Cartridge device and system for use in device for automated sterility test of radiopharmaceuticals by means of membrane filtration, and arrangement and use of device or system in such device

Abstract

The invention relates to a cassette 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 a cassette device (1) according to the invention, the invention also relates 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 means of membrane filtration, in particular in a corresponding device (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), which connections (4a-4j) can selectively communicate with one another by means of the valves (3a-3f) and the lines (5ab-5ef), a first filter unit (7d) and at least five hoses (5a, 5b, 5d, 5f, 5g), which communicate with respective connections (4a, 4b, 4d, 4f, 4g) of the distributor unit (2), wherein one hose (5d) communicates with the first filter unit (7d) and the four hoses (5a, 5b, 5f, 5g) are configured in such a way that one hose in each case communicates with a first outer container (16a) with a buffer solution, an outer container (16b) with a nutrient solution, an outer radiation-shielding container (16f) for a waste liquid or an outer radiation-shielding container (16g) for a sample material.

Description

Technical Field

[0001] The present invention relates to a cassette device for use in an apparatus for automated sterility testing of radiopharmaceuticals by means of membrane filtration, a system and an arrangement comprising the cassette device according to the invention, and 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, in particular in corresponding apparatus. Background Art

[0002] According to the European Pharmacopoeia 11.0, chapter 2.6.1 "Sterility" (Ph.Eur.2.6.1-Sterility Test) or the United States Pharmacopoeia (USP <71> ) is an important part of the quality control of human or veterinary drugs and medical products produced under aseptic conditions. Drugs 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. Decisive for the sterility testing of drugs and medical products is the compliance with sterility testing conditions (Class A clean room, see Annex 1 of the EU GMP Guide), which is usually ensured by using isolators (sterile boxes) to avoid contamination.

[0003] The sterility test preferably uses a membrane filtration method. The membrane filtration method is a method for mechanically enriching microorganisms from any amount of filterable research material. Even if the microbial content is extremely low, this method can accurately determine the number of microorganisms. Here, a certain volume of liquid is filtered through a membrane filter with a defined pore size, and the microorganisms contained therein are trapped on the filter surface. The filter is then placed on a culture medium. The nutrients of the culture medium can make it possible to grow individual microorganisms into diagnosable colonies. As an alternative, the contaminated filter can be transferred to a liquid culture medium. Depending on the culture medium, the proliferation of microorganisms is indicated by turbidity or (if the culture medium contains indicator pigments) by color changes.

[0004] In the case of 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 have a negative effect on the sterility test and, in particular, must not have antimicrobial properties. Insoluble products (e.g. implants, surgical sutures) are tested by direct inoculation, i.e. the product is introduced directly into the culture medium. However, the sterility test of radiopharmaceuticals has been a problem to date.

[0005] In order to reduce the risk of contamination, several quality measures can be implemented in the production of radiopharmaceuticals (grade C, grade A, automated methods, disposable sterile consumables, precursors with low microbial load, regularly performed "media filling steps"), but these measures still do not exempt the regulatory requirement for sterility testing of the final product to exclude risks to patients.

[0006] In the field of radiopharmaceuticals, sterility testing must be performed retrospectively due to the short half-life of the radionuclides and incubation times of at least 10 days. The European Pharmacopoeia monographs (e.g. 68Ga-Edotreotide or 18F-PSMA) therefore accept sterility testing after product release (Freigabe), although previous studies have shown that testing should be performed as early as possible (e.g. membrane filtration) to reduce the probability of false negative results. As early as 2010, the EANM Commission on Radiopharmaceuticals recommended: "Sterility testing should be started as soon as possible after the production of SSRP (sterile radiopharmaceuticals). If samples need to be stored for longer periods of time for sterility testing, it should be demonstrated that longer periods do not adversely affect the test results." The United States Pharmacopoeia (with individual exceptions) stipulates that the incubation period (Inkubationszeit) of radiopharmaceutical samples must not be later than 30 hours after production.

[0007] Nevertheless, the relevant guidelines (EU, US, Australia) all acknowledge 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 the decay has reached the allowed low value. In the case of 177Lu or 225Ac radiopharmaceuticals with half-lives of 6, 7 or 10 days, this means that the interval between production and the start of testing can be as long as several months, which does not meet the requirement of "testing as soon as possible".

[0008] The implementation of membrane filtration for radiopharmaceuticals has hitherto been problematic due to the challenges of handling and storing the radioactive filtrate. The radioactive filtrate is typically retained in an isolator until it decays below the exemption limit, which not only takes up valuable space but also poses a potential risk of contamination and a hazard to the operator. In addition, conventional suction equipment for membrane filtration is difficult to introduce into isolators, as these isolators are typically used to manufacture radiopharmaceuticals. Therefore, sterility testing of radioactive materials, especially radiopharmaceuticals and / or diagnostic agents, often employs direct inoculation. The disadvantage here is that the testing is limited to small sample sizes, as radioactivity poses a problem for microbiological testing. In addition, sterility testing of radiopharmaceuticals by direct inoculation does not comply with the European Pharmacopoeia (Ph.Eur.2.6.1 - Sterility Testing), the United States Pharmacopoeia (USP <71> ) and the regulatory requirements of the European Pharmacopoeia Monograph 04 / 2022:0125, it can be considered that membrane filtration is clearly preferred.

[0009] As an alternative, the radioactive material is tested for sterility by membrane filtration after radioactive decay, in particular after approximately three months. However, this method is only suitable for radioactive materials containing short-lived nuclides. Long-lived nuclides are excluded because they are too time-consuming. Current research results (see poster paper: "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) show that otherwise it is not possible to ensure that microbial contaminants that may be present in the pharmaceutical preparation survive for a long time until the start of use (Ansatz). It is also disadvantageous that sterility testing several months after the production of the radioactive material is less convincing, especially based on the adverse effects of radioactivity on microbial growth.

[0010] EP 3944867A1 also discloses a device and a method for sterility testing of radioactive materials using an isolator and a radiation shielding container for radioactive materials. When "isolator" or "radiation shielding container" is mentioned in this application, it is especially the isolator or radiation shielding container known from EP 3944867A1, especially the waste container. The corresponding disclosure in EP 3944867A1 should therefore be incorporated into the disclosure of the present application. Summary of the invention

[0011] The object of the present invention is in particular to provide a device for automated sterility testing of radiopharmaceuticals by means of membrane filtration, which is compatible with existing radiopharmaceutical production plants, ensures adequate radiation protection and enables sterility testing to be carried out directly after the production of the radiopharmaceutical and in accordance with currently valid legal regulations, in order to improve the quality and validity of the test results and thus ultimately improve patient protection. In addition, the device should be as cost-effective and simple to use as possible.

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

[0013] The present invention is technically closely related to the sterility test by means of membrane filtration standardized in Chapter 2.6.1 "Sterility" of the European Pharmacopoeia Edition 11.0 and provides a particularly suitable and advantageous cassette device (optionally as a consumable material therefor) for the efficient and reliable implementation of sterility tests, in particular for radiopharmaceuticals, but is not limited thereto.

[0014] Some of the terms used below should be understood as follows (but not limiting):

[0015] A “radiopharmaceutical” is understood to be a drug which is used for diagnostic or therapeutic purposes and contains a radioactive component, so that it can emit radioactive radiation. This also includes “radiotherapeutic drugs”.

[0016] A "cassette device" is understood herein to be a device which is provided for connection to a device in order to realize a specific function. Thus, by using different cassettes, different functions can be realized with the same device. Preferably, the cassette device according to the invention is configured and designed as described above for use in systems and devices for sterility testing of radiopharmaceuticals with the aid of membrane filtration in accordance with the European Pharmacopoeia, 11.0, chapter 2.6.1 "Sterility". However, uses other than this are not excluded.

[0017] A “system” or “arrangement” is understood to be a combination of a device and other elements for realizing an intended function. In the present case, the “function” preferably relates to sterility testing by means of membrane filtration.

[0018] "Device" is understood here as a machine that can be connected to different boxes or other components to achieve a specific function. The device can include a plurality of modules that achieve different functions. Through actuators, such as actuators, the device can automatically interact with the corresponding components of the box or operate the components.

[0019] A "radiation shielding container" is understood to be a container that can hold radioactive materials and prevents radiation from escaping through the container to the greatest extent possible. This is particularly understood to be a radiation shielding container according to EP 3944867A1. An "isolator" (also called "sterile operating box" or "glove box") is understood to be a device that is tightly and gas-tightly closed relative to the surrounding workspace. A defined environment for handling radioactive materials can be created in the isolator. This is currently understood to be particularly understood to be an isolator according to EP 3944867A1.

[0020] "Sample material" is preferably understood to mean the radiopharmaceutical for which the sterility test is to be carried out. It can be present, for example, in the form of a solid, a powder or the like. "Buffer solution" is understood to mean a liquid with which the sample material is mixed or in which the sample material is dissolved in order to be able to carry out the subsequent membrane filtration. "Nutrient solution" is understood to mean a liquid which, after filtering the buffer solution together with the sample material dissolved therein, is supplied to the membrane filter in order to promote the growth of microorganisms. "Waste liquid" is understood to mean the liquid which remains after the filtration and must be disposed of.

[0021] "Connected" is understood to mean the establishment or presence of a fluid connection, so that liquids or gases can be exchanged. "Connected" is preferably understood to mean "functionally connected" and includes, on the one hand, a physical or mechanical connection of system components (e.g., plugging on or plugging in), and on the other hand, the connection is also functional and allows, in particular, a unidirectional or multidirectional exchange of gases and liquids. Where mentioned accordingly below, the corresponding device components and system components are accordingly arranged and configured for this purpose.

[0022] The cassette device according to the present invention is intended to be used in an apparatus / system for automated sterility testing of radiopharmaceuticals by means of membrane filtration (optionally, by means of membrane filtration, the sterility testing standardized in the 11.0 edition of the European Pharmacopoeia, chapter 2.6.1 "Sterility"). The cassette device comprises a distributor unit having a base plate, a valve (especially a three-way valve), a pipeline and an interface, a first filter unit and at least five hoses. Optionally and preferably, the pipeline connects different interfaces to different valves and connects the interfaces via these valves, that is, it is a connector between the components. The interfaces are selectively interconnected through the valves, and the hoses are connected to the corresponding interfaces of the distributor unit. Preferably, "selective" should be understood as switchable and flexibly selectable. Therefore, according to the needs in the application, different interfaces can be connected or communicated to each other in a targeted and demanded manner. Preferably, "corresponding" should be understood as a functional association, for example, the interface is assigned its own ("corresponding") hose and the valve is assigned its own interface and vice versa, thereby generating a functional component pairing that is interconnected or can be interconnected. Preferred component pairings and component allocations are also shown by way of example in the drawings and can be derived. In addition, a hose is connected to the first filter unit and in addition four hoses are configured in such a way that one hose in each case is connectable to a first external container for / with a buffer solution, an external container for / with a nutrient solution, an external radiation shielding container for / with a waste liquid or an external radiation shielding container for / with a sample substance.

[0023] Cassette device according to the present invention, especially its corresponding parts are used to be connected with the external parts of whole testing system or to be communicated with them, for example above-mentioned different containers.This actual connection is realized in the scope of " system for automated sterility testing " according to the present invention equally.In this system, the different parts of cassette device are then actually and are in and are connected or communicated with corresponding system parts (container etc.) function.Term " outside " preferably does not relate to the parts of cassette device itself, but relates to cassette device and is connected with its function in use and therefore forms the parts of the overall system that is especially used for carrying out sterility testing by means of membrane filtration.

[0024] In order to manufacture medicines, especially radiopharmaceuticals, cassette devices have been used in combination with corresponding equipment (modules) to generate, isolate and / or mix the various components of medicines aseptically and automatically. Since the cassette device according to the present invention can be used in combination with the same equipment, these equipment can be used not only for the manufacture of medicines but also for subsequent sterility testing, which can save time and cost, such as the time and cost for transportation to external laboratories. In addition, based on closed systems and automation, the quality of the test results and the protection of personnel are improved, because in contrast to manual testing, the possible contamination and differences of sample materials and the possible contamination or radiation damage to personnel can be minimized when implementing sterility testing. In addition, membrane filtration can achieve the separation of microorganisms from radioactive materials, so that the microbial load of the medicine can be directly determined after the manufacture of the medicine, rather than determining it after the radioactive decay, which further improves the quality of the results. In order to further improve radiation protection, sterility testing by means of membrane filtration can be implemented in an isolator.

[0025] Preferably, the cassette device further comprises a second filter unit and another hose, wherein the other hose is connected to a corresponding interface of the dispenser unit and the second filter unit.

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

[0027] Preferably, the cassette device also includes a syringe and another hose for a syringe pump, and the other hose is communicated with the corresponding interface of the distributor unit and the syringe. "Syringe pump" refers to the arrangement structure composed of a syringe and an additional operating unit or a syringe pump module at present. The operating unit can be a motor-driven clamping device at this time, and the syringe is inserted into the clamping device and the syringe piston can be reciprocated by the motor.

[0028] The syringe provided for the syringe pump enables the predetermined amount of liquid to be drawn and outputted with high precision. It is thus possible to ensure that the predetermined mixing ratio of the corresponding liquid is accurately maintained, thereby enabling constant test conditions and thus high-quality test results to be achieved. Optionally, the cassette device may also have a syringe pump.

[0029] Preferably, the cassette device further comprises another hose, which is in communication with a corresponding interface of the dispenser unit and is configured to be in communication or communicable with a second external container having a nutrient solution.

[0030] Providing two nutrient solutions, in particular two different and pure nutrient solutions, enables the microorganisms remaining in the one or more filter units to be exposed to different nutrient solutions, so that the quality of the test results, in particular with regard to the microbial load caused by different types of microorganisms, can be further improved. In addition, if two filter units are provided, the first filter unit can be supplied with the first nutrient solution and the second filter unit can be supplied with the second nutrient solution, so that the corresponding filter unit can be used, for example, to determine the microbial load caused by different types of microorganisms.

[0031] Preferably, the cassette device also includes at least four or at least / preferably five injection needles installed at the distal end of the corresponding hose (i.e., preferably away from / facing away from the dispenser unit), and the injection needles are configured and arranged to be connected or connectable to an external container for / having a buffer solution, a first external container for / having a nutrient solution, a second external container for / having a nutrient solution, an external radiation shielding container for / having a waste liquid, or an external radiation shielding container for / having a sample material.

[0032] Providing an injection needle at the distal end of the hose facilitates connecting the hose to a corresponding container and ensures that liquid does not accidentally leak out, thereby preventing personnel from being contaminated by, in particular, radioactive materials to the greatest extent possible.

[0033] Preferably the distributor unit has 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 (as defined below) be interconnected or in communication.

[0034] The equipment for manufacturing medicine is usually configured to accommodate a cassette device with six valves and eight or ten interfaces, so that the cassette device with six valves and eight or ten interfaces according to the present invention can also be used with this. In addition, the number of valves and interfaces claimed is particularly suitable for automated sterility testing of radiopharmaceuticals by membrane filtration.

[0035] It is further preferred that the dispenser unit includes first, second, third, fourth and fifth pipelines, a first three-way valve, which is configured to establish selective communication between an interface for supplying a buffer solution, an interface for connecting to a syringe for a syringe pump and the first pipeline, a second three-way valve, which is configured to establish selective communication between an interface for supplying a first nutrient solution, the first pipeline and the second pipeline, a third three-way valve, which is configured to establish selective communication between an interface for supplying a second nutrient solution, the second pipeline and the third pipeline, a fourth three-way valve, which is configured to establish selective communication between an interface for connecting to a first filter unit, the third pipeline and the fourth pipeline, a fifth three-way valve, which is configured to establish selective communication between an interface for connecting to a second filter unit, the fourth pipeline and the fifth pipeline, and a sixth three-way valve, which is configured to establish selective communication between an interface for discharging waste liquid, an interface for supplying a sample solution and the fifth pipeline.

[0036] The claimed arrangement of six three-way valves, five lines and corresponding interfaces for supplying a buffer solution, a sample solution and two nutrient solutions, for discharging waste liquid and for connecting to a syringe and two filter units is particularly suitable for use in existing devices for manufacturing drugs and for automated sterility testing of radiopharmaceuticals by means of membrane filtration.

[0037] Preferably, at least one of the first, second, fourth and fifth lines is an integral part of the distributor unit and the third line is an integral part of the external hose or the distributor 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 part of the distributor unit or the base plate. The integrated embodiment can be realized, for example, by additive manufacturing or 3D printing.

[0038] The advantage of configuring the first, second, fourth and fifth conduits as an integral component of the distributor unit is that external conduits or connecting hoses for this can be avoided, thereby improving the compactness and stability of the cassette device. Configuring the third conduit as an external hose is structurally simpler and can therefore be manufactured more cost-effectively.

[0039] Preferably, the distributor unit further comprises at least one accessory, preferably at least two accessories, at least one of the lines being arranged inside the accessory or one of the accessories or between the base plate and the accessory or one of the accessories and / or at least one of the valves extending through the base plate and / or extending through the accessory or one of the accessories. An "accessory" is to be understood herein as a component that is different from the base plate, which is connected to the base plate by a connection, for example riveting, and in this case preferably the lines and / or valves are fixedly or clamped to the base plate.

[0040] Providing at least one attachment is a simple and cost-effective possibility for configuring the lines and valves as an integral component of the distributor unit by arranging them therein or between the base plate and the attachment or extending through the base plate and / or through the attachment. In addition, the lines and valves are thus better protected, thereby improving the stability of the distributor unit. Providing two attachments is particularly advantageous in terms of construction.

[0041] Preferably, the first and / or second filter unit comprises a filter cartridge, each with a membrane filter, at least one inlet valve, at least one outlet valve and optionally at least one discharge hose, at least one of the respective inlet valves being connected to the respective interface of the distributor unit via a respective hose and / or at least one of the respective outlet valves being configured to be connected to an external radiation shielding container for waste liquid via a discharge hose. The connection or connection is preferably achieved here by a one-piece hose connection, but also includes a multi-piece connection with additional components connected in between.

[0042] The claimed design of the filter unit with inlet valve, outlet valve and membrane filter enables controlled inlet and outlet of liquid, so that the filter unit can be separated from the cassette after filtration without liquid accidentally escaping, which could constitute a health risk. The membrane filter can then be removed and further processed and checked separately to determine the microbial load. Providing a discharge hose also has the advantage that liquid can be discharged from the filter unit into a shielding container for waste liquid without coming into contact with ambient air.

[0043] Preferably, the inlet valve and / or the outlet valve comprises a sterile filter in order to enable sterile venting and / or exhausting of the respective filter unit or filter cartridge.

[0044] The valve of the filter unit can be connected to the ambient air via a sterile filter, so that sterile ventilation or exhaust of the filter unit can be achieved, thereby facilitating the injection or discharge of liquid into or from the filter unit. Due to the sterile filter, no contaminants can enter the filter unit from the outside, which would distort the results.

[0045] The distributor unit of the preferred cassette device is configured to be accommodated by the first external actuator module, and the valve is configured to be automatically operated by the first external actuator module and / or the inlet valve and / or the outlet valve of the first filter unit and / or the second filter unit are configured to be accommodated and automatically operated by the second external actuator module and / or the syringe of the described cassette device is configured to be accommodated and automatically operated by an external syringe pump module or an operating unit and / or the discharge hose of the described cassette device is configured to be accommodated by an external hose pump module." module " is preferably understood to be the following equipment unit at present, and the described equipment unit is assumed certain tasks in the whole system for example in order to carry out sterility testing by means of membrane filtration. A plurality of modules can then be combined and assembled into an overall system, for example, for carrying out sterility testing by means of membrane filtration.

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

[0047] Preferably, all components of the cassette device are designed for single use or, except for the discharge hose, all components of the cassette device are designed for single use and the discharge hose is designed or embodied as a permanent line and / or flushable.

[0048] Designing the components for single use has the advantage that time and costs for cleaning after use can be saved and residues after insufficient cleaning, which would distort the test results, can be avoided. Since no liquid from the discharge hose reaches the rest of the cassette device, the discharge hose can be reused without prior cleaning, thereby saving costs.

[0049] The system for automated sterility testing of radiopharmaceuticals by means of membrane filtration according to the present invention comprises a box device according to the present invention, a container for / having a buffer solution, a first container for / having a nutrient solution and preferably a second container for / having a nutrient solution, a radiation-shielding container for waste liquid and a radiation-shielding container for sample material, wherein corresponding hoses of the box device are connected to the container for / having a buffer solution, the first container for / having a nutrient solution, the second container for / having a nutrient solution, the radiation-shielding container for waste liquid and the radiation-shielding container for sample material, preferably so as to transport liquid from or to the containers, optionally automatically, via a dispenser unit of the box device.

[0050] Providing containers with buffer solutions and nutrient solutions and radiation shielding containers for sample materials and waste liquids (which are connected to corresponding hoses of the cassette device) can in particular enable automated transport of liquids for sterility testing of radiopharmaceuticals by means of membrane filtration. Radiation shielding containers have the advantage that they shield the radioactive substances contained therein, so that there is essentially no leakage of radioactivity, thereby improving personnel protection. In particular, radiation shielding containers according to EP3944867A1 can be used, in particular as and for waste containers. In order to further improve radiation protection, the system can also be installed in an isolator preferably according to EP3944867A1.

[0051] The arrangement according to the invention comprises a cassette according to the invention and a packaging in which the cassette is sterilely packaged and in which the cassette is located in a disassembled, partially disassembled or assembled state.

[0052] The sterile packaging of the cassette ensures that the cassette is protected from external contamination, which could distort the results of the sterility test. Providing the cassette in a disassembled or partially disassembled state may be advantageous for cost reasons, but is preferably provided in an assembled state to avoid possible contamination by manual assembly and to provide a "plug and play" solution.

[0053] 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.

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

[0055] The cassette arrangement according to the invention is particularly suitable for use in automated sterility testing of radiopharmaceuticals by means of membrane filtration, in particular in corresponding devices. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Other features and advantages of the present invention are derived from the following description of the embodiments with reference to the accompanying drawings. The accompanying drawings are as follows:

[0057] Figure 1 An embodiment of a dispenser unit of a cassette device according to the invention is shown, wherein the possible connections and wiring of the individual components of the dispenser unit according to a preferred embodiment are shown in a technically clear and focused manner;

[0058] Figure 2An embodiment of a cassette device according to the invention is shown, wherein the possible connections and wiring of the components of the cassette device according to a preferred embodiment are shown in a technically clear and focused manner;

[0059] Figure 3 The implementation of one embodiment of the cassette device according to the invention in an apparatus for automated sterility testing of radiopharmaceuticals is shown. DETAILED DESCRIPTION

[0060] The reference numerals used below and in the drawings and claims should in principle be considered informative and non-restrictive, especially with respect to their number. Nevertheless, at least partially identical letter components optionally represent functional groups of a cassette device according to the present invention. For example, reference numerals 3a, 4a and 5a represent that corresponding valves 3a, corresponding interfaces 4a and corresponding hoses 5a can form a functional subunit of a cassette device and are interconnected. Similarly, reference numeral 5ab represents a pipeline or pipeline section between valves 3a and 3b.

[0061] Figure 1 An embodiment of a dispenser unit (2) of a cassette device (1) according to the invention is shown, which can be connected to an actuator module (101) of an apparatus (100) for the automated production of radioactive substances, in particular radiopharmaceuticals, and / or the sterility testing thereof.

[0062] The distributor unit (2) comprises a plurality of valves (3a-3f) (especially three-way valves), a plurality of pipelines (5ab-5ef) and a plurality of interfaces (4a-4i), wherein the interfaces can be selectively connected to each other through the valves (3a-3f). The valves (3a-3f) are arranged on the distributor unit (2) so that when the cassette device (1) is connected to the actuator module (101), the valves can be automatically operated by the actuator mechanism of the actuator module.

[0063] exist Figure 1 In the exemplary embodiment shown in , a substantially rectangular distributor unit (2) comprises six three-way valves (3a-3f), eight or ten interfaces (4a-4i) and five internal or external lines (5ab-5ef) which connect the valves (3a-3f) to one another, wherein four valves (3a, 3c, 3d, 3f) are each arranged in a corner of the distributor unit (2) and two valves (3b, 3e) are each arranged on an edge of the distributor unit. The design of the distributor unit (2), in particular the arrangement of the valves 3a-3f, is compatible with an actuator module of the type "SLM2" of the company "Eckert & Ziegler".

[0064] Figure 1The valves ( 3 a , 3 f ) shown on the left are connected to two ports and one pipeline respectively, while the remaining valves ( 3 b , 3 c , 3 d , 3 e ) are connected to one port and two pipelines respectively. Figure 1 The connections ( 4 i , 4 j ) shown on the right in FIG. 5 are optional here, since they can also be connected to one another via an internal line ( 5 cd ) instead of via an external line ( 5 cd ).

[0065] Figure 2 An embodiment of a cassette device (1) according to the invention is shown, which can be connected to an actuator module (101) of an apparatus (100) for the automated production of radioactive substances, in particular radiopharmaceuticals, and / or the sterility testing thereof.

[0066] The five interfaces (4a, 4b, 4c, 4f, 4g) of the distributor unit (2) are connected to corresponding injection needles (6a, 6b, 6c, 6f, 6g) via corresponding hoses (5a, 5b, 5c, 5f, 5g), the two interfaces (4d, 4e) of the distributor unit (2) are connected to corresponding filter units (7d, 7e) via corresponding hoses (5d, 5e), and one interface (4h) of the distributor unit (2) is connected to a syringe (8h) via a corresponding hose (5h).

[0067] The injection needle (6a, 6b, 6c, 6f, 6g) is configured to be connectable to 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 shielding container (16f) for a waste solution, or a radiation shielding container (16g) for a sample material. The nutrient solutions in the first container and the second container (16b, 16c) may be the same or different.

[0068] The filter units (7d, 7e) are detachably connected to the cassette device (1) and each comprises 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 filter unit (7d, 7e) has two inlet valves (9d, 9e) in the form of two-way valves and one outlet valve (10d, 10e) in the form of a three-way valve.

[0069] One of the two inlet valves (9d, 9e) is configured to open or close the fluid connection between the distributor unit (2) and the corresponding filter cartridge, while the other of the two inlet valves (9d, 9e) is equipped with a sterile filter and is configured to open or close the fluid connection between the ambient air and the corresponding filter cartridge, so as to facilitate the fluid to enter and exit the corresponding filter cartridge. Alternatively, only one inlet valve (9d, 9e) in the form of a three-way valve can be provided respectively, and the inlet valve selectively connects the inlet of the filter cartridge to the distributor unit (2) or the ambient air. The corresponding outlet valve (10d, 10e) is also equipped with a sterile filter and is configured to selectively connect the discharge hose (17) to the filter cartridge or the ambient air, so as to facilitate the liquid to enter and exit the corresponding filter cartridge.

[0070] Figure 3 An embodiment of the system according to the invention in an apparatus (100) for automated sterility testing of radioactive substances, in particular radiopharmaceuticals, is shown. In addition to the cassette 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 shielding container (16f) for waste liquid, and a radiation shielding container (16g) for a 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).

[0071] The distributor 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 automatically operated by the corresponding actuators of the first actuator module (101).

[0072] according to Figure 1 and 2 In the naming, the first interface (4a) is connected to the container (16a) for buffer solution via the first hose (5a) and the first injection needle (6a), the second interface (4b) is connected to the first container (16b) for nutrient solution via the second hose (5b) and the second injection needle (6b), the third interface (4c) is connected to the second container (16c) for nutrient solution via the third hose (5c) and the third injection needle (6c), the sixth interface (4f) is connected to the radiation shielding container (16f) for waste liquid via the sixth hose (5f) and the fourth injection needle (6f), and the seventh interface (4g) is connected to the radiation shielding container (16g) for sample material via the seventh hose (5g) and the fifth injection needle (6g).

[0073] 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 automatically operated by corresponding actuators of the second actuator module (102).

[0074] Each outlet valve (10d, 10e) is connected to a radiation shielding container (16f) for waste liquid via a common discharge hose (17) or individual discharge hoses. The one or more discharge hoses (17) may be an integral part of the cassette device (1) and configured to communicate with the radiation shielding container (16f) for waste liquid.

[0075] 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 operated by a corresponding actuator of the first pump module (103), thereby aspirating liquid from the system or outputting liquid into the system. Therefore, the first pump module (103) can be a syringe pump module.

[0076] The discharge hose (17) is inserted into the second pump module (104) of the device (100) so that a corresponding actuator (not shown) of the second pump module (104) can interact automatically with the discharge hose (17) in order to generate a fluid flow therein, in particular in order to pump liquid out of the filter unit (7d, 7e).

[0077] The cassette device (1) is designed for single use, but can also be reused after thorough decontamination. The filter unit (7d, 7e) is detachably connected to the cassette device (1), so that the filter unit can be separated after filtration for further processing and research. Inlet and outlet valves (9d, 9e, 10d, 10e) can ensure that no contaminated or radioactive liquid can escape from the filter unit (7d, 7e).

[0078] The following components are particularly suitable for the cassette device (1) according to the invention within the scope of a specific embodiment and can be referred to as follows by a person skilled in the art:

[0079] Substrate (2): "C2-Manifold",

[0080] Hose (5a): "PE (polyethylene) extension tube, M / M (male / male) LL, 50cm", Hose (5b, 5c): "PE extension tube, M / F (male / female) LL, 20cm"

[0081] Hose (5d, 5e): "PE extension tube, M / F LL, 30cm",

[0082] Hose (5f, 5g): "PE extension tube, M / F LL, 20cm",

[0083] Hose (5h): "PE extension tube, M / F LL, 15cm",

[0084] Pipe (5cd): "PE extension tube, M / M LL, 10cm",

[0085] Injection needle (6a): "Codan Mikrospike",

[0086] Injection needle (6b, 6c): "Spikes Venting",

[0087] Injection needle (6f, 6g): "Needles Sterican 0.9x70mm 20Gx1 1 / 2", Syringe (8h): "BD10ml syringe",

[0088] Sterile filter: "0.2μm PTFE 28213 hydrophobic filter",

[0089] Connection parts between the filter cartridge and the outlet valve: 2 "Polypropylene male Luer interface (1 / 16", 1.6mm)" and "Silicone tube 1×3mm".

[0090] Standardized membrane filtration using the cassette device or system according to the invention can be carried out and implemented as follows. The valve of the distributor unit (2) is set so that a fluid connection is formed between the syringe (8h) and the container (16a) with the buffer solution and the buffer solution is sucked from the corresponding container (16a) by operating the syringe (8h). Then, the valve of the distributor unit (2) is set so that a fluid connection is formed between the syringe (8h) and the container (16g) with the sample material and the buffer solution is introduced into the corresponding container (16g) by operating the syringe (8h), in which the sample material is mixed with the buffer solution or dissolved in the buffer solution.

[0091] Then, the buffer solution in which the sample material is dissolved is sucked out again, and the valve of the distributor unit (2) is set so that a fluid connection exists between the syringe (8h) and the first filter unit (7d) and a part of the buffer solution is conveyed to the first filter unit (7d). Next, the valve of the distributor unit (2) is set so that a fluid connection is formed between the syringe (8h) and the second filter unit (7e) and the remaining part of the buffer solution is conveyed to the second filter unit (7e). The filtrate from the two filter units (7d, 7e) is introduced into a container (16f) for waste liquid via a discharge hose (17).

[0092] Then, the valve of the dispenser unit (2) is set so that a fluid connection is established between the syringe (8h) and the first container (16b) containing the nutrient solution and the first nutrient solution is sucked in. Next, the valve of the dispenser unit (2) is set so that a fluid connection is established between the syringe (8h) and the first filter unit (7d) and the nutrient solution is conveyed into the first filter unit (7d). The corresponding process is repeated for the second nutrient solution (16c) and the second filter unit (7e).

[0093] The inlet valve (9d, 9e) of the filter unit (7d, 7e) is then set so that the filter cartridge is separated from the rest of the system and connected to the ambient air via the sterile filter. The remaining liquid from the filter unit (7d, 7e) is conveyed via a discharge hose (17) into a container (16f) for waste liquid before closing the outlet valve (10d, 10e), separating the filter unit (7d, 7e) and removing the membrane filter for further processing and investigation.

[0094] Reference numerals list

[0095] 1 Cassette device

[0096] 2 Distributor units

[0097] 3a-3f valve, optional three-way valve

[0098] 4a-4j Interface

[0099] 5ab-5ef pipeline

[0100] 5a-5h hose

[0101] 6a-6c, 6f-6g Injection needle

[0102] 7d, 7e filter unit

[0103] 8d, 8e Membrane filter in filter cartridge

[0104] 9d, 9e Inlet valve

[0105] 10d, 10e outlet valve

[0106] 12 substrate

[0107] 16a Container for buffer solution

[0108] 16b First container for nutrient solution

[0109] 16c Second container for nutrient solution

[0110] 16f Container for waste liquid

[0111] 16g container for sample material

[0112] 17 Discharge hose

[0113] 100 devices

[0114] 101 First actuator module

[0115] 102 Second actuator module

[0116] 103 First pump module

[0117] 104 Second pump module

Claims

1. A cassette device (1) for use in an apparatus (100) for automated sterility testing of radiopharmaceuticals by membrane filtration, comprising: A distributor unit (2) comprising a base plate (12), valves (3a-3f), in particular three-way valves, pipelines (5ab-5ef) and interfaces (4a-4j), wherein the interfaces (4a-4j) can be selectively connected to each other via the valves (3a-3f) and the pipelines (5ab-5ef), The first filter unit (7d) and at least five hoses (5a, 5b, 5d, 5f, 5g), which are connected to corresponding interfaces (4a, 4b, 4d, 4f, 4g) of the distributor unit (2), A hose (5d) is connected to a first filter unit (7d) and four hoses (5a, 5b, 5f, 5g) are configured so that one of the hoses can be connected to a first external container (16a) having a buffer solution, an external container (16b) having a nutrient solution, an external radiation shielding container (16f) for waste liquid, or an external radiation shielding container (16g) for sample material.

2. The cassette device (1) according to claim 1, further comprising a second filter unit (7e) and another hose (5e), ​​wherein the other hose is connected to the corresponding interface (4e) of the dispenser unit (2) and the second filter unit (7e).

3. The cassette device (1) according to any one of the preceding claims, further comprising a syringe for a syringe pump (8h) and another hose (5h), wherein the other hose is connected to a corresponding interface (4h) of the dispenser unit (2) and the syringe (8h).

4. The cassette device (1) according to any one of the preceding claims further comprises another hose (5c), which is connected to a corresponding interface (4c) of the dispenser unit (2) and is configured to be able to communicate with a second external container (16c) having a nutrient solution.

5. The cassette device (1) according to any one of the preceding claims, further comprising at least four or at least five injection needles (6a, 6b, 6c, 6f, 6g) installed at the distal ends of corresponding hoses (5a, 5b, 5c, 5f, 5g), the injection needles (6a, 6b, 6c, 6f, 6g) being configured and arranged to be able to communicate with an external container (16a) having a buffer solution, a first external container (16b) having a nutrient solution, a second external container (16c) having a nutrient solution, an external radiation shielding container (16f) for waste liquid, or an external radiation shielding container (16g) for sample material.

6. The cassette device (1) according to any one of the preceding claims, wherein: The distributor 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).

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

8. The cassette device (1) according to claim 7, wherein: At least one of the first, second, fourth and fifth pipelines (5ab, 5bc, 5de, 5ef) is an integral component of the distributor unit (2) and the third pipeline (5cd) is an integral component of the external hose or the distributor 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 component of the distributor unit (2).

9. The cassette device (1) according to claim 8, wherein: The dispenser unit (2) further comprises at least one accessory, preferably at least two accessories, at least one of the pipes (5ab-5ef) being arranged inside the accessory or one of the accessories or between the base plate (12) and the accessory or one of the accessories, optionally fixed thereby, and / or at least one of the valves (3a-3f) extending through the base plate (12) and / or extending through the accessory or one of the accessories.

10. The cassette device (1) according to any one of the preceding claims, wherein: The first and / or second filter unit (7d, 7e) comprises a filter cartridge respectively 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 discharge hose (17), at least one of the corresponding inlet valves (9d, 9e) being connected to the corresponding interface (4d, 4e) of the distributor unit (2) via a corresponding hose (5d, 5e) and / or at least one of the corresponding outlet valves (10d, 10e) being configured to be connected to an external radiation shielding container (16f) for waste liquid via a discharge hose (17).

11. The cassette device (1) according to claim 10, wherein: The inlet valve (9d, 9e) and / or the outlet valve (10d, 10e) have a sterile filter in order to enable sterile ventilation and / or exhaust of the corresponding filter unit (7d, 7e).

12. The cassette device (1) according to any one of the preceding claims, wherein: The dispenser unit (2) of the cassette device (1) is configured to be received by a first external actuator module (101), and the valves (3a-3f) are configured to be automatically operated by the first external actuator module (101) and / or The inlet valve (9d, 9e) and / or the outlet valve (10d, 10e) of the first filter unit and / or the second filter unit (7d, 7e) are configured to be received by a second external actuator module (102) and automatically operated and / or The syringe (8h) of the cassette device (1) is configured to be received and automatically operated by an external syringe pump module or operating unit (103) and / or The discharge hose (17) of the cassette device (1) is configured to be received by an external hose pump module (104).

13. The cassette device (1) according to any one of the preceding claims, wherein: All components of the cassette device (1) are designed for single use, or all components of the cassette device (1) except the discharge hose (17) are designed for single use, and the discharge hose (17) is designed as a permanent line and / or is designed to be flushable.

14. A system for automated sterility testing of radiopharmaceuticals by membrane filtration, comprising: The cassette device (1) according to any one of the preceding claims, a container (16a) having a buffer solution, a first container (16b) with a nutrient solution and preferably also a second container (16c) with a nutrient solution, Radiation shielding containers for waste liquids (16f), Radiation shielding container for sample material (16 g), The corresponding hoses (5a, 5b, 5c, 5f, 5g) of the cassette device (1) are connected to a container (16a) with a buffer solution, a first container (16b) with a nutrient solution, a second container (16c) with a nutrient solution, a radiation shielding container (16f) for waste liquid, and a radiation shielding container (16g) for sample material, Preferably, the liquid is delivered from or into a container via a dispenser unit (2) of the cassette device (1), optionally automatically.

15. Arrangement comprising a cassette device (1) according to any one of claims 1 to 13 and a package, in which the cassette device (1) is sterilely enclosed, wherein: The cassette arrangement is located in the packaging in a disassembled, partially disassembled or assembled state.

16. Use of a cassette 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 means of membrane filtration.

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

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