (18), for example by connecting a line to one end of the second portion in the form of the guide member (10). Access to the receiving chamber (4) is thus facilitated. The passage is located along the central axis of the receiving chamber (4), preferably opposite the closable opening (6).

[0068] The receiving chamber (4) is advantageously arranged to be in fluid communication with (or in fluid communication with) at least one of the following elements or combinations of elements:

[0069] - means (16) for providing at least one decontamination fluid,

[0070] - means (17) for providing at least one flushing fluid,

[0071] - means (19) for providing at least one drying fluid,

[0072] - a first member (18) for removing at least one fluid, said removal member (18) optionally being directly connected to one of the ends (7c) of said receiving member (7),

[0073] - and second means (20) for removing (drying) the fluid.

[0074] In this way, the receiving chamber (4) can be prepared before receiving the first container (3) to ensure that the closable space (5) can ensure aseptic sampling when the opening (6) is closed after the first container (3) is introduced into the closable space.

[0075] This preferred embodiment means that the receiving chamber (4) can be in fluid communication with at least one of the above-mentioned elements (16, 17, 18, 19, 20).

[0076] Preferably, the receiving chamber (4) comprises a member (22) for opening the first container (3), which opening member is preferably located in the closable space (5). The opening member (22) is configured to allow access to the raw material (2) in the first container (3). For example, the opening member (22) can, for example, easily break one of the ends of the first container (3), which can be a container made of glass, or open / unscrew a bottle stopper, or even remove the lid of the first container (3). Therefore, this additional option associated with the presence of the opening member (22) allows access to the raw material (2) contained in any type of container (3), in particular when the first container (3) is accommodated in the receiving chamber (4).

[0077] In a particularly preferred embodiment, the receiving member (7) is integrally formed. In addition, the receiving member can also be processed from a plastic or metal material block.

[0078] For example, devices according to the present invention may be manufactured by a 3D printing process or by a molding process involving the use of a series of molds.

[0079] In a preferred embodiment according to the present invention, the device is a disposable device, preferably a portable device.

[0080] In a preferred embodiment according to the present invention, the volume of the first container (3) is less than 20 mL, preferably less than 15 mL or greater than 2 mL.

[0081] The first container (3) is preferably selected from the group consisting of ampoules, cryovials, vials (available from Aseptic Technologies). The material of the first container can be made of glass or plastic.

[0082] Advantageously, the device according to the invention can be operated using automated or even robotic systems.

[0083] Further embodiments of the method according to the invention are described in the dependent claims.

[0084] definition

[0085] The term "sterile" refers to the conditions under which sampling and transfer operations are performed. In the context of the present invention, the sampling device provided can collect raw materials aseptically. In other words, every action performed using the device according to the present invention is an aseptic operation, so that the environment (e.g., a closed space) remains sterile. This also applies to sampling components configured to collect and transfer raw materials aseptically.

[0086] In the present invention, the term "raw material" includes strains or any other biological material that can be propagated in culture medium. "Raw material" is preferably in the form of solution, suspension, emulsion or supernatant. Raw material is preferably selected from the group comprising (by) cells (human or animal origin), bacteria, infectious pathogens, viruses, (live) (micro) organisms, yeast, algae, prions and mixtures thereof (composed). Preferably, ingredients or excipients that can be used for sterile solution compositions can also constitute raw materials. Preferably, the raw material is in solid form and then dissolved before being introduced into the device of the present invention, or dissolved when the container is introduced into the device of the present invention. All features of this paragraph can be combined with each other.

[0087] "(Micro)organisms" means all organisms that are not visible to the naked eye. This term includes bacteria, protozoa, microalgae, microfungi. The definition also includes plant, animal or human eukaryotic cells, cell lines derived from tissues, cancerous cells or non-cancerous cells. The definition must also include all infectious agents, whether live or inert, such as viruses or prions. The above categories can be genetically modified.

[0088] "Sealing" refers to the ability to not allow fluid (liquid, gas), dust or moisture to pass through.

[0089] The term "closable space" is understood to mean that the space can be closed relative to the external environment, in particular the outside of the receiving chamber or relative to other surrounding compartments. This feature can be connected with a closable opening. Thus, when the opening is closed, the closable space is closed and preferably also sealed. Thus, the closable space can be accessed through the closable opening, which allows a certain flexibility for the user during (manual or automatic) handling.

[0090] This closable space is arranged to be decontaminated, in particular before sampling or before introducing the first container into the receiving chamber.

[0091] In the present invention, the term "first container" may be interpreted as a "(storage) container" containing the raw material to be collected. Thus, a first container of this type may be present in large quantities (in series). Thus, according to the disclosed embodiments, the present invention may involve a plurality of first containers. Thus, a plurality of containers may be present in the receiving chamber in order to operate the device in series, or a plurality of first containers may be added individually in series one by one.

[0092] The term "secondary container" relates to an expansion container. In other words, containers of this type can also be present in large numbers (in series). This allows the expansion of starting materials, in particular cell multiplication. For example, a bioreactor can serve as a second container and contain culture medium.

[0093] As described above, the pharmaceutical or biotechnology industry will use a sampling device according to the present invention to collect and optionally transfer raw materials (2). The latter can be proliferated in a culture medium. The raw material (2) can be in the form of a solution, a suspension or a supernatant. Therefore, a sampling member (1) is used to collect the raw material (2) from a first container (3) and optionally transfer it to a second container (8) to allow it to proliferate in a culture medium. This is generally referred to as "cell propagation" or "bacterial culture". In these cultures, those skilled in the art are also aware of the cultivation of infectious pathogens, human mesenchymal stem cells (hMSC), CAR-T cells (i.e., "chimeric antigen receptor-T"), the proliferation of which is for the purpose of being administered to patients. In addition, cultivation can also be used in the field of vaccine production and gene therapy.

[0094] According to the present invention, preferably a decontamination fluid selected from the group consisting of water, hydrogen peroxide, peracetic acid and mixtures thereof may be used.

[0095] Advantageously, the drying fluid may be compressed air.

[0096] Preferably, the flushing fluid may be water.

[0097] Thus, the devices of the present invention are suitable for use in cell or bacterial propagation or in the cultivation of infectious pathogens, to name a few examples.

[0098] According to a preferred embodiment of the present invention, a first container (3) containing at least one cell in a solution (2) is introduced into a closable opening (6). The container is closed. Then, a receiving member (7) positioned along the central axis of the receiving chamber (4) faces the opening (6) and receives the first container (3), which is stably fixed in the receiving member (7). The opening (6) is closed using a closing element (such as a plug). Therefore, when the opening (6) is hermetically closed, the receiving chamber (4) is sealed, which forms a closable space (5) in the receiving chamber (4). The receiving chamber (4) is then decontaminated using a fluid. After the receiving chamber (4) is decontaminated, the first container (3) is oriented toward the sampling member (1) together with the receiving member (7). The sampling member (1) is located in the closable space (5) and reaches the bottom of the first container (3). It should be noted that the sampling member (1) is located in a closed environment before sampling. The solution (2) is collected and transferred to a second container (8) containing a culture medium by a pumping system.

[0099] Advantageously, the material collected in the solution is aseptically transferred into a second container (8) having a volume greater than that of the first container (3). These steps can be performed multiple times, namely by introducing a plurality of containers of the same type as the first container (3) in series into the receiving chamber (4).

[0100] It should be noted that the first container (3) is intended to contain raw material (2) configured to be propagated in a culture medium. The second container (8) is itself intended to contain a culture medium and the raw material (2) contained in the first container (3).

[0101] In the case of cell propagation, the volume of the second container (8) is preferably increased following the complete amplification process (often referred to as an "end-to-end" process) in order to increase the amount of amplified material to the desired final volume. The purpose is to advantageously and ultimately provide an injectable solution, preferably for pharmaceutical applications or biotechnological applications.

[0102] Thus, according to a preferred embodiment, the device according to the invention is arranged to allow the aseptic production of injectable solutions for use in the pharmaceutical field or in biotechnological applications.

[0103] Optionally, there may also be a receiving chamber (4) having a plurality of receiving members (7) in order to collect the raw material (2) from a plurality of containers (3).

[0104] The sampling device of the invention allows aseptic sampling of raw material (2), and optionally transfer of raw material (2), which is arranged to proliferate in a culture medium. Aseptic sampling can avoid unnecessary contamination of the contents of the first container, such as microbial pathogens. This has the advantage of increasing production yields, since waste of raw material (2) caused by potential contamination is limited.

[0105] The device according to the invention comprises a receiving chamber (4) which is sealed when the closable opening (6) is closed. The seal prevents the passage of fluids (liquids or gases), dust and moisture. The purpose is thus to create a closed space (5) relative to the outside of the receiving chamber (4) and optionally to the surrounding environment outside the sampling member (1).

[0106] It is worth noting that the user can be replaced by an automated robotic system, thus eliminating the need for the user to be present.

[0107] Furthermore, the receiving member (7) is orientable within the closable space (5), which allows it to be oriented as desired within the closable space (5). It is thus advantageously possible to position the receiving member (7) towards the closable opening (6) in order to orient the first container (3) towards the sampling member (1), or even preferably to orient the first container (3) at a certain position in the receiving chamber (4) in order to optionally break one of the ends of the container (made of glass) in order to access its contents.

[0108] Advantageously, the device according to the invention is sterilized by irradiation with gamma rays, preferably before processing the sample, and even before the first container (3) is introduced into the device.

[0109] The device according to the invention can amplify or multiply starting materials. It is also preferred to use the device according to the invention to dilute starting materials or to perform formulation or sterility tests. BRIEF DESCRIPTION OF THE DRAWINGS

[0110] Other characteristics, details and advantages of the invention are discussed in the following description in a non-limiting manner and with reference to the accompanying drawings and examples.

[0111] Each element included in the present invention is referenced as follows:

[0112] Sampling components (1)

[0113] The end of the sampling member (1a)

[0114] Raw materials to be collected (2)

[0115] First container (3)

[0116] The proximal end (3a) of the first container

[0117] Receiving Room (4)

[0118] Enclosed space (5)

[0119] Closable opening (6)

[0120] Receiving member (7)

[0121] The first part (7a) of the receiving member

[0122] Second part of receiving member (7b)

[0123] The distal end (7c) of the receiving member

[0124] Second container (8)

[0125] Resealable element (9) - provides a seal

[0126] Guide member (10) - second part of receiving device (7b)

[0127] Sampling room (11)

[0128] The flexible portion (11a) of the sampling chamber (11)

[0129] Guide member (12) of sampling member (1)

[0130] The groove (12a) of the guide member (12)

[0131] The outer surface (12b) of the guide member (12)

[0132] The main body (13) of the sampling member (1)

[0133] Needle (14) of sampling member (1)

[0134] The flexible portion (15) of the receiving chamber (4)

[0135] Means (16) for providing at least one decontamination fluid

[0136] A fluid interface (16a) for at least one decontamination fluid

[0137] Means (17, 27) for providing at least one flushing fluid

[0138] Fluid connection (17a) for at least one flushing fluid

[0139] First liquid removal member (18)

[0140] A member (19) for providing a drying fluid, provided with a filter membrane and a hydrophobic filter

[0141] Fluid connection (19a) for at least one dry fluid

[0142] Fluid connection (19b) for decontaminating a fluid connection of at least one dry fluid

[0143] Second fluid removal member (20)

[0144] Rigid part 21 of the receiving chamber (4) (rigidity is defined relative to the flexible part (15))

[0145] Opening member (22) of first container (3)

[0146] A member (24) for receiving at least one filter cleaning fluid

[0147] At least one filter to remove fluid from the fluid connection (24a)

[0148] Components for storing used fluids (25)

[0149] Filter element with hydrophilic filter (26)

[0150] Means (27) for providing at least one flushing fluid to a sampling member (1)

[0151] A fluid interface (27a) for at least one flushing fluid for the sampling member (1)

[0152] Sampling line (27b, 27c)

[0153] Component for venting a container (8) and for extracting raw material (2)

[0154] Pumping member, pump (A)

[0155] Hydrophobic or hydrophilic filter (F), depending on intended use

[0156] Figure 1 is a schematic diagram of an embodiment of a device according to the present invention.

[0157] Figure 2 is a schematic diagram of a preferred embodiment of the device according to the present invention.

[0158] Figures 3 to 10 yes Figure 2 Schematic diagram of the device according to different operating steps.

[0159] Fig.11 is a schematic diagram of one embodiment of the device according to the present invention.

[0160] In the drawings, identical or similar elements are provided with the same reference numerals. DETAILED DESCRIPTION

[0161] Other characteristics and advantages of the invention will be elucidated in the following non-limiting description with reference to the accompanying drawings and examples.

[0162] Figure 1 A sterile sampling device according to one embodiment of the invention is shown, which device can be arranged to allow sampling of a raw material (2).The raw material (2) can be suspended cells or (micro)organisms.

[0163] Figure 1 The device comprises a member (1) for sampling a raw material in a solution and a sealed receiving chamber (4) having a closed space (5). The sampling member (1) is adjacent to the receiving chamber (4), which is provided with an opening (6) closed by a stopper and a receiving member (7). In addition, the sampling member (1) and the receiving chamber (4) appear to be separated by a closable element, in this case by a diaphragm (9). In addition, the sampling member (1) is located in a sampling chamber (11), which has a guide member (12). The guide member (12) is conical and is connected to the sampling member (1) at a body (13), such as a top end (14), one end of which is provided with a needle (14) and optionally a pump body (or pipeline) at the other end.

[0164] Thus, the sampling member (1) has a sealed body (13) at one end of which is provided with a needle (or any other member capable of allowing the raw material in the first container (3) to pass through). The other end of the body (13) (opposite to the needle) is provided with a pipeline (27b). Thus, the body (13), the needle (14) and the pipeline (27b) are in fluid communication.

[0165] The sampling chamber (11) is closed and sealed, and so is the sampling member (1), which is located in a closed environment, isolated from the closed space (5) of the receiving chamber (4).

[0166] Furthermore, the sampling chamber (11) comprises a flexible body (11a) which preferably functions like an accordion, having 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 member (1) is located inside the sampling chamber (11), such as Figure 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 state), and then the sampling member (1) is located in the closed space (5) of the receiving chamber (4). After the sampling is completed, the flexible body (11a) will return to the static position (accordion in an expanded state).

[0167] Optionally, the flexible body (11a) may also be a piston, which can also provide a closed environment for the sampling member. In the static position and the sampling position, the above operations are similar. Fig.11 This embodiment is shown.

[0168] At least a portion of the surface of the receiving chamber (4) is made of a flexible material (15), said portion optionally being adjacent to said receiving member (7), through which portion (15) the receiving member (7) passes in a sealed manner, preferably along the central axis of the receiving chamber (4). Figure 1A receiving chamber (4) is shown, part of its surface being made of a flexible material (15) and another part being made of a rigid material (21) (this rigidity being defined relative to the flexible material). Thus, the surface made of the flexible material (15) can be made of a ductile plastic, while the more rigid material (15) can be made of an elastomer, preferably rubber (less ductile).

[0169] The receiving member (7) of the receiving chamber (4) comprises a first part (7a) located in the closable space (5) and stably fixing (without manual intervention) a first container (3) containing raw material (2) to be collected, such as suspended cells (2). The first container (3) has a proximal part 3a (made of glass) and is closed when it is in the closable space (5). The first part (7a) is connected to a second part (7b) located outside the receiving chamber (4). The second part (7b) extends outside the receiving chamber (4) in the form of a guide member (10), which can be oriented relative to the central axis passing through the receiving chamber (4).

[0170] Furthermore, the second portion (7b) of the receiving member (7) has a distal end (7c) connected to the first member for removing at least one fluid (18). Thus, the receiving member (7) is in fluid communication with the closable space (5) of the receiving chamber (4).

[0171] Optionally, the distal end (7c) is closed and not connected to the first member for removing at least one fluid (18). In this embodiment, the member for removing at least one fluid (18) is located at another position of the receiving chamber (4) so ​​as to be separated from the distal end (7c) of the receiving member (7).

[0172] Furthermore, the receiving member (7) is located on the portion of the receiving chamber (4) made of flexible material (15).

[0173] The receiving chamber (4) also comprises, preferably in its rigid material part, a closing opening (6), means (22) for opening the first container (3) and a fluid connection (23) for the fluid.

[0174] The opening member (22) is capable of receiving the proximal end portion (3a) of the first container (3) and breaking the proximal end portion (3a) of the first container (3) by pivoting movement.

[0175] Depending on the type of closing member of the first container (3), the opening member (22) will have a shape and function that allows aseptic access to the first container (3). Such a closing member can be a stopper, a membrane or a capsule, among others.

[0176] Obviously, when the first container (3) is provided with a septum at the proximal end (3a) of the first container (3), the opening member (22) is not used (or even does not exist) in the receiving chamber (4).

[0177] like Figure 1 As shown, the opening member (22) can also be connected to a fluid connection, which is connected to a filter member (26). This filter member (26) can filter a fluid, here a flushing and / or decontamination fluid, to limit contamination and soiling of the receiving chamber (4). The filter member (26) is connected to a fluid connection for at least one filter cleaning fluid (24a), which takes the form of a pipeline (24a) located in a container (24), which serves as a member for receiving at least one filter cleaning fluid (24).

[0178] The filter element (26) is also connected to a means for providing a decontamination fluid (hydrogen peroxide) (16) via a decontamination fluid connection (16a). In addition, the filter element (26) is also connected to a means for providing a flushing fluid (water) (17) via a flushing fluid connection (17a).

[0179] Optionally, when the opening member (22) is absent, the supply connections (16, 17), the filtering member (26) and their respective lines (16a, 17a, 24a) are arranged to be in fluid communication with the receiving chamber (4).

[0180] exist Figure 1 In the embodiment shown, the receiving chamber (4) is also fluidically connected to a member (19) for providing a drying fluid (air). Thus, the top end (23) of the receiving chamber (4) is connected to the drying fluid (air) providing member (19) via a pipeline (19a). The drying fluid providing member (19) is then also connected to a pipeline (19b) which can remove the dried fluid from the receiving chamber (4) into a receiving container (via disposal, container (25)) via a pump (A).

[0181] The illustrated device also comprises fluid (here air) removal means (20), which may be located, for example, within the container (25) or elsewhere, depending on the arrangement of all the elements constituting the device of the invention.

[0182] In addition, the body (13), the needle (14) and the pipeline (27b) are in fluid communication. The sampling pipelines (27b, 27c) can transfer the raw material (2) (suspended cells) in solution to the second container (8). The sampling member (1) can also be rinsed using a member (27) for providing a rinsing fluid. The device can also include a removal member (28).

[0183] In practice, the second container may contain culture medium (not shown).

[0184] A second container (8) adjacent to the receiving chamber (4) is connected to the receiving chamber (4) via the sampling member (1), and the target raw material (2) is transferred therethrough.

[0185] The volume of the second container (8) is greater than that of the first container (3), and the second container (8) is configured to allow culturing when the raw material (2) collected from the first container (3) is transferred to the second container (8).

[0186] therefore, Figure 1 It includes several pipelines (16a, 17a, 18, 19a, 19b, 24a, 27a, 27b, 27c, 28) allowing at least one fluid to pass through, several pumps (A), and elements (19, 20, 24, 25, 26, 27) commonly used in the technical field of the present invention, and these elements can be connected to the device of the present invention in various ways.

[0187] During operation, decontamination fluid (hydrogen peroxide) is provided by the fluid providing member (16) until the receiving chamber (4) is partially filled.

[0188] Then, the stopper of the opening (6) is removed and a sterile vial (3) (provided by Aseptic Technologies) containing the suspended cells (2) is introduced into the receiving chamber (4), wherein the second portion (7b) of the receiving member (7) is oriented toward the opening (6). Thus, the vial (3) is stably accommodated in the receiving member (7). When the receiving member (7) is oriented, the flexible surface (15) of the receiving chamber (4) is deformed for proper orientation. When the vial (3) is placed in the receiving member (7), the latter is placed vertically along the central axis of the receiving chamber (4).

[0189] The decontamination step is then carried out by supplying the receiving chamber (4) with a decontamination fluid (hydrogen peroxide) until the receiving chamber (4) is completely filled with the decontamination fluid. Once the decontamination is complete, emptying is immediately carried out to eliminate the decontamination fluid in the disposal container (25) (line (18)).

[0190] After the decontamination step, the receiving chamber (4) is completely filled with a flushing fluid (water) using a flushing fluid supply means (17) to eliminate all traces of the decontamination fluid. Subsequently, an emptying step towards the disposal container (25) is performed. Preferably, this flushing step is dynamic, since it eliminates the decontamination fluid and is therefore not limited to a simple dilution.

[0191] Then a drying step is carried out by means of a drying fluid supply means (19), preferably by introducing compressed air.

[0192] When the proximal end (3a) of the vial (3) needs to be broken, it is oriented in the opening member (22) and then broken by a rotational / pivoting movement so as to be able to access the suspended cells (2) to be collected. This step is optional and is not necessary when access to the raw material (2) to be collected does not require breaking a part of the container (3). For example, this step is not necessary when the container is equipped with a septum or any other resealable element that allows access to the contents of the vial without breaking the container.

[0193] Then, the receiving member (7) containing the open vial is positioned towards the sampling member (1), preferably along the central axis of the sampling chamber. Thus, the opening of the vial is located opposite the septum (9).

[0194] As mentioned above, the flexible body (11a) of the sampling chamber can enable the needle (14) of the sampling member (1) to move from a static position (such as Figure 1 The flexible body (11a) is moved from the expanded accordion shape shown in the figure to the sampling position (compressed accordion shape) so as to be inserted into the closable space (5) of the receiving chamber (4). When the flexible body (11a) is in the sampling position, it is in a position folded back on itself (like a compressed accordion), and the sampling member (1) is then located in the closed space (5) of the receiving chamber (4), more precisely at the bottom of the vial (3) in which the suspended cells are to be collected.

[0195] By means of a pump or suction or piston system or any other sampling system that ensures aseptic sampling, the suspended cells are collected and transferred to a second container (8). The latter contains a culture medium that is mixed with the suspended cells to allow the cells to multiply. After sampling is completed, the flexible body (11a) is arranged to return to the rest position (accordion in the unfolded position).

[0196] Therefore, the needle (14) can be replaced by a catheter, which allows efficient sampling and transfer. In fact, the role of the needle in the device is quite passive, since it does not ensure the removal of suspended cells, but allows easy and efficient access to the bottom of the vial. Any other equivalent member is also suitable.

[0197] This type of processing can therefore generally be used for sterile sampling members (provided by the device according to the invention) in a closed system.

[0198] An "end-to-end" type process can also integrate the device of the invention, consisting of integrating all the steps of the production process from raw materials to the finished product. Thus, the device according to the invention can integrate the first step of a process called "end-to-end".

[0199] Figure 2 and Figure 1 Similar, and by using Figure 1The reference part describes another embodiment of the device according to the invention, except that the sampling member (1) is different. The sampling member 1 is located in a sampling chamber (11), and the sampling chamber (11) has a guide member (12) that allows the sampling member (1) to be moved, preferably along the central axis of the sampling chamber (11) towards the receiving chamber (4). The guide member (12) has a groove (12a) that extends longitudinally on the outer surface (12b) of the guide member (12) so that the sampling member (1) slides and thus introduces one of the ends (1a) of the sampling member (1) into the receiving chamber (4). In this case, the needle can thus be introduced into the closed space (5) of the receiving chamber (4).

[0200] As shown in the figure, a guide member (12) is provided on the main body (13) and is in the shape of a protrusion, extending to the outside of the sampling chamber (11).

[0201] In this embodiment, no flexible body (11a) is required, which makes it possible to have a partially rigid sampling chamber (11).

[0202] Above Figure 1 The operation of the device shown also applies here.

[0203] It should be noted that different processing steps are involved in decontamination, rinsing and drying. Those skilled in the art can combine these steps as needed according to the requirements in the processing process.

[0204] Figure 3-Figure 10 It is shown how to use the device, in particular when performing rinsing and / or stain removal and / or drying.

[0205] These Figure 2-Figure 10 It can also be understood as showing how the device is implemented in sequence.

[0206] Figure 3 The device according to the preferred embodiment is shown, when a decontamination fluid (such as hydrogen peroxide) is introduced into the receiving chamber (4), the receiving chamber (4) is partially filled with the decontamination fluid. The fluid may also be a flushing fluid such as water.

[0207] Figure 4 A device according to an advantageous embodiment is shown, wherein the step of placing the first container (3) in the receiving chamber (4) is performed by said receiving member (7), which is oriented towards the closable opening (6).

[0208] According to a particularly advantageous embodiment (not shown), the first container (3) is placed vertically along the central axis of the receiving chamber (4) when the decontamination fluid (such as hydrogen peroxide) partially or completely fills the receiving chamber (4). The fluid may be a flushing fluid (such as water). This step may be located at Figure 4After the steps shown.

[0209] Figure 5 The complete decontamination step by filling the entire receiving chamber (4) with the decontamination fluid is shown.

[0210] Figure 6 An advantageous embodiment is shown, in which a step of emptying the receiving chamber (4) of the decontamination (or flushing) fluid is performed.

[0211] Figure 7 A complete flushing step is shown by filling the entire receiving chamber (4) with flushing fluid.

[0212] Figure 8 An embodiment is shown, wherein flexibility of a portion of the receiving chamber (4) is shown.After positioning the first container (3) in the opening member (22), a step of opening the first container (3) is performed.

[0213] Fig. 9 A particular embodiment is shown in which the step of positioning the opening of the first container ( 3 ) opposite the sampling member ( 1 ) is performed by pivoting the receiving member ( 7 ).

[0214] Fig.10 A preferred embodiment is shown, wherein the sampling member (1) is placed in a first container (3) for sampling.

[0215] Fig.11 Another embodiment of the device of the present invention is shown, which comprises Figure 1 The elements described in the above description, except that the sampling chamber includes a rigid body (11b), which has a rest position and a sampling position. Therefore, when the rigid body (11b) is in the rest position, the entire sampling member (1) is located in the sampling chamber (11). When the rigid body (11b) is in the sampling position, the sampling member (1) is moved into the closed space (5) of the receiving chamber (4) to contact the raw material (2) to be collected (in solution). After sampling is completed, the rigid body (11b) is arranged to move back to the rest position.

[0216] In a preferred embodiment, the rigid body (11b) is a piston, such as Fig.11 As shown, it also provides an enclosed space for receiving a sampling device.

[0217] In another preferred embodiment, a stopper is provided on an inner wall of the sampling chamber (11), so as to prevent the rigid body (11b) from accidentally leaving the sampling chamber (11) when in a static position.

[0218] In a more preferred embodiment, the guide member (12) is in contact with the stopper to prevent the rigid body (11b) from accidentally detaching from the sampling chamber (11) when in the rest position.

[0219] When the first container (3) is provided with a resealable element, such as a septum or any equivalent element, Figure 8 The implementation shown is not required.

[0220] In the drawings, identical or similar elements have the same reference numerals.

[0221] In the context of the present invention, any singular article, such as "a", "an", "the", "the", "its", or any reference without a specific number may include a plural reference, such as "at least 2", "at least 3", "several", etc.

[0222] “Includes”, “comprising” or any equivalent terms or derivatives may be replaced by “consisting of” to define a list or exclusive selection possibilities, thereby excluding other elements not mentioned in the used expression.

[0223] It should be understood that the present invention is by no means limited to the above-described embodiments and that several modifications may be made thereto without departing from the scope of the appended claims.

Claims

1. A sterile sampling device for the proliferation of raw materials in a culture medium or for the cultivation of cells or microorganisms, the device comprising: a sampling member (1) for a raw material (2), preferably said raw material being in solution, said sampling member (1) being arranged to be propagated in a culture medium, said sampling member (1) being configured to aseptically collect said raw material (2) contained in a first container (3) of predetermined volume, and - a receiving chamber (4) having a closable space (5) and configured to allow the decontamination of the receiving chamber (4) by the passage of at least one fluid in the closable space (5), the receiving chamber (4) being provided with: o a closable opening (6) configured for passage of the first container (3) in the closable space (5) and, when closed, configured to close the receiving chamber (4), o A receiving member (7) capable of being oriented within the enclosable space (5) and configured to receive the first container (3) and position the first container (3) in the direction of the sampling member (1), the sampling member (1) being configured to aseptically collect the solution (2) contained in the first container (3) and arranged to aseptically transfer the solution (2) to a second container (8) having a volume greater than the volume of the first container (3).

2. The device according to claim 1, wherein the sampling member (1) is adjacent to the closable space (5) of the receiving chamber (4) before sampling, and is preferably in a closed and sealed environment.

3. Device according to any of the preceding claims, wherein the sampling member (1) is separated from the receiving chamber (4) via a resealable element (9), the resealable element (9) being selected from the group consisting of a diaphragm, a membrane and a solenoid valve.

4. A device according to any one of the preceding claims, wherein: During the sampling, a portion of the sampling member (1) is located in the closable space (5) of the receiving chamber (4).

5. Device according to any of the preceding claims, wherein the sampling member (1) is located in a sampling chamber (11), the sampling chamber (11) having a guide member (12) for the sampling member (1).

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

7. A device according to claim 5, wherein the guide member (12) has a groove (12a) extending longitudinally on the outer surface (12b) of the guide member (12) for sliding the sampling member (1) so as to introduce one end (1a) of the sampling member (1) into the receiving chamber (4).

8. Device according to any of the preceding claims, wherein the sampling member (1) has a body (13) arranged to allow the raw material (2) to pass therethrough and provided with a suction member (14), preferably a needle (14) or a line, at one end of the body (13).

9. The device according to any of the preceding claims, wherein the sampling chamber (11) is closed and sealed.

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

11. Device according to any of the preceding claims, comprising a second container (8) adjacent to the receiving chamber (4), the second container (8) being connected to the receiving chamber (4) via the sampling member (1).

12. The device according to claim 11, wherein the volume of the second container (8) is greater than the volume of the first container (3), and the second container (8) is arranged to allow cultivation when the raw material (2) collected from the first container (3) is transferred to the second container (8).

13. A device according to any of the preceding claims, wherein the receiving member (7) has a first part (7a) extending into the enclosable space (5) and a second part (7b) extending outside the receiving chamber (4) in the form of a guide member (10), preferably extending along a central axis passing through the receiving chamber (4).

14. Device according to any of the preceding claims, wherein the portion in the form of a guide member (10) is in fluid communication with the receiving chamber (4).

15. The device according to any one of the preceding claims, wherein the receiving chamber (4) is configured to be in fluid communication with at least one of the following elements or a combination thereof: - means (16) for providing at least one decontamination fluid, - means (17) for providing at least one flushing fluid, - means (19) for providing at least one drying fluid, - a first member (18) for removing at least one fluid, said removal member (18) optionally being directly connected to one of the ends (7c) of said receiving member (7), and - Second means (20) for removing the drying fluid.

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