Cartridge device and system for use in an apparatus for automated sterility testing of radiopharmaceuticals by means of membrane filtration, as well as arrangement and use of the device and of the system 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 means of membrane filtration; a system and an arrangement comprising the cartridge device (1) according to the invention; and the use of the cartridge device according to the invention or of the system according to the invention for automated sterility testing of radiopharmaceuticals by means of membrane filtration, in particular in a corresponding apparatus (100). The cartridge device (1) according to the invention comprises: a distributor unit (2) having a base plate (12), valves (3a-3f), in particular three-way valves, lines (5ab-5ef), and connections (4a-4j), wherein the connections (4a-4j) can communicate selectively with one another via the valves (3a-3f) and lines (5ab-5ef); a first filter unit (7d); and at least five hoses (5a, 5b, 5d, 5f, 5g) which communicate with corresponding connections (4a, 4b, 4d, 4f, 4g) of the distributor unit (2), wherein one hose (5d) communicates with the first filter unit (7d) and four hoses (5a, 5b, 5f, 5g) are designed such that one hose thereof communicates with a first external container with buffer solution (16a), one hose thereof communicates with an external container with nutrient solution (16b), one hose thereof communicates with an external radiation-shielded container for waste solution (16f), and one hose thereof communicates with an external radiation-shielded container for sample material (16g).

Description

[0001] Cassette device and system for use in an apparatus for automated sterility testing of radiopharmaceuticals by membrane filtration, and arrangement and use of the device or system in such an apparatus

[0002] Technical area

[0003] The present invention relates to a cassette device for use in an apparatus for automated sterility testing of radiopharmaceuticals by means of

[0004] Membrane filtration, a system and an arrangement comprising the cassette device according to the invention, as well as the use of the cassette device according to the invention or the system according to the invention for automated sterility testing of radiopharmaceuticals by means of

[0005] Membrane filtration, especially in an appropriate apparatus.

[0006] Background and state of the art

[0007] An important part of the quality control of medicinal products and medical devices manufactured under aseptic conditions for use in humans or animals is the sterility test according to the European Pharmacopoeia "European Pharmacopoeia" 11.0, 2.6.1 "Sterility" (Ph. Eur. 2.6.1 - Testing for sterility) or "US Pharmacopoeia" (USP <71> ). Medicinal products and medical devices include aqueous solutions, soluble powders, oils and oily solutions, ointments and creams, infusion bags, implants, e.g., heart valves or stents, and surgical sutures. Crucial for the sterility testing of medicinal products and medical devices is compliance with aseptic testing conditions (cleanroom class A, see EU GMP Guidelines, Annex 1), which is often achieved by using an isolator (sterile box) for

[0008] Contamination avoidance is ensured. Sterility testing is preferably carried out using the membrane filtration method. The membrane filtration method is a process for the mechanical enrichment of microorganisms from any quantity of filterable test material. Even with minimal germ content, this method enables exact germ count determinations. A specific volume of a liquid is filtered through a membrane filter with a defined pore size, whereby the germs contained therein are retained on the filter surface. The filter is then placed on a nutrient medium. The nutrients in the medium enable the individual germs to grow into diagnosable colonies. Alternatively, the contaminated filters can be transferred to liquid nutrient media.Depending on the medium, the proliferation of microorganisms is indicated either by turbidity or, if indicator dyes are contained in the medium, by color changes.

[0009] In the case of non-filterable solutions, the medicinal product or medical device is dissolved or diluted in aqueous or oily solvents and then filtered. The solvent used must not negatively influence the sterility test, in particular it must not exhibit any antimicrobial properties. In the case of insoluble products (e.g., implants, surgical suture material), the test is performed using the direct-loading method, whereby the product is introduced directly into the culture medium. Sterility testing of radiopharmaceuticals has been a problem to date.

[0010] In order to reduce the risk of contamination, many quality aspects can already be implemented during the production of radiopharmaceuticals (Class C, Class A, automated processes, sterile consumables for single use, precursors with low bacterial load, periodically performed "Media Fill Procedures"), but even these measures do not release from the legally required performance of the sterility testing of the

[0011] End products to eliminate risks for patients.

[0012] In the field of radiopharmacy, sterility testing must be performed retrospectively due to the short half-life of the radionuclides and the incubation time of at least 10 days. The monographs of the European Pharmacopoeia (e.g. 68Ga-edotreotide or 18F-PSMA) therefore accept sterility testing after release, although studies presented in the past indicated that testing (e.g. membrane filtration) should be started as early as possible to reduce the likelihood of false negative results. As early as 2010, the EANM Radiopharmacy Committee recommended: "Sterility testing should begin as soon as possible after completion of SSRP production. If the sample for sterility testing is stored for an extended period, small radiopharmacies should demonstrate that the longer period does not adversely affect the test results." The "U.S.Pharmacopoeia" specifies (with some exceptions) the start of the sample incubation period to be no later than 30 hours after the preparation of a radiopharmaceutical.

[0013] Regardless, relevant guidelines (EU, US, AUS) recognize the need to test radiopharmaceuticals as soon as possible after manufacture. Comparing literature, guidelines and guidance documents, it seems difficult to justify the current practice of sending samples to an external company for sterility testing after decay has reached acceptable low levels. In the case of 177Lu or 225Ac radiopharmaceuticals with half-lives of 6, 7 and 10 days respectively, this means that several months elapse between manufacture and the start of testing, which does not meet the requirement to test as soon as possible. Due to the challenges of handling and storing the radioactive filtrate, implementing the membrane filtration process for radiopharmaceuticals has been problematic.The radioactive filtrates often remain in the isolators and consume valuable space until they decay below the exemption limit, posing a potential contamination risk and a danger to operators. Furthermore, it is difficult to integrate the conventional extraction systems for membrane filtration into the isolators, as these are typically used for the production of radiopharmaceuticals. Therefore, the sterility testing of radioactive substances, particularly radioactive pharmaceuticals and / or diagnostics, is often carried out using the direct loading method. A disadvantage is that the testing is limited to a small sample quantity, as radioactivity is problematic for germ testing. Furthermore, the sterility testing of radioactive pharmaceuticals using the direct loading method does not comply with the legal requirements of the European Pharmacopoeia (Ph. Eur. 2.6.1 - Sterility Testing), the US Pharmacopoeia (USP <71> )and Ph . Eur .-Monograph 04 / 2022:0125, here a clear preference for membrane filtration can be assumed.

[0014] Alternatively, the sterility testing of radioactive substances can be performed using a membrane filter after the radioactivity has subsided, particularly after approximately three months. However, this method can only be performed for radioactive substances containing short-lived nuclides. Long-lived nuclides are excluded due to the high time required. Current research results (see poster presentation: "Time-dependent sterility testing to determine the viability of microorganisms and autosterilization in radiopharmaceutical therapeutics," A. Gummesson et al., EANM'21 Virtual Congress, October 20-23, 2021) suggest that, in addition, there is no guarantee that any microbiological contaminants present in the medicinal product that survive for a long time until preparation will be removed.Another disadvantage is that sterility testing several months after the radioactive substances have been produced is of little significance, particularly due to the negative influence of radioactivity on germ growth.

[0015] EP 3944867 A1 further discloses a system and a method for testing the sterility of radioactive substances, comprising an insulator and a radiation-shielded container for radioactive substances. When reference is made in this application to an "insulator" or a "radiation-shielded container," this refers in particular to the insulator or radiation-shielded container, in particular waste container, known from EP 3944867 A1. The corresponding disclosures in EP 3944867 A1 are therefore to be incorporated into the disclosure of this application.

[0016] The object of the present invention is, among other things, to provide a device for automated sterility testing of radiopharmaceuticals using membrane filtration. This device is compatible with existing equipment for producing radiopharmaceuticals, ensures adequate radiation protection, and allows the sterility testing to be performed immediately after the radiopharmaceuticals have been produced and in accordance with currently applicable legal regulations, in order to improve the quality and significance of the test results and thus ultimately patient protection. The device should also be as cost-effective and easy to use as possible.

[0017] Description of the invention

[0018] The present invention is defined in the appended claims, which disclose a cassette device according to the invention, preferred embodiments thereof, a system according to the invention, an arrangement according to the invention, and uses according to the invention. The present invention is technologically closely related to the sterility testing by means of membrane filtration standardized in "European Pharmacopoeia" 11.0, 2.6.1 "Sterility" and provides a particularly suitable and advantageous cassette device, optionally as a consumable therefor, for its efficient and safe implementation, in particular on radiopharmaceuticals, but is not limited thereto.

[0019] Some of the terms used below are to be understood in particular, but not restrictively, as follows:

[0020] "Radiopharmaceuticals" are drugs used for diagnostic or therapeutic purposes that contain radioactive components and thus emit radioactive radiation. This also includes "radiotherapeutics."

[0021] A "cassette device" is understood here to mean a device which is intended to be connected to an apparatus in order to fulfil a specific function. By using different cassettes, different functions can thus be fulfilled with the same apparatus. Preferably, as already mentioned above, the cassette device according to the invention is set up and designed to be used in systems and devices for the sterility testing of radiopharmaceuticals by means of membrane filtration in accordance with "European Pharmacopoeia" 11.0, 2.6.1 "Sterility". However, uses which deviate from this are not excluded.

[0022] A "system" or "arrangement" is understood to be the combination of a device with other elements that are used to fulfill the intended function. In the present case, these "functions" preferably relate to sterility testing using membrane filtration. An "apparatus" is understood here to be a machine that can be connected to various cassettes or other components in order to fulfill specific functions. The apparatus can consist of several modules that fulfill different functions. Using actuators such as control elements, the apparatus can automatically interact with or operate corresponding components of the cassette.

[0023] A "radiation-shielded container" is understood to be a container that can hold radioactive substances and largely prevents radiation from escaping through the container. In particular, this is understood to be a radiation-shielded container according to EP 3944867 A1. An "isolator", also known as a "sterile box" or "glove box", is understood to be a system that is hermetically and gas-tightly sealed from the surrounding work space. A defined atmosphere for processing radioactive substances can be created within the isolator. In particular, this is understood to be an isolator according to EP 3944867 A1.

[0024] “Sample material” is preferably understood to mean a radiopharmaceutical on which the sterility test must be carried out. It can, for example, be in the form of a solid, a powder or similar. “Buffer solution” is understood to mean a liquid that is mixed with the sample material or in which the sample material is dissolved in order to be able to carry out subsequent membrane filtration. “Nutrient solution” is understood to mean a liquid that is added to the membrane filter after filtration of the buffer solution with the sample material dissolved in it in order to promote bacterial growth. “Waste solution” is understood to mean the liquid that remains after filtration and must be disposed of. “Communicating” is understood to mean the creation or existence of a fluid connection so that liquids or gases can be exchanged."Communicating" is preferably understood here as "functionally connected" and includes, on the one hand, a physical or mechanical connection (e.g., plugging or unplugging) of system components, which is also functional and allows one-way or multi-way exchange, in particular of gases and liquids. Where mentioned accordingly below, the corresponding device and system components are arranged and configured accordingly.

[0025] The cassette device according to the invention is intended to be used in an apparatus or system for the automated sterility testing of radiopharmaceuticals by means of membrane filtration, optionally the sterility testing by means of membrane filtration standardized in “European Pharmacopoeia” 11.0, 2.6.1 “Sterility”. It comprises a distribution unit with a base plate, valves, in particular three-way valves, lines and connections, a first filter unit and at least five hoses. Optionally and preferably, the lines connect the various connections with and via the various valves, i.e., they are the connecting means between these components. The connections can communicate selectively with one another via the valves, while the hoses communicate with the corresponding connections of the distribution unit. Preferably, “selective” is to be understood here as switchable among one another and flexibly selectable.Depending on the application requirements, the various connections can be connected or communicated with one another in a targeted and needs-based manner. Preferably, "corresponding" is to be understood as a functional relationship, e.g. a connection is assigned its own ("corresponding") hose and a valve is assigned its own connection and vice versa, resulting in functional component pairings that communicate or can communicate with one another. Preferred component pairings and assignments are also shown and can be seen in the drawings as examples. One hose also communicates with the first filter unit and four hoses are further designed so that one hose each can be connected to a first external container for / with buffer solution, an external container for / with nutrient solution, an external radiation-shielded container for / with waste solution oran external radiation-shielded container for / with sample material.

[0026] The cassette device according to the invention, in particular its corresponding components, are intended to be connected to external components of an overall test system or to communicate with them, for example the various containers mentioned above. Such an actual connection is realized within the framework of the "system for automated sterility testing" also according to the invention. In this system, the various components of the cassette device are and are then actually functionally connected to the corresponding system components (containers, etc.) or communicate with them. The term "external" preferably refers to components that are not part of the cassette device itself, but are components with which the cassette device is functionally connected during use and thus forms an overall system, among other things, for sterility testing by means of membrane filtration.

[0027] For the production of pharmaceuticals, in particular radiopharmaceuticals, cassette devices are already used in conjunction with corresponding equipment (modules) in order to generate, isolate and / or mix the individual components of the pharmaceuticals in a sterile and automated manner. Since the cassette device according to the invention can be used in conjunction with the same equipment, this can be used both for the production and for the subsequent sterility testing of the pharmaceuticals, thus saving time and costs, e.g. for transport to an external laboratory. Thanks to the closed system and the automation, the quality of the test results and personal protection are also improved because, in contrast to manual testing, possible contamination of the sample material and differences in the performance of the sterility test as well as possible contamination or radiation exposure of persons can be minimized.Membrane filtration also allows the separation of microbes from radioactive material, allowing the microbial contamination of pharmaceuticals to be determined immediately after their manufacture and not only after the radioactivity has subsided, thereby further improving the quality of the results. To further improve radiation protection, sterility testing can be performed using membrane filtration in an isolator.

[0028] Preferably, the cassette device further comprises a second filter unit and a further hose which communicates with a corresponding connection of the distribution unit and the second filter unit.

[0029] The provision of two filter units has the advantage that the germs remaining in the respective filter units can be exposed to different incubation conditions such as different nutrient media, incubation temperatures or incubation times, whereby the quality of the test results, in particular with regard to bacterial contamination by different types of germs, can be further improved.

[0030] Preferably, the cassette device further comprises a syringe for a syringe pump and another tube that communicates with a corresponding connection of the distribution unit and the syringe. In this case, a "syringe pump" refers to an arrangement comprising a syringe and an additional actuating unit or syringe pump module. The actuating unit can be a motor-driven clamping device in which the syringe is inserted and the syringe plunger can be moved back and forth by a motor.

[0031] Providing a syringe for a syringe pump allows specified amounts of liquid to be aspirated and dispensed with high precision. This ensures that the specified mixing ratios of the respective liquids are precisely maintained, thereby achieving consistent test conditions and thus high-quality test results. Optionally, the cassette device can also be equipped with a syringe pump.

[0032] Preferably, the cassette device further comprises a further tube which communicates with a corresponding connection of the distribution unit and is configured to communicate or be able to communicate with a second external container with nutrient solution.

[0033] The provision of two nutrient solutions, in particular two different and pure nutrient solutions, makes it possible for the germs remaining in the filter unit or in the filter units to be exposed to different nutrient solutions, whereby the quality of the test results, in particular with regard to germ contamination by different types of germs, can be further improved. If two filter units are also provided, the first filter unit can be supplied with the first nutrient solution and the second filter unit with the second nutrient solution, so that the respective filter units can be used, for example, to determine the germ contamination by different types of germs.

[0034] Preferably, the cassette device further comprises at least four or at least / preferably five cannulas, attached to the distal end of the corresponding tubes, i.e. preferably remote / facing away from the distribution unit, wherein the cannulas are designed and provided in such a way as to communicate or be able to communicate with the external container for / with buffer solution, the first external container for / with nutrient solution, the second external container for / with nutrient solution, the external radiation-shielded container for / with waste solution or the external radiation-shielded container for / with sample material.

[0035] The provision of cannulas at the distal end of the tubes makes it easier to connect the tubes to the respective containers and ensures that no liquid can accidentally escape to the outside, thus preventing contamination of persons, especially by radioactive material, as far as possible.

[0036] The distribution unit preferably comprises at least six valves, preferably all in the form of three-way valves, and at least eight connections, optionally ten connections. These valves and connections can optionally be "interconnected" or communicate with each other, as defined below.

[0037] Apparatus for the production of pharmaceuticals is usually designed to accommodate cassette devices with six valves and eight or ten connections, so that the cassette device according to the invention with six valves and eight or ten connections can also be used therewith. Furthermore, the claimed number of valves and connections is particularly suitable for the automated sterility testing of radiopharmaceuticals using membrane filtration.

[0038] More preferably, the distribution unit comprises a first, second, third, fourth and fifth line, a first three-way valve which is configured to establish selective communication between a connection for supplying buffer solution, a connection for connecting to the syringe for a syringe pump and the first line, a second three-way valve which is configured to establish selective communication between a connection for supplying a first nutrient solution, the first line and the second line, a third three-way valve which is configured to establish selective communication between a connection for supplying a second nutrient solution, the second line and the third line, a fourth three-way valve which is configured to establish selective communication between a connection for connecting to the first filter unit, the third line and the fourth line, a fifth three-way valve,which is arranged to establish selective communication between a connection for connection to the second filter unit, the fourth line and the fifth line, and a sixth three-way valve which is arranged to establish selective communication between a connection for the discharge of waste solution, a connection for the supply of sample solution and the fifth line.,

[0039] The claimed arrangement of the six three-way valves, five lines and the respective connections for supplying the buffer solution, the sample solution and the two nutrient solutions, for removing waste solution and for connecting to the syringe and the two filter units is particularly suitable for use in an existing apparatus for producing pharmaceuticals and for the automated sterility testing of radiopharmaceuticals by means of membrane filtration.

[0040] Preferably, at least one of the first, second, fourth, and fifth lines is an integral component of the distribution unit or the base plate, and the third line is an external hose or an integral component of the distribution unit or the base plate, and / or at least one of the first, second, third, fourth, fifth, and sixth three-way valves is an integral component of the distribution unit or the base plate. Integral embodiments can be produced, for example, by additive manufacturing or 3D printing.

[0041] Designing the first, second, fourth, and fifth lines as an integral part of the distribution unit has the advantage of eliminating the need for external lines or connecting hoses, thus improving the compactness and robustness of the cassette device. Designing the third line as an external hose is structurally simpler and therefore more cost-effective to manufacture.

[0042] 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 case, an “attachment” is to be understood as a component different from the base plate, which is connected to the base plate by connecting means, for example riveting, and in this case preferably fastens or clamps the lines and / or the valves to the base plate.

[0043] The provision of at least one attachment represents a simple and cost-effective way of forming the lines and valves as integral components of the distribution unit by arranging them within or between the base plate and the attachment, or by extending through the base plate and / or the attachment. Furthermore, the lines and valves are better protected, thereby improving the robustness of the distribution unit. The provision of two attachments is particularly advantageous from a design perspective.The first and / or the second filter unit preferably comprises filter cartridges, each having 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 communicates with a corresponding connection of the distribution unit via a corresponding hose and / or at least one of the respective outlet valves is configured to communicate with the external radiation-shielded container for waste solution via the drain hose. The communication or connection is preferably effected by a one-piece hose connection, but multi-piece connections with intermediate additional components are also included.

[0044] The claimed design of the filter units with inlet valves, outlet valves and membrane filters allows for the controlled introduction and discharge of liquid in order to separate the filter units from the cassette device after filtration without liquid being able to accidentally escape to the outside, which would pose a health risk. The membrane filter can then be removed and further processed and examined separately to determine the microbial load. The provision of a drain hose also has the advantage that liquid can be drained from the filter units into a shielded container for waste solution without contact with the ambient air.

[0045] Preferably, the inlet valves and / or the outlet valves comprise sterile filters to enable sterile ventilation and / or venting of the respective filter units or filter cartridges.

[0046] The sterile filters allow the valves of the filter units to communicate with the ambient air, allowing sterile ventilation and venting of the filter units, which facilitates filling and draining of the filter units with liquid. Thanks to the sterile filters, no external contamination can enter the filter units, which would otherwise falsify the results.

[0047] Preferably, the distribution unit of the cassette device is configured to be received by a first external actuator module, and the valves are configured to be automatically actuated by the first external actuator module or its subcomponents, and / or the inlet valves and / or the outlet valves of the first and / or second filter unit are configured to be received by a second external actuator module and automatically actuated, and / or the syringe of the cassette device is configured to be received by an external syringe pump module or an actuating unit and automatically actuated, and / or the drain hose of the cassette device is configured to be received by an external peristaltic pump module. In the present case, a “module” is preferably understood to mean an apparatus unit which has a specific task in an overall system, e.g. for sterility testing by means of membrane filtration.Several modules can then be combined and assembled to form a complete system, e.g. for sterility testing using membrane filtration.

[0048] The compatibility of the distribution unit, the valves of the filter units, the syringe and the drain hose with corresponding external actuator or pump modules represents a simple and cost-effective way to automate membrane filtration for sterility testing.

[0049] Preferably, all components of the cassette device are designed for single use, or all components of the cassette device with the exception of the drain hose are designed for single use, and the drain hose is designed or constructed as a permanent line and / or flushable. Designing the components for single use has the advantage of saving time and money on cleaning after use, and avoiding residues from inadequate cleaning that would falsify the test result. Since no liquid can leak from the drain hose into the rest of the cassette device, it can be reused without prior cleaning, thus saving costs.

[0050] A system according to the invention for the automated sterility testing of radiopharmaceuticals by means of membrane filtration comprises a cassette device according to the invention, a container for / with buffer solution, a first container for / with nutrient solution and preferably a second container for / with nutrient solution, a radiation-shielded container for waste solution and a radiation-shielded container for sample material, wherein the corresponding tubes of the cassette device communicate with the container for / with buffer solution, the first container for / with nutrient solution, the second container for / with nutrient solution, the radiation-shielded container for waste solution and the radiation-shielded container for sample material, preferably in order to transport liquids from the containers or into the containers via the distribution unit of the cassette device, optionally to transport them automatically.

[0051] The provision of containers with buffer solution and nutrient solution as well as radiation-shielded containers for sample material and waste solution, which communicate with the corresponding tubes of the cassette device, enables in particular the automated transport of liquids for sterility testing of radiopharmaceuticals by means of membrane filtration. The radiation-shielded containers have the advantage that they shield the radioactive substances contained therein, so that essentially no radioactivity can escape to the outside, thereby improving personal protection. In particular, radiation-shielded containers according to EP 3944867 A1 can be used, in particular as s and for the waste container. To further improve radiation protection, the system can also be housed in an isolator, preferably according to EP 3944867 A1.

[0052] An arrangement according to the invention comprises a cassette device according to the invention and a package in which the cassette device is enclosed in a sterile manner, wherein the cassette device is in a disassembled, partially disassembled or assembled state in the package.

[0053] The sterile packaging of the cassette device ensures that the cassette device is protected from external contamination that would contaminate the sterility test results. Providing the cassette device in a disassembled or partially disassembled state may be advantageous for cost reasons; however, providing it in an assembled state is preferred to avoid possible contamination during manual assembly and to provide a plug-and-play solution.

[0054] A first use according to the invention relates to the use of the cassette device according to the invention or the system according to the invention for automated sterility testing of radiopharmaceuticals by means of membrane filtration.

[0055] A second use according to the invention relates to the use of the cassette device according to the invention or the system according to the invention in an apparatus for automated sterility testing of radiopharmaceuticals by membrane filtration. The cassette device according to the invention is particularly suitable for use in automated sterility testing of radiopharmaceuticals by membrane filtration, in particular in a corresponding apparatus.

[0056] Short description of the drawings

[0057] Further features and advantages of the present invention will become apparent from the following description of the embodiments with reference to the accompanying drawings. These drawings show:

[0058] Fig. 1 shows an embodiment of a distribution unit of a cassette device according to the invention, wherein possible connections and interconnections of the components of the

[0059] Distribution unit according to a preferred

[0060] The design is technically clear and relevant;

[0061] Fig. 2 shows an embodiment of an inventive

[0062] Cassette device, wherein possible connections and interconnections of the components of the cassette device according to a preferred embodiment are also highlighted in a technically clear and relevant manner;

[0063] Fig. 3 shows an implementation of an embodiment of the cassette device according to the invention in an apparatus for automated sterility testing of radiopharmaceuticals;

[0064] Description of preferred embodiments

[0065] The reference numerals used below and in the drawings and claims are generally to be considered informative and non-limiting, particularly with regard to their number. Notwithstanding this, at least partially identical letter components optionally indicate functional groups of the cassette device according to the invention. For example, reference numerals 3a, 4a, and 5a indicate that the corresponding valve 3a, the corresponding connection 4a, and the corresponding hose 5a form a functional subunit of the cassette device and can communicate with each other. Similarly, reference numeral 5ab denotes a line or a line section between the valves 3a and 3b.

[0066] Fig. 1 shows an embodiment of a distribution unit (2) of a cassette 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.

[0067] The distribution 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 selectively communicate with one another via the valves (3a-3f). The valves (3a-3f) are arranged on the distribution unit (2) such that, when the cassette device (1) is connected to an actuator module (101), they can be automatically actuated by the actuators of the latter.

[0068] In the exemplary embodiment shown in Fig. 1, the substantially rectangular distribution unit (2) comprises six three-way valves (3a-3f), eight or ten connections (4a-4i), and five internal or external lines (5ab-5ef) that interconnect the valves (3a-3f), with four valves (3a, 3c, 3d, 3f) each arranged in a corner and two valves (3b, 3e) each arranged on an edge of the distribution unit (2). The design of the distribution unit (2), in particular the arrangement of the valves (3a-3f), is compatible with an actuator module of the type "SLM2" from "Eckert & Ziegler". While the valves (3a, 3f) shown on the left in Fig. 1 are each connected to two ports and one line, the remaining valves (3b, 3c, 3d, 3e) are each connected to one port and two lines. The valves shown in Fig.1 The connections (4i, 4j) shown on the right are optional, since they can be connected to each other via an internal line (5cd) instead of an external line (5cd).

[0069] Fig. 2 shows an embodiment of a cassette 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.

[0070] Five connections (4a, 4b, 4c, 4f, 4g) of the distribution unit (2) are connected to corresponding cannulas (6a, 6b, 6c, 6f, 6g) via corresponding tubes (5a, 5b, 5c, 5f, 5g), two connections (4d, 4e) of the distribution unit (2) are connected to corresponding filter units (7d, 7e) via corresponding tubes (5d, 5e), and one connection (4h) of the distribution unit (2) is connected to a syringe (8h) via a corresponding tube (5h).

[0071] The cannulas (6a, 6b, 6c, 6f, 6g) are configured to be connectable to a container for buffer solution (16a), a first container for nutrient solution (16b), a second container for nutrient solution (16c), a radiation-shielded container for waste solution (16f), or a radiation-shielded container for sample material (16g). The nutrient solutions in the first and second containers (16b, 16c) can be the same or different.

[0072] The filter units (7d, 7e) are detachably connected to the cassette 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 embodiment shown, each of the filter units (7d, 7e) has two inlet valves (9d, 9e) in the form of two-way valves and a

[0073] Outlet valve (lOd, lOe) in the form of a three-way valve.

[0074] While one of the respective two inlet valves (9d, 9e) is configured to open or close a fluid connection between the distribution unit (2) and the respective filter cartridge, the other of the respective two inlet valves (9d, 9e) is equipped with a sterile filter and configured to open or close a fluid connection between the ambient air and the respective filter cartridge in order to facilitate the inlet and outlet of liquid from the respective filter cartridge. Alternatively, only one inlet valve (9d, 9e) in the form of a three-way valve can be provided, which selectively connects the inlet of the filter cartridge to the distribution unit (2) or the ambient air. The respective outlet valves (10d, 10e) are also equipped with sterile filters and configured to selectively connect the drain hose (17) to the filter cartridges or the ambient air in order to facilitate the inlet and outlet of liquid from the respective

[0075] filter cartridge to facilitate.

[0076] Fig. 3 shows an embodiment of a system according to the invention in an apparatus (100) for automated sterility testing of radioactive substances, in particular radiopharmaceuticals. In addition to the cassette device, the system according to the invention comprises a container for buffer solution (16a), a first container for nutrient solution (16b), a second container for nutrient solution (16c), a radiation-shielded container for waste solution (16f), and a radiation-shielded container for sample material (16g). 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). The distribution unit (2) of the cassette device (1) is inserted into the first actuator module (101) of the apparatus (100), so that the valves (3a-3f) of the cassette device (1) can be actuated automatically by corresponding actuators of the first actuator module (101).

[0077] According to the nomenclature of Fig. 1 and 2, the first connection (4a) is connected via the first tube (5a) and the first cannula (6a) to the container for buffer solution (16a), the second connection (4b) via the second tube (5b) and the second cannula (6b) to the first container for nutrient solution (16b), the third connection (4c) via the third tube (5c) and the third cannula (6c) to the second container for nutrient solution (16c), the sixth connection (4f) via the sixth tube (5f) and the fourth cannula (6f) to the radiation-shielded container for waste solution (16f), and the seventh connection (4g) via the seventh tube (5g) and the fifth cannula (6g) to the radiation-shielded container for sample material (16g).

[0078] The filter units (7d, 7e) of the cassette 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 automatically by corresponding actuators of the second actuator module (102).

[0079] The outlet valves (10d, 10e) are connected to the radiation-shielded waste solution container (16f) via a common drain hose (17) or separate drain hoses. The drain hose (17) or the drain hoses can be part of the cassette device (1) and can be configured to communicate with the radiation-shielded waste solution container (16f).

[0080] The syringe (8h) of the cassette device (1) is inserted into the first pump module (103) of the apparatus (100), so that the syringe (8h) can be automatically actuated by a corresponding actuator of the first pump module (103), whereby fluid can be sucked from the system or discharged into the system. The first pump module (103) can thus be a syringe pump module.

[0081] The drain hose (17) is inserted into the second pump module (104) of the apparatus (100) so that a corresponding actuator (not shown) of the second pump module (104) can interact automatically with the drain hose (17) to generate a fluid flow therein, in particular to pump liquid out of the filter units (7d, 7e).

[0082] The cassette device (1) is designed for single use, but could also be reused after thorough decontamination. The filter units (7d, 7e) are detachably connected to the cassette device (1), allowing them to be removed after filtration for further treatment and examination. The inlet and outlet valves (9d, 9e, 10d, 10e) ensure that no contaminated or radioactive fluid can escape from the filter units (7d, 7e).

[0083] For the cassette device (1) according to the invention, the following components are particularly suitable within the scope of a specific embodiment and can be designated as follows for the person skilled in the art: Base plate (2): "C2-Manifold",

[0084] Hose (5a): “PE (polyethylene) extension, M / M

[0085] (male / male) LL, 50cm", hoses (5b, 5c): "PE extension, M / F (male / female) LL,

[0086] 20 cm" , Hoses (5d, 5e) : "PE extension, M / F LL, 30cm",

[0087] Hoses (5f, 5g): "PE extension, M / F LL, 20cm",

[0088] Hose (5h): "PE extension, M / F LL, 15cm",

[0089] Cable (5cd) : "PE extension, M / M LL, 10cm",

[0090] Cannula (6a): “Codan microspike”,

[0091] Cannulas (6b, 6c) : "Spikes Venting", Cannulas (6f, 6g) : "Needles Sterican 0.9x70mm 20Gxl 1 / 2" Syringe (8h) : "Syringe BD 10ml",

[0092] Sterile filter: "Hydrophobic filter 0.2pm PTFE 28213",

[0093] Connection between filter cartridges and outlet valves: 2 “Luer connectors male PP, 1 / 16" 1.6mm” and “silicone tube 1x3mm”.

[0094] Standardized membrane filtration using the cassette device or system according to the invention can be carried out and performed as follows. The valves of the distribution unit (2) are set so that a fluid connection exists between the syringe (8h) and the container with buffer solution (16a), and by actuating the syringe (8h), buffer solution is aspirated from the corresponding container (16a). Then, the valves of the distribution unit (2) are set so that a fluid connection exists between the syringe (8h) and the container with sample material (16g), and by actuating the syringe (8h), the buffer solution is directed into the corresponding container (16g), where the sample material mixes with or dissolves in the buffer solution.

[0095] Next, the buffer solution with the sample material dissolved in it is sucked in again, the valves of the distribution unit (2) are adjusted so that fluid communication exists between the syringe (8h) and the first filter unit (7d), and a portion of the buffer solution is pumped into the first filter unit (7d). Then, the valves of the distribution unit (2) are adjusted so that fluid communication exists between the syringe (8h) and the second filter unit (7e), and the remainder of the buffer solution is pumped into the second filter unit (7e). The filtrate from both filter units (7d, 7e) is pumped into the waste solution container via the drain hose (17).

[0096] (16f)

[0097] The valves of the distribution unit (2) are then adjusted so that fluid communication exists between the syringe (8h) and the first container with nutrient solution (16b), and the first nutrient solution is drawn in. The valves of the distribution unit (2) are then adjusted so that fluid communication exists between the syringe (8h) and the first filter unit (7d), and the nutrient solution is conveyed into the first filter unit (7d). A similar procedure is repeated for the second nutrient solution (16c) and the second filter unit (7e).

[0098] The inlet valves (9d, 9e) of the filter units (7d, 7e) are then adjusted so that the filter cartridges are separated from the rest of the system and connected to the ambient air via sterile filters. The remaining liquid from the filter units (7d, 7e) is conveyed through the drain hose (17) into the waste solution container (16f) before the outlet valves (10d, 10e) are closed, the filter units (7d, 7e) are separated, and the membrane filters are removed for further treatment and examination.

[0099] List of reference symbols

[0100] 1 cassette device

[0101] 2 distribution unit

[0102] 3a-3f valves, optional three-way valves,

[0103] 4a-4j connections

[0104] 5ab-5ef lines

[0105] 5a-5h hoses

[0106] 6a-6c, 6f-6g cannulas

[0107] 7d, 7e filter units

[0108] 8d, 8e membrane filter in filter cartridge

[0109] 9d, 9e intake valves lOd, lOe exhaust valves

[0110] 12 Base plate

[0111] 16a Container for buffer solution

[0112] 16b first container for nutrient solution c second container for nutrient solution f container for waste solution g container for sample material

[0113] Abi ass hose 0 Apparatus 1 first actuator module 2 second actuator module 3 first pump module 4 second pump module

Claims

Patent claims 1. Cassette device (1) for use in an apparatus (100) for automated sterility testing of radiopharmaceuticals by means of membrane filtration, comprising a distribution unit (2) with a base plate (12), valves (3a-3f), in particular three-way valves, lines (5ab-5ef) and connections (4a-4j), wherein the connections (4a-4j) can communicate selectively with each other via the valves (3a-3f) and lines (5ab-5ef), a first filter unit (7d) and at least five tubes (5a, 5b, 5d, 5f, 5g) which are connected to corresponding connections (4a, 4b, 4d, 4f, 4g) of the Distributor unit (2), wherein a tube (5d) communicates with the first filter unit (7d) and four tubes (5a, 5b, 5f, 5g) are arranged such that one tube each can communicate with a first external container with buffer solution (16a), an external container with nutrient solution (16b), an external radiation-shielded container for waste solution (16f) or an external radiation-shielded container for sample material (16g).

2. Cassette device (1) according to claim 1, further comprising a second filter unit (7e) and a further hose (5e) communicating with a corresponding connection (4e) of the distribution unit (2) and the second filter unit (7e).

3. Cassette device (1) according to one of the preceding claims, further comprising a syringe for a syringe pump (8h) and a further tube (5h) which communicates with a corresponding connection (4h) of the distribution unit (2) and the syringe (8h). Cassette device (1) according to one of the preceding claims, further comprising a further tube (5c) which communicates with a corresponding connection (4c) of the distribution unit (2) and is arranged to be able to communicate with a second external container with nutrient solution (16c). Cassette device (1) according to one of the preceding claims, further comprising at least four or at least five cannulas (6a, 6b, 6c, 6f, 6g) attached to the distal end of the corresponding tubes (5a, 5b, 5c, 5f, 5g), wherein the cannulas (6a, 6b, 6c, 6f, 6g) are designed and provided to be able to communicate with the external container with buffer solution (16a), the first external container with nutrient solution (16b), the second external container with nutrient solution (16c), the external radiation-shielded container for waste solution (16f) or the external radiation-shielded container for sample material (16g).Cassette device (1) according to one of the preceding claims, wherein the distribution unit (2) has 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). Cassette device (1) according to claim 6, wherein the distribution unit (2) has: a first, second, third, fourth and fifth line (5ab, 5bc, 5cd, 5de, 5ef), a first three-way valve (3a) which is configured to establish selective communication between a connection (4a) for supplying buffer solution, a connection (4h) for connecting to the syringe (8h) and the first line (5ab). a second three-way valve (3b) configured to establish selective communication between a connection (4b) for supplying a first nutrient solution, the first line (5ab) and the second line (5bc), a third three-way valve (3c) configured to establish selective communication between a connection (4c) for supplying a second nutrient solution, the second line (5bc) and the 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 fifth three-way valve (3e) configured to establish selective communication between a connection (4e) for connecting to the second filter unit (7e), the fourth line (5de) and the fifth line (5ef) , and a sixth three-way valve (3f) ,which is configured to establish selective communication between a port (4f) for removing waste solution, a port (4g) for supplying sample solution, and the fifth line (5ef). The cassette device (1) according to claim 7, wherein at least one of the first, second, fourth, and fifth lines (5ab, 5bc, 5de, 5ef) is an integral part of the distribution unit (2), and the third line (5cd) is an external tube or an integral part of the distribution unit (2), and / or 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 distribution unit (2). Cassette device (1) according to claim 8, wherein the distributor unit (2) further comprises at least one attachment, preferably at least two attachments, wherein at least one of the lines (5ab-5ef) is arranged inside the attachment or one of the attachments or between the base plate (12) and the attachment or one of the attachments, optionally fastened thereby, and / or at least one of the valves (3a-3f) extends through the base plate (12) and / or through the attachment or one of the attachments.Cassette device (1) according to one of the preceding claims, wherein the first and / or the second filter unit (7d, 7e) comprise filter cartridges, each having a membrane filter (8d, 8e), at least one inlet valve (9d, 9e), at least one outlet valve (10d, 10e) and preferably at least one drain hose (17), wherein at least one of the respective inlet valves (9d, 9e) communicates 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-shielded container for waste solution (16f) via the drain hose (17). Cassette device (1) according to claim 10, wherein the inlet valves (9d, 9e) and / or the outlet valves (10d, 10e) comprise sterile filters to enable sterile ventilation and / or venting of the respective filter units (7d, 7e).Cassette device (1) according to one of the previous. Claims, wherein the distribution unit (2) of the cassette device (1) is established by a first external Actuator module (101) to be received, and the valves (3a-3f) are set up to be automatically actuated by the first external actuator module (101) and / or wherein the inlet valves (9d, 9e) and / or the outlet valves (10d, 10e) of the first and / or second filter unit (7d, 7e) are set up to be received by a second external actuator module (102) and automatically actuated and / or wherein the syringe (8h) of the cassette device (1) is set up to be received by an external syringe pump module or an actuating unit (103) and automatically actuated and / or wherein the drain tube (17) of the cassette device (1) is set up to be received by an external peristaltic pump module (104).Cassette device (1) according to one of the preceding claims, wherein all components of the cassette device (1) are designed for single use, or wherein all components of the cassette device (1) with the exception of the drain hose (17) are designed for single use, and the drain hose (17) is designed as a permanent line and / or is flushable. System for the automated sterility testing of radiopharmaceuticals by means of membrane filtration, comprising a cassette device (1) according to one of the preceding claims, a container with buffer solution (16a), a first container with nutrient solution (16b) and preferably a second container with nutrient solution (16c), a radiation-shielded container for waste solution (16f), and a radiation-shielded container for. Sample material (16g), wherein the corresponding tubes (5a, 5b, 5c, 5f, 5g) of the cassette device (1) communicate with the container with buffer solution (16a), the first container with nutrient solution (16b), the second container with nutrient solution (16c), the radiation-shielded container for waste solution (16f), and the radiation-shielded container for sample material (16g), preferably in order to transport liquids from the containers or into the containers via the distribution unit (2) of the cassette device (1), optionally in an automated manner. An arrangement comprising: the cassette device (1) according to one of claims 1 to 13 and a package in which the cassette device (1) is sterilely enclosed, wherein the cassette device is located in a disassembled, partially disassembled, or assembled state in the package.Use of a cassette device (1) according to one of claims 1 to 13 or of a system according to claim 14 for automated sterility testing of radiopharmaceuticals by membrane filtration. Use of a cassette device (1) according to one of claims 1 to 13 in an apparatus (100) for automated sterility testing of radiopharmaceuticals by membrane filtration.

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