Cartridge devices and systems for use in an apparatus for automated sterility testing of radiopharmaceuticals by membrane filtration, and the placement and use of the devices and systems in such an apparatus

Abstract

The present invention relates to a cartridge device (1) for use in an apparatus (100) for automated sterility testing of radiopharmaceuticals by membrane filtration, to systems and arrangements comprising the cartridge device (1) according to the invention, and in particular to the use of the cartridge device according to the invention or the system according to the invention for automated sterility testing of radiopharmaceuticals by membrane filtration in a corresponding apparatus (100). The cartridge device (1) according to the invention comprises a base plate (12), a distributor unit (2) having valves (3a-3f), in particular three-way valves, lines (5ab-5ef) and connections (4a-4j), the distributor unit having valves (3a-3f), in particular three-way valves, lines (5ab-5ef) and connections (4a-4j), the first filter unit (7d) and the corresponding connections (4a, 4b, 4d, 4f, 4f) of the distributor unit (2 ... and at least five hoses (5a, 5b, 5d, 5f, 5g) communicating with the first filter unit (7d), one hose (5d) communicating with the first filter unit (7d), and four hoses (5a, 5b, 5f, 5g), one hose in each case configured to communicate with a first external container (16a) containing a buffer solution, an external container (16b) containing a nutrient solution, an external radiation-shielding container (16f) for waste liquid, and an external radiation-shielding container (16g) for sample material.

Description

[Technical Field]

[0001] The present invention relates to a cartridge device for use in an apparatus for automated sterility testing of radiopharmaceuticals by membrane filtration, to systems and arrangements comprising a cartridge device according to the invention, and in particular to the use of a cartridge device according to the invention or a system according to the invention for automated sterility testing of radiopharmaceuticals by membrane filtration in a corresponding apparatus. [Background technology]

[0002] European Pharmacopoeia 11.0, 2.6.1 "Sterility" (Ph.Eur.2.6.1-Sterility Test) or United States Pharmacopoeia (USP <71> Sterility testing by ) forms an important part of the quality control of pharmaceutical and medical products manufactured under aseptic conditions for human or animal use. Pharmaceutical and medical products include aqueous solutions, soluble powders, oils and oily solutions, ointments and creams, infusion bags, implants such as heart valves or stents, and surgical suture materials. Compliance with sterility testing conditions (Cleanroom Grade A, see Annex 1 of the EU GMP Guidelines) is critical for sterility testing of pharmaceutical and medical products and is often ensured by the use of isolators (sterile boxes) to prevent contamination.

[0003] Sterility testing is preferably performed using membrane filtration, a method for mechanically concentrating microorganisms from a given amount of filterable test material. This method allows for accurate microbial counts, even with minimal microbial content. In this method, a fixed volume of liquid is filtered through a membrane filter of a specified pore size, retaining the microorganisms on the filter surface. The filter is then transferred to a culture medium. The nutrients in the culture medium allow individual microorganisms to grow into diagnostic colonies. Alternatively, the contaminated filter can be transferred to a liquid culture medium. Depending on the medium, microbial growth is indicated by turbidity or, if an indicator dye is included in the medium, by a color change.

[0004] For non-filterable solutions, the drug or medical product is dissolved or diluted in an aqueous or oily solvent and then filtered. The solvent used must not adversely affect the sterility test, and in particular must not have antibacterial properties. For insoluble products (e.g., implants, surgical suture materials), testing is performed by the direct inoculation method, in which the product is introduced directly into the culture medium. Sterility testing of radiopharmaceuticals remains problematic to this day.

[0005] Although many quality aspects can already be implemented during the manufacture of radiopharmaceuticals to reduce the risk of contamination (Grade C, Grade A, automated processes, sterile disposable consumables, precursors with low microbial load, regular media filling procedures), even these measures do not exempt from carrying out legally required sterility testing of the final product to eliminate the risk to patients.

[0006] In the field of radiopharmaceuticals, sterility testing must be performed retrospectively due to the short half-life of radionuclides and incubation periods of at least 10 days. Therefore, while European Pharmacopoeia monographs (e.g., 68Ga-Edotreotide or 18F-PSMA) accept post-release sterility testing, previously presented studies have indicated that testing (e.g., membrane filtration) should be initiated as early as possible to reduce the possibility of false-negative results. The EANM Radiopharmacy Committee recommended in 2010: "Sterility testing should begin as soon as possible after the completion of SSRP production. If samples for sterility testing are held for longer storage times, small-scale radiopharmaceuticals should demonstrate that a longer period does not adversely affect the test results." The United States Pharmacopoeia (with some exceptions) sets the start of the sample incubation period at 30 hours after radiopharmaceutical production.

[0007] Regardless, relevant guidelines (EU, US, AUS) recognize the need to test radiopharmaceuticals as soon as possible after production. Comparing the literature, guidelines, and manuals, it seems difficult to justify the common practice of sending samples to external companies for sterility testing after decay has reached an acceptably low level. In the case of 177Lu or 225Ac radiopharmaceuticals, which have half-lives of 6.7 and 10 days, respectively, this means several months between production and the start of testing, which is inconsistent with the need to start testing as quickly as possible.

[0008] Due to challenges in handling and storing radioactive filtrate, the performance of membrane filtration methods for radiopharmaceuticals has remained problematic to date. Radioactive filtrate often remains within the isolator, occupying valuable space until decay below acceptable limits, posing potential contamination risks and risks to workers. Furthermore, installing conventional extraction systems for membrane filtration in isolators is difficult, as these are typically used in the manufacture of radiopharmaceuticals. Therefore, sterility testing of radioactive materials, particularly radiopharmaceuticals and / or diagnostic agents, is often performed by the direct inoculation method. The drawback is that testing is limited to small sample volumes, as radioactivity poses a problem for microbial testing. Furthermore, sterility testing of radiopharmaceuticals by the direct inoculation method is not supported by the European Pharmacopoeia (Ph.Eur.2.6.1-Sterility Testing) or the United States Pharmacopoeia (USP), where a clear preference for membrane filtration is evident. <71> ) and does not meet the legal requirements according to Ph.Eur. Monograph 04 / 2022:0125.

[0009] Alternatively, sterility testing of radioactive materials can be performed using membrane filtration after radioactivity has decayed, typically after approximately three months. However, this method can only be used for radioactive materials with short-lived nuclides. Long-lived nuclides are excluded due to the long time required. Current research results (see the contributor article "Time-dependent sterility testing to determine the viability of microorganisms and autosterilization in radiopharmaceutical therapeutics," A. Gummesson et al., EANM'21 Virtual Congress, October 20 to 23, 2021) suggest that there is still no guarantee that microbiological impurities present in pharmaceutical preparations will persist for extended periods of time until initiation. A further drawback is that sterility testing of radioactive materials several months after production is less informative, especially due to the adverse effects of radioactivity on microbial growth.

[0010] EP 3944867 A1 further discloses a system and method for testing the sterility of radioactive material, comprising an isolator and a radiation-shielding container for the radioactive material. When referring to an "isolator" or a "radiation-shielding container" in the present application, it is intended in particular to refer to the isolator and radiation-shielding container, in particular a waste container, known from EP 3944867 A1. Accordingly, the corresponding passages of the disclosure of EP 3944867 A1 should be included in the disclosure of the present application. Summary of the Invention [Problem to be solved by the invention]

[0011] The object of the present invention is, inter alia, to provide a device for automated sterility testing of radiopharmaceuticals by membrane filtration, which is compatible with existing equipment for producing radiopharmaceuticals and allows sterility testing to be performed immediately after radiopharmaceutical production in accordance with currently applicable legal regulations, in order to ensure sufficient radiation protection and improve the quality and useful value of the test results, and thus patient protection. The device should also be as cost-effective and easy to use as possible. [Means for solving the problem]

[0012] The invention is defined in the accompanying claims which disclose a cartridge device according to the invention, preferred embodiments thereof, a system according to the invention, an arrangement according to the invention, and a use according to the invention.

[0013] The present invention is closely related in technology to sterility testing by membrane filtration as standardized in European Pharmacopoeia 11.0, 2.6.1 "Sterility" and provides a particularly suitable and advantageous cartridge device, although not limited thereto, for safe and efficient performance, especially for radiopharmaceuticals, optionally as a consumable.

[0014] Some of the terms used below should be understood in particular, but not limited to, the following:

[0015] "Radiopharmaceuticals" should be understood as pharmaceuticals that are used for diagnostic or therapeutic purposes and contain radioactive components so as to emit radioactive radiation. This term also includes "radiotherapy."

[0016] In the present application, a "cartridge device" is to be understood as a device intended to be connected to an apparatus to perform a specific function. Thus, different functions can be performed with the same apparatus by using different cartridges. As already mentioned above, the cartridge device according to the present invention is preferably configured and adapted for use with systems and devices for sterility testing of radiopharmaceuticals by membrane filtration according to the European Pharmacopoeia 11.0, 2.6.1 "Sterility", although other uses are not excluded.

[0017] A "system" or "arrangement" should be understood as a combination of a device with further elements useful for performing the intended functions. In the present application, these "functions" preferably relate to sterility testing by membrane filtration.

[0018] In this application, an "apparatus" should be understood as a machine that can be connected to various cartridges or other components to perform a specific function. The apparatus may be composed of multiple modules that perform different functions. Using actuators, such as actuating members, the apparatus can interact with and actuate corresponding components of the cartridges in an automated manner.

[0019] A "radiation-shielding container" is to be understood as a container capable of containing radioactive material and which largely prevents radiation from leaking through the container to the outside, in particular a radiation-shielding container according to EP-A-3944867. An "isolator," also known as an "aseptic box" or "glove box," is to be understood as a system that is airtight and gas-tight sealed from the surrounding working space. A defined atmosphere for processing radioactive material can be generated inside the isolator, in particular an isolator according to EP-A-3944867.

[0020] "Sample material" is preferably understood as the radiopharmaceutical that must be subjected to a sterility test. It may be, for example, in the form of a solid, powder, etc. "Buffer solution" is to be understood as the liquid that is mixed with the sample material or in which the sample material is dissolved so that subsequent membrane filtration can be performed. "Nutrient solution" is to be understood as the liquid that is applied to the membrane filtration after filtration of the buffer solution in which the sample material has been dissolved in order to promote the growth of microorganisms. "Waste liquid" is to be understood as the liquid that remains after filtration and must be disposed of.

[0021] "Communication" should be understood as the establishment or existence of a fluid connection such that liquids or gases can be exchanged. In the present application, "communication" should preferably be understood as "functionally connected," which on the one hand includes the physical or mechanical connection (e.g., attachment or pugging-in) of system components, which is also functional and allows, in particular, unidirectional or multidirectional exchange of gases and liquids. When referred to below, corresponding devices and system components are arranged and configured accordingly.

[0022] The cartridge device according to the present invention is intended for use in an apparatus or system for automated sterility testing of radiopharmaceuticals by membrane filtration, possibly as standardized in European Pharmacopoeia 11.0, 2.6.1 "Sterility." It comprises a distributor unit having a base plate, a valve, particularly a three-way valve, lines, connectors, a first filter unit, and at least five hoses. The lines optionally and preferably connect the various connectors to and through the various valves, i.e., are the connection means between these components. The connectors can be selectively connected to one another via the valves, while the hoses communicate with corresponding connectors on the distributor unit. In this application, "selectively" should preferably be understood to mean interchangeable and flexibly selectable. Thus, depending on the requirements during use, the various connectors can be connected or communicated with one another in a purposeful and necessary manner. "Corresponding" should preferably be understood as a functional association, e.g., a connection is assigned its own ("corresponding") hose, a valve is assigned its own connection, and vice versa, resulting in functional component pairings that communicate or can communicate with each other. Preferred component pairings and assignments are also shown by way of example in the figures and are apparent therefrom. One hose furthermore communicates with the first filter unit, and four hoses furthermore are configured such that one hose can communicate in each case with a first external container for / containing a buffer solution, an external container for / containing a nutrient solution, an external radiation-shielding container for / containing waste liquid, and an external radiation-shielding container for / containing sample material.

[0023] The cartridge device according to the present invention and in particular its corresponding components are intended to be connected to or communicate with external components of an overall testing system, such as the various containers mentioned above. Such actual connections are realized as part of a "system for automated sterility testing" according to the present invention. In this system, the various components of the cartridge device are actually functionally connected to or communicate with corresponding system components (such as containers). The term "external" preferably refers to components that are not part of the cartridge device itself, but to which the cartridge device is functionally connected during use and thus form an overall system, particularly for sterility testing by membrane filtration.

[0024] For the production of pharmaceuticals, particularly radiopharmaceuticals, cartridge devices are already used with corresponding equipment (modules) to generate, isolate, and / or mix the individual components of pharmaceuticals in a sterile and automated manner. Because the cartridge device according to the present invention can be used in combination with the same equipment, it can be used for both pharmaceutical production and subsequent sterility testing, thus saving time and costs for transport, for example, to external laboratories. In contrast to manual testing, closed systems and automation also improve the quality of test results and human protection, since contamination of sample materials and differences in sterility test performance, as well as human contamination or radiation exposure, can be minimized. Membrane filtration also allows for the separation of microorganisms from radioactive materials, so that the microbial load of pharmaceuticals can be determined immediately after production, not just after radioactivity decay, further improving the quality of results. To further improve radiation protection, membrane filtration sterility testing can be performed in an isolator.

[0025] Preferably, the cartridge device further comprises a second filter unit and a further hose in communication with corresponding connections of the distributor unit and the second filter unit.

[0026] Providing two filter units has the advantage that the microorganisms remaining in each filter unit can be exposed to different incubation conditions, such as different culture media, incubation temperatures or incubation times, thereby further improving the quality of the test results, particularly with regard to microbial contamination with different types of microorganisms.

[0027] Preferably, the cartridge device further comprises a syringe for the syringe pump and an additional hose communicating with the corresponding connections of the dispenser unit and the syringe. In the present application, a "syringe pump" is to be understood as an arrangement consisting of a syringe and an additional actuation unit or syringe pump module. The actuation unit here may be a motor-driven clamping device into which a syringe is inserted and whose syringe plunger can be moved back and forth by a motor.

[0028] The provision of a syringe for the syringe pump means that a predetermined amount of liquid can be drawn in and expelled with high precision, which allows the predetermined mixing ratio of the respective liquids to be accurately maintained, thereby achieving consistent test conditions and therefore high-quality test results. The cartridge device can also optionally have a syringe pump.

[0029] The cartridge device also preferably includes a further hose that communicates with a corresponding connection on the dispenser unit and that is configured to communicate or be communicable with a second external container containing the nutrient solution.

[0030] Providing two nutrient solutions, in particular two different unmixed nutrient solutions, allows the microorganisms remaining in one or more filter units to be exposed to different nutrient solutions, which can further improve the quality of the test results, in particular with respect to microbial contamination with different types of microorganisms. Furthermore, when two filter units are provided, the first filter unit may be provided with a first nutrient solution and the second filter unit with a second nutrient solution, so that each filter unit can be used, for example, to determine microbial contamination with different types of microorganisms.

[0031] The cartridge device preferably further comprises at least four or at least / preferably five cannulas attached to the distal ends of the corresponding hoses, i.e. preferably away / not facing the dispenser unit, the cannulas being configured and arranged to communicate with or be communicable with an external container for / containing a buffer solution, a first external container for / containing a nutrient solution, a second external container for / containing a nutrient solution, an external radiation-shielding container for / containing waste liquid, and an external radiation-shielding container for / containing a sample substance.

[0032] Providing a cannula at the distal end of the hose makes it easier to connect the hose to the respective container and ensures that liquid does not accidentally leak outside, thus largely preventing contamination of people, especially with radioactive materials.

[0033] The distributor unit preferably comprises at least six valves, preferably all in the form of three-way valves, and at least eight connections, optionally ten connections, which may optionally be "interconnected" or in communication with each other, as defined below.

[0034] Apparatus for producing pharmaceuticals is usually configured to accommodate cartridge devices with six valves and eight or ten connections, and therefore cartridge devices according to the invention with six valves and eight or ten connections can also be used. The claimed number of valves and connections is even more particularly suitable for automated sterility testing of radiopharmaceuticals by membrane filtration.

[0035] Even more preferably, the distributor unit comprises: first, second, third, fourth and fifth lines; a first three-way valve configured to establish selective communication between a connection for supplying a buffer solution, a connection for connecting to a syringe for a syringe pump and the first line; a second three-way valve configured to establish selective communication between a connection for supplying a first nutrient solution, the first line and the second line; and a connection for supplying a second nutrient solution, the second line and the third line. a third three-way valve configured to establish a connection for connecting to the first filter unit and selectively communicate between the third line and the fourth line; a fourth three-way valve configured to establish a connection for connecting to the second filter unit and selectively communicate between the fourth line and the fifth line; and a sixth three-way valve configured to establish a selective communication between a connection for removing waste liquid, a connection for supplying a sample solution, and the fifth line.

[0036] The claimed arrangement of six three-way valves, five lines and respective connections for supplying buffer, sample solution and two nutrient solutions, for removing waste liquid, and for connecting to syringes and two filter units is particularly suitable for use in existing equipment for manufacturing pharmaceuticals and for automated sterility testing of radiopharmaceuticals by membrane filtration.

[0037] At least one of the first, second, fourth and fifth lines is preferably an integral part of the distributor unit or base plate, the third line is preferably an external hose or is an integral part of the distributor unit or base plate, and / or at least one of the first, second, third, fourth, fifth and sixth three-way valves is preferably an integral part of the distributor unit or base plate. Integral embodiments can be produced, for example, by additive manufacturing or 3D printing.

[0038] Configuring the first, second, fourth, and fifth lines as an integral part of the distributor unit has the advantage of avoiding external lines or connecting hoses, improving the compactness and robustness of the cartridge device. Configuring the third line as an external hose is structurally simpler and therefore cheaper to manufacture.

[0039] The distributor unit preferably further comprises at least one attachment, preferably at least two attachments, wherein at least one of the lines is arranged inside the attachment or one of the attachments, or between the base plate and the attachment or one of the attachments, and / or at least one of the valves extends through the base plate and / or through the attachment or one of the attachments. In the present application, an "attachment" should be understood as a component other than the base plate, which is connected to the base plate by connecting elements such as rivets, and which preferably attaches the lines and / or valves to the base plate or fixes them by clamps.

[0040] Providing at least one attachment represents a simple and cost-effective way of forming the lines and valves as an integral part of the distributor unit by locating them in or between the base plate and the attachment, or by extending them through the base plate and / or the attachment. The lines and valves are even better protected, improving the robustness of the distributor unit. Providing two attachments is particularly advantageous structurally.

[0041] The first and / or second filter units preferably comprise filter cartridges each comprising a membrane filter, at least one inlet valve, at least one outlet valve, and optionally at least one drain hose, wherein at least one of the respective inlet valves is configured to communicate with a corresponding connection of the distributor unit via a corresponding hose and / or at least one of the respective outlet valves is configured to communicate with an external radiation-shielding container for waste liquid via a drain hose. The communication or connection is preferably by a one-piece hose connection, although multi-piece connections with additional intermediate components are also included.

[0042] The claimed structure of the filter unit, with its inlet and outlet valves and membrane filter, allows for the entry and exit of liquid in a controlled manner so that the filter unit can be separated from the cartridge device after filtration without the liquid accidentally leaking outside, which would pose a health risk. The membrane filter can then be removed and further processed and analyzed separately to determine the microbial load. The provision of a drain hose has the added advantage that the liquid can be drained from the filter unit into a sealed waste container without contact with ambient air.

[0043] The inlet and / or outlet valves preferably comprise sterile filters to allow sterile venting and / or degassing of the respective filter unit or filter cartridge.

[0044] The filter unit's valve allows it to communicate with the ambient air through a sterile filter, allowing for sterile venting or degassing of the filter unit, making it easier to fill or drain liquid. The sterile filter prevents external contaminants from entering the filter unit, which could tamper with the results.

[0045] The dispenser unit of the cartridge device is preferably configured to be received by a first external actuator module, the valves are preferably configured to be actuated in an automated manner by the first external actuator module or its subcomponents, and / or the inlet and / or outlet valves of the first and / or second filter units are preferably configured to be received and actuated in an automated manner by a second external actuator module, and / or the syringe of the cartridge device is preferably configured to be received and actuated in an automated manner by an external syringe pump module or actuation unit, and / or the discharge hose of the cartridge device is preferably configured to be received by an external hose pump module. In this application, a "module" is preferably understood as an equipment unit assigned a specific task in the overall system, for example, for sterility testing by membrane filtration. Multiple modules can then be combined and assembled to form a complete system, for example, for sterility testing by membrane filtration.

[0046] The compatibility of the distributor unit, filter unit valves, syringes and discharge hoses with corresponding external actuators or pump modules provides a simple and cost-effective method of automating membrane filtration for sterility testing.

[0047] All components of the cartridge device are preferably configured for single use, or all components of the cartridge device except for the drain hose are preferably configured for single use, with the drain hose being configured or constructed as a permanent line and / or to be flushable.

[0048] Configuring the components for single use has the advantage of saving time and costs for cleaning after use and preventing residues from insufficient cleaning that could falsify test results. Because liquid cannot enter the rest of the cartridge device from the discharge hose, it can also be reused without prior cleaning, thus saving costs.

[0049] A system according to the invention for automated sterility testing of radiopharmaceuticals by membrane filtration comprises a cartridge device according to the invention, a container for / containing a buffer solution, a first container for / containing a nutrient solution, preferably a second container for / containing the nutrient solution, a radiation-shielded container for waste liquid, and a radiation-shielded container for sample material, wherein corresponding hoses of the cartridge device are in communication with the container for / containing the buffer solution, the first container for / containing the nutrient solution, the second container for / containing the nutrient solution, the radiation-shielded container for waste liquid, and the radiation-shielded container for sample material, preferably in an automated manner, for transporting liquids from or into the containers via a distributor unit of the cartridge device.

[0050] The provision of radiation-shielding containers for buffer and nutrient solutions, as well as sample materials and waste liquids, communicating with the corresponding hoses of the cartridge device, allows for automated liquid transport, particularly for sterility testing of radiopharmaceuticals by membrane filtration. The radiation-shielding containers have the advantage of shielding the radioactive materials contained therein, preventing substantial leakage of radioactivity to the outside, thus improving personnel protection. In particular, the radiation-shielding containers according to EP-A-3944867 can be used as and for waste containers. To further improve radiation protection, the system can be further housed in an isolator, preferably according to EP-A-3944867.

[0051] An arrangement according to the present invention comprises a cartridge device according to the present invention and packaging in which the cartridge device is aseptically enclosed, the cartridge device being in a disassembled, partially disassembled or assembled state within the packaging.

[0052] The sterile packaging of the cartridge device ensures that it is protected from external contamination which would falsify the results of the sterility test. Although it may be cost advantageous to provide the cartridge device in a disassembled or partially disassembled state, it is preferred that it be provided assembled to prevent the possibility of contamination from manual assembly and to provide a "plug and play" solution.

[0053] A first use according to the invention relates to the use of a cartridge device or system according to the invention for automated sterility testing of radiopharmaceuticals by membrane filtration.

[0054] A second use according to the invention relates to the use of a cartridge device or system according to the invention in an apparatus for automated sterility testing of radiopharmaceuticals by membrane filtration.

[0055] The cartridge device according to the invention is particularly suitable for use in the automated sterility testing of radiopharmaceuticals by membrane filtration, in particular in corresponding apparatus.

[0056] Further features and advantages of the present invention will become apparent from the following description of embodiments with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0057] [Figure 1] 1 shows an embodiment of a dispenser unit of a cartridge device according to the invention, where the possible connections and interconnections of the components of the dispenser unit according to the preferred embodiment are also shown in a technically clear and relevant manner. [Figure 2] 1 is an embodiment of a cartridge device according to the invention, where possible connections and interconnections of the components of the cartridge device according to a preferred embodiment are also shown in a technically clear and relevant manner. [Figure 3] FIG. 1 shows the implementation of one embodiment of a cartridge device according to the invention in an apparatus for automated sterility testing of radiopharmaceuticals. DETAILED DESCRIPTION OF THE INVENTION

[0058] The reference numbers used below and in the drawings and claims are to be taken as reference in nature and not as limitation, particularly in terms of quantity. Regardless, components with at least partly the same letter optionally indicate functional groups of the cartridge device according to the invention. For example, the reference numbers 3a, 4a, and 5a indicate that the corresponding valve 3a, the corresponding connection 4a, and the corresponding hose 5a form functional subunits of the cartridge device and can communicate with each other. Similarly, the reference number 5ab indicates a line or line section between the valves 3a and 3b.

[0059] FIG. 1 shows an embodiment of a dispenser unit (2) of a cartridge device (1) according to the invention, which can be connected to an actuator module (101) of an apparatus (100) for the automated production and / or sterility testing of radioactive substances, in particular radiopharmaceuticals.

[0060] The distributor unit (2) comprises a plurality of valves (3a-3f), in particular three-way valves, a plurality of lines (5ab-5ef), and a plurality of connections (4a-4i) that can be selectively connected to one another via the valves (3a-3f). The valves (3a-3f) are arranged in the distributor unit (2) so that they can be actuated in an automated manner by an actuator of the actuator module (101) when the cartridge device (1) is connected to the actuator module (101).

[0061] In the embodiment shown by way of example in Fig. 1, the substantially rectangular distributor unit (2) comprises six three-way valves (3a-3f), eight or ten connections (4a-4i) and five internal or external lines (5ab-5ef) connecting the valves (3a-3f) to one another, with four valves (3a, 3c, 3d, 3f) located at each corner and two valves (3b, 3e) located at each edge of the distributor unit (2). The configuration of the distributor unit (2), and in particular the arrangement of the valves (3a-3f), is compatible with actuator modules of the type "SLM2" from the company "Eckert & Ziegler."

[0062] The valves (3a, 3f) shown on the left side of Fig. 1 are each connected to two connections and one line, while the other valves (3b, 3c, 3d, 3e) are each connected to one connection and two lines. The connections (4i, 4j) shown on the right side of Fig. 1 are optional, since they can also be connected to each other via an internal line (5cd) instead of via an external line (5cd).

[0063] FIG. 2 shows an embodiment of a cartridge device (1) according to the invention, which can be connected to an actuator module (101) of an apparatus (100) for the automated production and / or sterility testing of radioactive substances, in particular radiopharmaceuticals.

[0064] The five connectors (4a, 4b, 4c, 4f, 4g) of the distributor unit (2) are connected to corresponding cannulas (6a, 6b, 6c, 6f, 6g) via corresponding hoses (5a, 5b, 5c, 5f, 5g), the two connectors (4d, 4e) of the distributor unit (2) are connected to corresponding filter units (7d, 7e) via corresponding hoses (5d, 5e), and the one connector (4h) of the distributor unit (2) is connected to a syringe (8h) via a corresponding hose (5h).

[0065] The cannulae (6a, 6b, 6c, 6f, 6g) are configured to be connectable to a buffer solution container (16a), a first nutrient solution container (16b), a second nutrient solution container (16c), a radiation-shielding waste container (16f), and a radiation-shielding sample material container (16g), respectively. The nutrient solutions in the first and second containers (16b, 16c) may be the same or different.

[0066] The filter units (7d, 7e) are detachably connected to the cartridge device (1) and each contain a filter cartridge with a membrane filter (8d, 8e), at least one inlet valve (9d, 9e), and at least one outlet valve (10d, 10e). In the illustrated embodiment, each of the filter units (7d, 7e) comprises two inlet valves (9d, 9e) in the form of a two-way valve and one outlet valve (10d, 10e) in the form of a three-way valve.

[0067] One of the two inlet valves (9d, 9e) is configured to open and close the fluid connection between the distributor unit (2) and the respective filter cartridge, and the other of the two inlet valves (9d, 9e) is equipped with a sterile filter and is configured to open and close the fluid connection between the ambient air and the respective filter cartridge to facilitate the inflow and outflow of liquid into and out of the respective filter cartridge. Alternatively, only one inlet valve (9d, 9e) in the form of a three-way valve may be provided in each case, selectively connecting the inlet of the filter cartridge to the distributor unit (2) or to the ambient air. Each outlet valve (10d, 10e) is also equipped with a sterile filter and is configured to selectively connect the outlet hose (17) to the filter cartridge or to the ambient air to facilitate the inflow and outflow of liquid into and out of the respective filter cartridge.

[0068] 3 shows an embodiment of the system according to the invention in an apparatus (100) for automated sterility testing of radioactive materials, in particular radiopharmaceuticals. In addition to the cartridge device, the system according to the invention comprises a container (16a) for a buffer solution, a first container (16b) for a nutrient solution, a second container (16c) for a nutrient solution, a radiation-shielded container (16f) for waste liquid, and a radiation-shielded container (16g) for sample material. The apparatus (100) comprises a first actuator module (101), a second actuator module (102), a first pump module (103), and a second pump module (104).

[0069] The distributor unit (2) of the cartridge device (1) is inserted into the first actuator module (101) of the apparatus (100) so that the valves (3a-3f) of the cartridge device (1) can be actuated in an automated manner by corresponding actuators of the first actuator module (101).

[0070] According to the representations in Figures 1 and 2, the first connection (4a) is connected to a container (16a) for the buffer solution via a first hose (5a) and a first cannula (6a), the second connection (4b) is connected to a container (16b) for the first nutrient solution via a second hose (5b) and a second cannula (6b), the third connection (4c) is connected to a container (16c) for the second nutrient solution via a third hose (5c) and a third cannula (6c), the sixth connection (4f) is connected to a radiation-shielded container (16f) for the waste liquid via a sixth hose (5f) and a fourth cannula (6f), and the seventh connection (4g) is connected to a radiation-shielded container (16g) for the sample material via a seventh hose (5g) and a fifth cannula (6g).

[0071] The filter units (7d, 7e) of the cartridge device (1) are inserted into the second actuator module (102) of the apparatus (100) so that the outlet valves (10d, 10e) of the filter units (7d, 7e) can be actuated in an automated manner by corresponding actuators of the second actuator module (102).

[0072] The outlet valves (10d, 10e) are connected to a radiation-shielded waste container (16f) via a common drain hose (17) or separate drain hoses. One or more drain hoses (17) may be part of the cartridge device (1) and may be configured to communicate with the radiation-shielded waste container (16f).

[0073] The syringe (8h) of the cartridge device (1) is inserted into a first pump module (103) of the apparatus (100) so that the syringe (8h) can be actuated in an automated manner by a corresponding actuator of the first pump module (103) to draw liquid from or deliver liquid to the system. Thus, the first pump module (103) can be a syringe pump module.

[0074] The discharge hose (17) is inserted into a second pump module (104) of the apparatus (100) so that a corresponding actuator (not shown) of the second pump module (104) can interact in an automated manner with the discharge hose (17) to generate a fluid flow therein, in particular to pump liquid from the filter units (7d, 7e).

[0075] The cartridge device (1) is designed for single use, but can also be reused after thorough decontamination. The filter units (7d, 7e) are detachably connected to the cartridge device (1) so that they can be separated for further processing and inspection after filtration. Inlet and outlet valves (9d, 9e, 10d, 10e) ensure that contaminated or radioactive liquids do not leak from the filter units (7d, 7e).

[0076] In the context of a particular embodiment, the following parts are particularly suitable for the cartridge device (1) according to the invention and can be conveniently designated as follows for the skilled person:

[0077] Base plate (2): "C2 manifold", Hose (5a): "PE (polyethylene) extension, M / M (male / male) LL, 50 cm" Hose (5b, 5c): "PE extension, M / F (male / female) LL, 20cm", Hose (5d, 5e): "PE extension, M / F LL, 30cm", Hose (5f, 5g): "PE extension, M / F LL, 20cm", Hose (5h): "PE extension, M / F LL, 15cm", Line (5cd): "PE extension, M / M LL, 10cm", Cannula (6a): "Codan Microspike", Cannula (6b, 6c): "Spikes Venting", Cannula (6f, 6g): "Needles Sterican 0.9 x 70mm 20G x 1 1 / 2" Syringe (8h): "BD Syringe 10ml", Sterile filter: "Hydrophobic filter 0.2 μm PTFE 28213", Connections between the filter cartridge and the outlet valve: two "Luer connectors male PP, 1 / 16 inch 1.6 mm" and "1 x 3 mm silicone hose".

[0078] Standardized membrane filtration using a cartridge device or system according to the present invention can be carried out as follows: the valves of the distributor unit (2) are set to fluidically connect the syringes (8h) to the containers (16a) containing buffer solution, and the syringes (8h) are actuated to withdraw the buffer solution from the corresponding containers (16a). The valves of the distributor unit (2) are then set to fluidically connect the syringes (8h) to the containers (16g) containing the sample material, and the syringes (8h) are actuated to supply the buffer solution to the corresponding containers (16g), with the sample material being mixed with or dissolved in the buffer solution.

[0079] The buffer solution containing the dissolved sample material is then drawn back, and the valve of the distributor unit (2) is set to fluidically connect the syringe (8h) to the first filter unit (7d), transferring a portion of the buffer solution to the first filter unit (7d). The valve of the distributor unit (2) is then set to fluidically connect the syringe (8h) to the second filter unit (7e), transferring the remainder of the buffer solution to the second filter unit (7e). The filtrate from both filter units (7d, 7e) is supplied to a waste container (16f) through a discharge hose (17).

[0080] The valves of the distributor unit (2) are then set to fluidly connect the syringe (8h) to the first container (16b) containing the nutrient solution, and the first nutrient solution is drawn in. The valves of the distributor unit (2) are then set to fluidly connect the syringe (8h) to the first filter unit (7d), and the nutrient solution is delivered to the first filter unit (7d). The corresponding procedure is repeated for the second nutrient solution (16c) and the second filter unit (7e).

[0081] The inlet valves (9d, 9e) of the filter units (7d, 7e) are then set so that the filter cartridges are isolated from the rest of the system and connected to the ambient air via the sterile filter. After the remaining liquid from the filter units (7d, 7e) has been conveyed through the discharge hose (17) to a waste container (16f), the outlet valves (10d, 10e) are closed, the filter units (7d, 7e) are isolated, and the membrane filters are removed for further processing and inspection. [Explanation of symbols]

[0082] 1 Cartridge Device 2. Distribution unit 3a to 3f valves, optionally three-way valves; 4a~4j connection part 5ab~5ef line 5a~5h hose 6a~6c, 6f~6g Cannula 7d, 7e Filter unit 8d, 8e Membrane filter in filter cartridge 9d, 9e Inlet valve 10d, 10e Outlet valve 12 Base Plate 16a Buffer solution container 16b First container for nutrient solution 16c Second container for nutrient solution 16f Waste liquid container Container for 16g sample material 17 Discharge hose 100 devices 101 first actuator module 102 second actuator module 103 First Pump Module 104 Second Pump Module

Claims

1. A cartridge device (1) for use in an apparatus (100) for automated sterility testing of radiopharmaceuticals by membrane filtration, comprising: a distributor unit (2) having a base plate (12), valves (3a-3f), in particular three-way valves, lines (5ab-5ef) and connections (4a-4j), said connections (4a-4j) being selectively communicable with one another via said valves (3a-3f) and said lines (5ab-5ef); a first filter unit (7d); At least five hoses (5a, 5b, 5d, 5f, 5g) communicating with corresponding connections (4a, 4b, 4d, 4f, 4g) of the distributor unit (2); Equipped with A cartridge device in which one hose (5d) communicates with the first filter unit (7d) and four hoses (5a, 5b, 5f, 5g) are configured so that one hose can communicate in each case with a first external container (16a) containing a buffer solution, an external container (16b) containing a nutrient solution, an external radiation-shielding container for waste liquid (16f) or an external radiation-shielding container for sample material (16g).

2. a second filter unit (7e); a further hose (5e) in communication with the distributor unit (2) and the corresponding connection (4e) of the second filter unit (7e); The cartridge device (1) of claim 1, further comprising:

3. Syringe for syringe pump (8h), a further hose (5h) in communication with the distributor unit (2) and the corresponding connection (4h) of the syringe (8h); 10. The cartridge device (1) according to any one of the preceding claims, further comprising:

4. 10. The cartridge device (1) according to any one of the preceding claims, further comprising a further hose (5c) in communication with the corresponding connection (4c) of the distributor unit (2) and configured to be able to communicate with a second external container containing a nutrient solution (16c).

5. 10. The cartridge device (1) of claim 1, further comprising at least four or at least five cannulas (6a, 6b, 6c, 6f, 6g) attached to the distal ends of the corresponding hoses (5a, 5b, 5c, 5f, 5g), the cannulas (6a, 6b, 6c, 6f, 6g) being configured and arranged to be able to communicate with the external container (16a) containing a buffer solution, the first external container (16b) containing a nutrient solution, the second external container (16c) containing a nutrient solution, the external radiation-shielding container (16f) containing a waste liquid, and the external radiation-shielding container (16g) containing a sample material.

6. A cartridge device (1) according to any one of the preceding claims, wherein the distributor unit (2) comprises at least six valves (3a-3f), preferably all in the form of three-way valves, and at least eight connections, optionally ten connections (4a-4j).

7. The distributor unit (2) First, second, third, fourth and fifth lines (5ab, 5bc, 5cd, 5de, 5ef); a first three-way valve (3a) configured to establish selective communication between a connection (4a) for supplying a buffer solution, a connection (4h) for connecting to said syringe (8h), and said first line (5ab); a connection (4b) for supplying a first nutrient solution and a second three-way valve (3b) configured to establish selective communication between said first line (5ab) and said second line (5bc); a connection (4c) for supplying a second nutrient solution, and a third three-way valve (3c) configured to establish selective communication between said second line (5bc) and said third line (5cd); a fourth three-way valve (3d) configured to establish selective communication between a connection (4d) for connecting to the first filter unit (7d), the third line (5cd) and the fourth line (5de); a connection (4e) for connecting to the second filter unit (7e) and a fifth three-way valve (3e) configured to establish selective communication between the fourth line (5de) and the fifth line (5ef); a sixth three-way valve (3f) configured to establish selective communication between a connection (4f) for removing waste liquid, a connection (4g) for supplying a sample solution, and said fifth line (5ef); A cartridge device (1) according to claim 6, comprising:

8. at least one of the first, second, fourth and fifth lines (5ab, 5bc, 5de, 5ef) is an integral part of the distributor unit (2), and the third line (5cd) is an external hose or is an integral part of the distributor unit (2), and / or 8. The cartridge device (1) of claim 7, wherein at least one of the first, second, third, fourth, fifth and sixth three-way valves (3a, 3b, 3c, 3d, 3e, 3f) is an integral part of the distributor unit (2).

9. The cartridge device (1) according to claim 8, wherein the distributor unit (2) further comprises at least one attachment, preferably at least two attachments, and wherein at least one of the lines (5ab-5ef) is arranged inside the or one of the attachments or between the base plate (12) and the or one of the attachments, and optionally fixed thereby, and / or at least one of the valves (3a-3f) extends through the base plate (12) and / or through the or one of the attachments.

10. the first and / or second filter units (7d, 7e) each comprise a filter cartridge comprising a membrane filter (8d, 8e), at least one inlet valve (9d, 9e), at least one outlet valve (10d, 10e) and preferably at least one discharge hose (17); 10. A cartridge device (1) according to any one of the preceding claims, wherein at least one of the respective inlet valves (9d, 9e) is configured to communicate with a corresponding connection (4d, 4e) of the distributor unit (2) via a corresponding hose (5d, 5e), and / or at least one of the respective outlet valves (10d, 10e) is configured to communicate with the external radiation-shielding container (16f) for waste liquid via the discharge hose (17).

11. 11. The cartridge device (1) according to claim 10, wherein the inlet valve (9d, 9e) and / or the outlet valve (10d, 10e) comprise a sterile filter for enabling sterile venting and / or degassing of the respective filter unit (7d, 7e).

12. the distributor unit (2) of the cartridge device (1) is configured to be received by a first external actuator module (101), and the valves (3a-3f) are configured to be actuated in an automated manner by the first external actuator module (101); and / or the inlet valves (9d, 9e) and / or the outlet valves (10d, 10e) of the first and / or second filter units (7d, 7e) are configured to be received and actuated in an automated manner by a second external actuator module (102); and / or the syringe (8h) of the cartridge device (1) is configured to be received and actuated in an automated manner by an external syringe pump module or actuation unit (103); and / or 10. A cartridge device (1) according to any one of the preceding claims, wherein the discharge hose (17) of the cartridge device (1) is configured to be received by an external hose pump module (104).

13. all components of said cartridge device (1) are configured for single use, or A cartridge device (1) as described in any one of the preceding claims, wherein all components of the cartridge device (1) except the drain hose (17) are configured for single use, and the drain hose (17) is configured or constructed as a permanent line and / or to be flushable.

14. 1. A system for automated sterility testing of radiopharmaceuticals by membrane filtration, comprising: A cartridge device (1) according to any one of the preceding claims, a container (16a) containing a buffer solution; a first container (16b) containing a nutrient solution; a second container (16c) preferably containing a nutrient solution; a radiation shielding container for waste liquid (16f); A radiation-shielding container for the sample material (16 g) Equipped with the corresponding hoses (5a, 5b, 5c, 5f, 5g) of the cartridge device (1) are connected to the container (16a) containing the buffer solution, the first container (16b) containing the nutrient solution, the second container (16c) containing the nutrient solution, the radiation-shielded container (16f) for waste liquid, and the radiation-shielded container (16g) for sample material; A system, optionally automated and communicating, for transporting liquid from or into said container, preferably via said distributor unit (2) of said cartridge device (1).

15. A cartridge device (1) according to any one of claims 1 to 13; The cartridge device (1) is aseptically sealed in a package. Including, Arrangement wherein said cartridge device is in a disassembled, partially disassembled or assembled state within said packaging.

16. Use of a cartridge device (1) according to any one of claims 1 to 13 or a system according to claim 14 for automated sterility testing of radiopharmaceuticals by membrane filtration.

17. Use of a cartridge device (1) according to any one of claims 1 to 13 in an apparatus (100) for automated sterility testing of radiopharmaceuticals by membrane filtration.

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