Method for preparing a filling operation

Abstract

A method for preparing a filling operation, comprising the following steps: providing a filling system that comprises a liquid source, a barrier system for providing a controlled environment, a filling device arranged in the barrier system for filling a pharmaceutical liquid, a fluid path extending between the liquid source and the filling device for conducting the pharmaceutical liquid, and a filter assembly arranged in the fluid path with at least one filter housing and a filter element; introducing the pharmaceutical liquid from the liquid source into the fluid path; passing a defined amount of the pharmaceutical liquid through the filter assembly in order to wet each filter element; performing an integrity test of each filter element wetted with the pharmaceutical liquid; and forwarding the passed pharmaceutical liquid to the filling device in order to at least partially flush the fluid path.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a continuation application of International patent application PCT / EP2024 / 074054, filed Aug. 28, 2024, which claims the priority of German patent application DE 10 2023 124 844.8, filed Sep. 14, 2023. Both applications PCT / EP2024 / 074054 and DE 10 2023 124 844.8 are herewith incorporated by reference in their entireties.FIELD

[0002] The present invention generally relates to a method for preparing a filling operation. Furthermore, the present invention generally relates to a method for producing a pharmaceutical product.BACKGROUND

[0003] The filter integrity test is a fundamental requirement for process filtration applications in the pharmaceutical industry, in particular in manufacturing processes of pharmaceutical products. In particular, various guidelines for quality assurance of production procedures in pharmaceutical production (e.g. the production of medicinal products and active pharmaceutical ingredients) prescribe subjecting a filter system to an integrity test before and after use. By way of example, reference may be made to the so-called GMP guidelines (the abbreviation GMP stands for “Good Manufacturing Practice”, in German “Gute Herstellungspraxis”), which prescribe verification of the integrity of such filter systems before and after use in the manufacture of medicinal products.

[0004] A filter integrity test prior to use ensures the intactness of the filter element before processing a batch and can thus prevent a non-intact filter element from being used. By means of a filter integrity test after filtration of a production batch, it can be determined whether the integrity of a filter was maintained during the filling process. If a defect is detected immediately after processing of the production batch, an immediate response is possible, so that delays are avoided and the processing step can be repeated quickly.

[0005] Particular attention is paid to the filter integrity test prior to use in the manufacture of pharmaceutical products. In order to ensure that a filter system tested by the filter manufacturer has not been damaged during handling or installation, and during an optional sterilization process at the filling site, it is mandatory that the filter system is tested for integrity after installation and before use (i.e. before the filter system is used to filter the final product).

[0006] In the field of sterile manufacturing or filling processes, so-called PUPSIT filter tests may be applied, which are, for example, a regulatory requirement in pharmaceutical production for European markets. The abbreviation PUPSIT stands for “Pre-Use Post-Sterilization Integrity Testing”, which indicates that the filter system, in particular a single-use filter system, has to be tested for integrity after installation and sterilization and before use. In addition, a filter used for sterilizing a liquid is to be subjected to a non-destructive integrity test after use before the filter is removed from its housing or the single-use filter system is removed. The integrity test procedure should be validated, and the test results should correlate with the microbial retention capability of the filter determined during validation. Examples of tests that are used are the bubble point test, the diffusion test, the water intrusion test or the pressure hold test.

[0007] The test methods are generally divided into two classes: destructive and non-destructive.

[0008] Since destructive filter integrity tests such as, for example, the bacterial retention test (in English: “Bacterial retention test” or “Bacterial challenge test”) generally preclude further use of the filter elements, non-destructive test methods are preferred in pharmaceutical production. A non-destructive filter integrity test thus paves the way for an in-process filter integrity test, which means that the filters can remain in the fluid path for performing the filter integrity test. A bubble point test, a diffusion test and / or a pressure hold test may be considered as non-destructive filter integrity tests, which are preferably used in filtration processes of pharmaceutical production.

[0009] The bubble point test is one of the test methods most frequently used in the pharmaceutical industry. In this method, use is made of the capillary forces and the surface tension of a liquid applied to the filter. Before the start of the test, the filter element to be tested is therefore to be subjected to a wetting liquid in order to wet the filter surface or filter membrane, in particular completely. Subsequently, a pressure, in particular a gas pressure, is applied to the filter element and gradually increased until the gas is released again on the opposite side of the filter element. If the pressure exceeds a certain value, the bubbles characteristic of the bubble point test appear on the opposite side of the filter element, which means that the liquid has been forced through the filter and the previously acting capillary forces have been overcome. The pressure value is determined and documented. If the pressure is below a certain limit value (depending on the wetting liquid, this is either specified by the filter manufacturer or determined on a product-specific basis within the scope of filter validation), this is an indication that the filter is not intact. In this case, the filter cannot be used in the filling operation and has to be replaced. The bubble point test is a highly informative test method for verifying the maximum pore size of a filter surface as well as critical damage to a filter surface.

[0010] The diffusion test makes use of the natural diffusion of gas molecules according to Fick's law. Similar to the bubble point test, the respective filter element is to be wetted with a wetting liquid before the start of the test.

[0011] Subsequently, a pressure is applied which preferably corresponds to approximately 70% to 80% of the specified bubble point pressure. Due to the tendency toward concentration equalization, the gas molecules diffuse through the water-filled pores of the respective filter element. The higher the pressure and the larger the filter surface, the greater the amount of gas diffused. In the so-called forward flow test, the system continuously replaces the amount of gas measured on the sterile side of the filter by supplying the same amount of gas on the non-sterile side. In this way, the differential pressure remains constant over the entire test duration and only the small pressure drops are measured. The pressure hold test, also known as a pressure decay test, is a variant of the diffusion test. In the pressure hold test, however, no further gas is supplied. Instead, only the total pressure drop is measured once, in particular by means of a test device. The following applies to both the diffusion test and the pressure hold test: if the calculated flow rate is higher than the permissible limit value, there is reason to assume that the filter element is damaged.

[0012] Pure water or the pharmaceutical liquid to be filtered, i.e. the original product, is generally used as the wetting liquid. Using the original product as the wetting liquid has the advantage over water that the fluid path extending between the product source and the filling location and in which the filter elements are arranged does not have to be freed of water residues after performing the filter integrity test, which can improve the quality of the subsequent filling process and reduce the downtimes of the filling system.

[0013] In addition, in pharmaceutical filtration processes, in particular in in-process filtration processes, components of the fluid path extending between a product source and the filling location, in particular those components located downstream of a filter assembly arranged in the fluid path, have to be completely flushed before the actual filling operation can be carried out. The reason for the flushing is that undesirable residues may be present in components of the filling system, such as, for example, in lines, in particular hoses, in connections, in seals or the like, which have to be removed. The residues may, for example, be so-called “extractables” and “leachable”. The term “extractables” as used herein means chemical compounds that can be extracted from a material, for example from components of the filling system or a manufacturing process. These compounds could be released from the material during the manufacturing process or storage. “Leachables” refers to the amount of compounds that can migrate from a material into a liquid, for example into a pharmaceutical liquid.

[0014] A method for filtering a liquid raw material in a process stream in order to obtain a pharmaceutical product is known, for example, from document EP 2 925 420 B1.

[0015] Furthermore, a system and a method for in-process integrity testing of a filter are known, for example, from document EP 1 849 484 B1.

[0016] In addition, an automated single-use filtration device is known from document DE 10 2017 127 017 A1.

[0017] In conventional filling systems, flushing of the fluid path is generally carried out separately from the filter integrity test. In particular, conventionally, the wetting liquid used for performing the filter integrity test (e.g. the pharmaceutical product or water) is removed from the fluid path via a fluid outlet branching off from the fluid path after wetting of the filter has been carried out, before it enters a barrier system (e.g. an isolator). In conventional filling systems, flushing of the fluid path is carried out in a separate process by introducing a flushing liquid, preferably the pharmaceutical product, into the fluid path and using it for flushing. In addition, in conventional flushing, the flushing medium, in particular the pharmaceutical product, is generally filled into the original primary packaging (e.g. vials, syringes, etc.), which then have to be removed from the barrier system.

[0018] However, the known methods still leave room for improvement. Since the filter integrity test and the flushing of the fluid path are carried out independently of one another in conventional pharmaceutical filling processes, a high product loss is recorded because neither the wetting medium nor the flushing medium can be used for the final production. Carrying out flushing and performing the filter integrity test separately also proves disadvantageous with regard to the downtimes of the filling system, since the processes are time-consuming.

[0019] It is therefore an object of the present application to provide an improved method for preparing a filling operation for producing a pharmaceutical product, as well as to provide an improved method for producing a pharmaceutical product. In particular, it is an object of the present application to provide an efficient method for preparing a filling operation for producing a pharmaceutical product, as well as an efficient method for producing a pharmaceutical product, reducing product loss.SUMMARY

[0020] According to a first aspect, a method for preparing a filling operation is proposed, comprising the following steps:

[0021] providing a filling system, which comprises a liquid source, a barrier system, in particular an isolator, for providing a controlled environment, a filling device arranged in the barrier system for filling a pharmaceutical liquid, a fluid path extending between the liquid source and the filling device for conducting the pharmaceutical liquid from the liquid source to the filling device, and a filter assembly arranged in the fluid path with at least one filter housing and a filter element arranged in the respective filter housing;

[0022] introducing the pharmaceutical liquid from the liquid source into the fluid path;

[0023] passing a defined amount of the introduced pharmaceutical liquid through the filter assembly in order to wet each filter element of the filter assembly;

[0024] performing an integrity test of each filter element wetted with the pharmaceutical liquid; and

[0025] forwarding the passed pharmaceutical liquid to the filling device in order to at least partially flush the fluid path.

[0026] A barrier system is to be understood as a system that provides a physical and aerodynamic barrier, for example by means of positive air pressure, between an external environment, for example an external cleanroom environment, and a working process. Various barrier systems are known in the prior art. A barrier system may, for example, be an isolator or a restricted access barrier system, a so-called RABS (“Restricted Access Barrier System”). The RABS may be an open RABS or a closed RABS.

[0027] The present application primarily relates to aseptic isolators as barrier systems. However, the present application may also be applied in other barrier systems. The term “isolator” is generally understood to mean a container that is hermetically and gas-tight sealed from the surrounding working area. Within an isolator, a defined atmosphere can be generated for processing sensitive or hazardous products. In this context, isolators are typically used in biopharmaceutical process engineering, for example as part of a filling installation having a plurality of process and processing stations, in order to create a highly pure or sterile, that is to say germ-free, environment.

[0028] The term “pharmaceutical liquid” is understood to mean a pharmaceutical product liquid. Accordingly, wetting of the filter element and flushing of the fluid path are carried out not using water, but using the “original product”.

[0029] A filling operation is to be understood as an operation or process in which a pharmaceutical liquid is filled into one or more containers, in particular vials, cartridges, bottles, syringes, packages and / or the like, in order to produce the pharmaceutical end product. Whether the filling operation is actually carried out preferably depends on the result of the filter integrity test.

[0030] The fluid path ensures fluid transport, in particular liquid transport, between the product source and the filling device arranged in the barrier system and may, for example, comprise one or more hoses or one or more pipes. In particular, a fluid path is to be understood as a path that the pharmaceutical liquid takes from the liquid source to the filling device. Various components such as, for example, valves, filter elements, connecting elements and / or the like may be integrated in the fluid path, which are preferably part of the fluid path.

[0031] Preferably, the fluid path is at least partially configured as a single-use filling path or disposable filling path. In other words, the fluid path or parts of the fluid path may be configured as disposable parts. In the conventional sense, a disposable part is a component that is designed for single use only. Disposable parts are generally manufactured at low cost and are used in particular in the medical field, since cleaning costs and cleaning effort, in particular of filling devices, often exceed the cost of the individual components. Cleaning is particularly complex in the pharmaceutical field, since purity and cleanliness, for example of filling installations, are of great importance. Even the smallest residues of liquids from a previous use may lead to contamination in the filling process.

[0032] A filling device is to be understood as means for filling liquids into containers, in particular vials, cartridges, bottles, syringes and / or the like. The filling device may, for example, comprise one or more filling devices. A filling device may, for example, be or comprise a filling needle, an end of a line or a hose, in particular an open end, a dosing unit and / or the like. The filling device may also be configured as a disposable part.

[0033] The filter assembly comprises at least one filter housing. For example, the filter assembly may comprise one filter housing or a plurality of filter housings. In the case of a plurality of filter housings, the filter housings may, for example, be arranged in series in the fluid path. The filter housing may be understood as a structure that contains and protects the filter element. It preferably comprises inlet and outlet connections in order to enable flow of the pharmaceutical liquid to be filtered. The filter element may comprise one or more filters or filter media that are configured to filter impurities, particles, solids and / or other undesirable substances out of the pharmaceutical liquid. The filter element may be a sterile filter element that preferably comprises one or more sterile filters. The pore size of the membranes used for this purpose is preferably approximately ≤0.22 μm. The filter element may be present in various shapes and embodiments, for example as a membrane filter or depth filter, depending on the specific requirements of the application.

[0034] The pharmaceutical liquid is preferably introduced from the product source into the fluid path. The product source may, for example, be a container containing or comprising the pharmaceutical liquid, which is in fluid connection with the fluid path. Introducing the pharmaceutical liquid may, for example, be carried out using a pump or a valve, in particular on the product source side.

[0035] In order to conduct the pharmaceutical liquid through the fluid path, pumps may, for example, be used. Alternatively or additionally, the pharmaceutical liquid may be conducted at least in sections through the fluid path by applying a gas, in particular a gas under pressure or overpressure. Alternatively or additionally, it may be provided that the pharmaceutical liquid is conducted at least in sections through the fluid path by utilizing gravity.

[0036] The step of passing the defined amount of the introduced pharmaceutical liquid through the filter assembly ensures wetting of the filter element of each filter housing. “Passing” in this context means that a defined amount is conducted into the filter assembly and downstream out of the filter assembly. Preferably, the amount of liquid discharged from the filter assembly is smaller than the amount of liquid introduced into the filter assembly. Passing the defined amount of the introduced pharmaceutical liquid through the filter assembly ensures, on the one hand, wetting and, on the other hand, ensures a reliable filter integrity test, in particular if this is carried out on the basis of or by means of a bubble point test, a diffusion test and / or a pressure hold test.

[0037] Preferably, flushing of the fluid path is carried out exclusively by means of the passed pharmaceutical liquid. This may, for example, be achieved in that a (first) valve located upstream of the filter element in the fluid path is closed after a sufficiently large amount of the introduced pharmaceutical liquid is already present in the filter assembly in order to wet the filter or each filter, and in that the (first) valve remains closed during forwarding of the passed pharmaceutical liquid.

[0038] Flushing is part of the cleaning and validation process, in particular in order to ensure that the filling system complies with the required purity and sterility standards.

[0039] In other words, an amount of the pharmaceutical liquid introduced into the fluid path, which is used for wetting the filter element or each filter element, is also used for flushing the section of the fluid path downstream of the filter assembly by forwarding the passed pharmaceutical liquid to the filling device. In this way, any residues in the fluid path can be removed efficiently and easily. In particular, any “extractables” and “leachables” can be removed from the fluid path in order to ensure that the end product meets safety and quality requirements. Since flushing of the fluid path is carried out by means of the passed pharmaceutical liquid, considerable product savings can additionally be achieved.

[0040] The steps of introducing and / or passing and / or wetting and / or performing and / or forwarding may be carried out in a computer-assisted manner. This may, for example, be achieved by controlling corresponding valves, filter test devices, pumps and / or sensors, which are preferably connected to a control device for data exchange.

[0041] According to a second aspect, a method for producing a pharmaceutical product is proposed, comprising the following steps:

[0042] performing a method for preparing a filling operation according to the first aspect; and

[0043] performing the filling operation in the filling system based on a result of the filter integrity test.

[0044] The step of performing the filling operation is preferably carried out (in time) after the step of performing the method for preparing the filling operation. For performing the filling operation, pharmaceutical liquid may be conducted from the product source through the intact filter assembly and dispensed via the filling device or by means of the filling device into one or more containers arranged in the barrier system.

[0045] The integrity test is generally carried out using automatically operating filter test devices that are connected via pressure lines to a pressurized gas source and to the respective filter element. Such automatically operating filter test devices are commercially available. In order to determine a result of the filter integrity test, that is to say to determine the intactness of the filter element or of each filter element, for example a bubble point test, a diffusion test and / or a pressure hold test may be used. For example, a control device may determine the bubble point pressure, that is to say the pressure at which first bubbles begin to form in the wetted filter element while the wetted filter element, in particular on the raw side, is subjected to a gas under a test pressure. The bubble point pressure may, for example, be detected by pressure sensors arranged in a connected filter test device. The assessment of filter integrity is based on a comparison of the determined pressure with a permissible limit value. If a deviation between the determined bubble point pressure and the reference pressure is detected, this is an indication that the filter element is not intact. Alternatively or additionally, the control device may determine an amount of gas that passes through the wetted filter element while the wetted filter element, in particular on the raw side, is subjected to a gas under a test pressure. The amount of gas passing through the filter element may, for example, be measured by flow sensors arranged in a connected filter test device. The assessment of filter integrity is based on a comparison, by means of the control device, of the determined flow rate with a permissible limit value. If the control device determines, for example, that the determined flow rate is higher than a permissible limit value, this is an indication that the filter element is not intact. It is also conceivable that the control device determines the time required to reach a previously selected pressure and then compares this with a reference time. If the measured time deviates from the reference time by a predetermined amount, this is again an indication of a defective filter element. The integrity test is usually carried out using automatically operating filter test devices that are connected via pressure lines to a pressurized gas source and to the respective filter element. Such automatically operating filter test devices are commercially available.

[0046] Preferably, the filling operation is carried out when each filter element is intact. If it is determined during the filter integrity test that at least one filter element is not intact, this may result in the filling operation not being carried out. In this case, the defective filter element or the filter assembly may be replaced and the procedure repeated.

[0047] The object stated at the outset is thus fully achieved.

[0048] According to a first embodiment of the aspects, it may be provided that each filter element is sterilized before the step of performing the filter integrity test and / or before the step of wetting each filter element.

[0049] Sterilization serves to eliminate or reduce microbial contamination in order to ensure a sterile environment and to ensure the quality and safety of the pharmaceutical products to be manufactured. For example, steam sterilization, dry sterilization and / or radiation sterilization may be considered. In this way, a PUPSIT-compliant filter integrity test can be carried out. Preferably, the filter assembly is sterilized before the step of performing the filter integrity test and / or before the step of wetting each filter element

[0050] According to a further embodiment of the aspects, it may be provided that the forwarded pharmaceutical liquid is dispensed, in particular filled, via or by means of the filling device into at least one reject container arranged in the barrier system.

[0051] In other words, the forwarded pharmaceutical liquid is removed or discharged from the fluid path. In this way, any impurities and / or residues that could impair the quality or safety of the pharmaceutical products to be manufactured are transferred in a controlled manner into a reject container. The reject container is preferably not a final product container such as, for example, a vial, a cartridge, a syringe and / or the like, but rather a bottle.

[0052] Optionally, it may be provided that at least part of the forwarded pharmaceutical liquid is dispensed, in particular filled, via or by means of the filling device into at least one reject container arranged in the barrier system.

[0053] An advantage of this configuration is that any impurities and / or residues that could impair the quality or safety of the pharmaceutical products to be manufactured are transferred in a controlled manner into a reject container. Furthermore, proper disposal can be ensured.

[0054] According to a further embodiment of the aspects, it may be provided that the at least one reject container is removed from the barrier system, in particular by robotic assistance.

[0055] Removal of the at least one reject container from the barrier system may, for example, be carried out manually, in particular by means of glove ports. Such glove ports enable isolated intervention in the isolator without contaminating it or the pharmaceutical products, product-contacting parts and / or materials contained therein. However, this “manual” handling is time-consuming and may present an increased risk of contamination and / or safety risk, for example as a result of leaks.

[0056] Alternatively or additionally, removal of the at least one reject container from the barrier system may be carried out by robotic assistance, in particular by means of one or more handling robots.

[0057] Removal of the at least one reject container may, for example, be carried out via a transfer system of the barrier system, which serves to transfer objects into or out of the barrier system. A transfer system may comprise a transfer lock that can be coupled to the barrier system from the outside. Objects can be transferred into or out of the barrier system via the transfer lock. A transfer system may, for example, be configured as a port system, in particular as an alpha-beta port system. Such transfer systems comprise an alpha port and a beta container. The beta container serves as the transfer lock. The beta container comprises a beta port. The alpha port is preferably arranged on a wall of the barrier system that surrounds an interior of the barrier system. The alpha port and the beta port can be coupled to one another in order to connect the interior of the isolator with an interior volume of the beta container. In the coupled state, objects can be introduced from the beta container into the barrier system or objects can be removed from the barrier system into the beta container. The at least one reject container provided with the “flushing liquid” may be removed from the barrier system (in time) before the start of a filling operation or a production cycle. Alternatively, the at least one reject container may remain in the barrier system until the end of production and be removed after a cleaning process with doors of the barrier system open.

[0058] Removal of the “flushing liquid” from the barrier system prevents any impurities from entering the further production process and impairing the quality or safety of the pharmaceutical products produced. At the same time, the “wetting liquid” is removed from the barrier system.

[0059] According to a further embodiment of the aspects, it may be provided that the at least one reject container containing the forwarded pharmaceutical liquid is closed, in particular by robotic assistance.

[0060] By closing the reject container containing the“flushing liquid”, the risk of contamination in the barrier system can be reduced. Closing the respective reject container may, for example, be carried out by means of a gripping device of a handling robot. Preferably, the handling robot or a gripping device of the handling robot is configured to place a closure onto the respective reject container in order to securely close it. Closing of the at least one reject container is preferably carried out in the barrier system.

[0061] According to a further embodiment of the aspects, it may be provided that the at least one reject container is removed from the barrier system, in particular discharged, by means of one or more handling robots.

[0062] The respective handling robot may comprise an end effector, wherein a gripping device is arranged on the end effector. The end effector may comprise the gripping device or carry the gripping device. The handling robot preferably comprises a multi-jointed arm, at the end of which the end effector is arranged. The arm thus carries the end effector. The end effector can be moved in space by means of the arm. For moving the arm, drive means, such as, for example, one or more drive devices, may be provided. The arm may be fastened to a support structure that is arranged in or on the handling station. The reach of the arm is preferably configured such that the end effector can be moved between a filling location, at which the reject containers are filled, and a port that enables discharge of the reject containers.

[0063] According to a further embodiment of the aspects, it may be provided that the filling system further comprises an intermediate container, in particular an intermediate bag, which is arranged in the fluid path between the filter assembly and the filling device and is in fluid communication with the filter assembly and the filling device, wherein the pharmaceutical liquid passed through the filter assembly is supplied to the intermediate container for intermediate storage before the pharmaceutical liquid is supplied to the filling device.

[0064] The intermediate container serves for intermediate storage of the pharmaceutical liquid passed through the filter assembly and is preferably arranged in the vicinity of the filling location. The intermediate container may, for example, be arranged outside the barrier system. In order to realize multi-lane filling within the barrier system, the intermediate container may be in fluid communication with the filling device by means of a plurality of fluid paths. Preferably, for this purpose, the intermediate container comprises a plurality of outlets that correspond to the plurality of fluid paths. Each outlet of the intermediate container may be assigned to one fluid path. For conveying the pharmaceutical liquid from the intermediate container to the filling device, one or more pumps (e.g. one or more peristaltic pumps) may be arranged in the fluid path between the intermediate container and the filling device. Preferably, a pump is arranged in each fluid path of the plurality of fluid paths. The intermediate container may, for example, be an intermediate bag made of a flexible material.

[0065] Optionally, the intermediate container may serve to eliminate gas inclusions in the pharmaceutical liquid. This process corresponds to “venting” or “degassing” and serves to ensure that the liquid is free of air bubbles, since these may have undesirable effects on the production process or the quality of the end product.

[0066] The pharmaceutical liquid is introduced into the intermediate bag. In this process, the liquid flows through the inlet connection into the bag. As the liquid flows into the bag, the air or gas contained in the liquid rises upward. This enables the accumulation of air inclusions in the upper chamber of the bag, while the liquid collects in the lower chamber. In order to remove the air inclusions, the intermediate container may comprise a venting mechanism. This may, for example, be a special valve or a filtration medium that allows air to pass but retains the liquid. As a result, the air inclusions can escape and the liquid is gradually freed from air bubbles.

[0067] According to a further embodiment of the aspects, it may be provided that, for performing the integrity test, each filter element of the filter assembly is tested for integrity by means of a filter integrity test, in particular a non-destructive filter integrity test.

[0068] In other words, the filter integrity test is carried out by subjecting each filter element wetted with the pharmaceutical liquid to a filter integrity test.

[0069] Various types of filter integrity tests may be considered, including destructive and non-destructive (i.e. non-destructive) filter integrity tests, in order to test the filters for integrity before the filling operation or before a production cycle. Since destructive filter integrity tests such as, for example, the bacterial retention test generally preclude further use of the filter elements, the integrity test is preferably carried out by means of a non-destructive filter integrity test.

[0070] A non-destructive filter integrity test is particularly suitable for an in-process filter integrity test, which means that the respective filter element can remain in the fluid path for performing the filter integrity test. If the integrity or intactness of the respective filter element is determined, the filling operation can be carried out without prior removal or extraction of the filter element from the fluid path. An in-process filter integrity test is particularly relevant in sterile filling operations in the pharmaceutical industry in order to reduce the risk of contamination.

[0071] According to a further embodiment of the aspects, it may be provided that, for performing the integrity test, each filter element is subjected to a bubble point test, a diffusion test and / or a pressure hold test.

[0072] These are informative and proven test methods for verifying filter integrity.

[0073] According to a further embodiment of the aspects, it may be provided that the filter assembly is part of a single-use filter system.

[0074] In contrast to reusable filter systems, in which filter elements can be cleaned, validated and reused, single-use filter systems are regarded as a closed unit and are not reused after application. Rather, a single-use filter system is completely disposed of after use.

[0075] A single-use filter system is to be understood as a unit of filter housings and filter elements that are regarded as one unit and are completely disposed of after use. The single-use filter system preferably comprises inlet and outlet connections in order to connect the filter assembly to the fluid path. These connections enable entry of the liquid to be filtered into the system and exit of the filtered liquid from the system.

[0076] According to a further embodiment of the aspects, it may be provided that the fluid path comprises a first section, a second section in which the filter assembly is arranged, and a third section, wherein the first section extends between the product source and the second section, and wherein the third section extends between the second section and the filling device.

[0077] According to a further embodiment of the aspects, it may be provided that a first valve is arranged upstream of the filter assembly in the fluid path, which separates the first section and the second section from one another.

[0078] In other words, the first section of the fluid path extends between the product source and a first valve arranged upstream of the filter assembly in the fluid path. The first valve serves to regulate or interrupt the flow of the pharmaceutical liquid in the fluid path, depending on the requirements of the process. This enables precise liquid dosing or supply. The first valve may also serve to regulate the pressure in the second section of the fluid path. It can increase or decrease the pressure in order to achieve the desired operating conditions. Preferably, the first valve can be actuated by means of an electronic control device.

[0079] According to a further embodiment of the aspects, it may be provided that the step of passing the defined amount of the introduced pharmaceutical liquid comprises a step of opening the first valve until an amount of the pharmaceutical liquid introduced into the fluid path flows from the first section of the fluid path into the second section of the fluid path, and a step of closing the first valve.

[0080] By opening the first valve, the pharmaceutical liquid introduced into the fluid path, in particular in the first section of the fluid path, can flow from the first section into the second section of the fluid path. By closing the first valve, a further inflow of liquid from the first section can be prevented. In this way, an amount of the pharmaceutical liquid used for wetting the filter element and / or an amount of the pharmaceutical liquid used for flushing the fluid path can be metered, product loss.

[0081] According to a further embodiment of the aspects, it may be provided that the step of passing the defined amount of the introduced pharmaceutical liquid further comprises a step of wetting, in particular with the first valve open, each filter element with or by means of the pharmaceutical liquid that has flowed into the second section, the step of closing the first valve when each filter element is sufficiently wetted, and a step of discharging the pharmaceutical liquid used for wetting each filter element from the filter assembly, in particular into the third section of the fluid path.

[0082] For example, it may be provided that the first valve is only closed again after the pharmaceutical liquid used for wetting each filter element has been discharged, in particular completely, from the filter assembly. Alternatively, it may, for example, be provided that the first valve is closed again before the pharmaceutical liquid used for wetting the filter element or each filter element is discharged from the filter assembly, but after sufficient wetting of the filter element or each filter element, so that the step of discharging from the filter assembly is carried out with the first valve closed.

[0083] The filter element is “sufficiently wetted” when the requirements for the degree of wetting of the respective filter element specified by the respective filter integrity test method are fulfilled. For example, in the bubble point test, the filter membrane should be completely wetted with the liquid, which is achieved by a longer wetting time. Incomplete wetting may under certain circumstances lead to an incorrect measurement and is therefore to be avoided.

[0084] According to a further embodiment of the aspects, it may be provided that the step of discharging from the filter assembly is carried out with the first valve closed.

[0085] In other words, the first valve is closed before the pharmaceutical liquid used for wetting each filter element is discharged from the filter assembly, but after the respective filter element or each filter element has been sufficiently wetted.

[0086] In order to discharge the liquid used for wetting the filter element or each filter element from the filter assembly, an air supply may be ensured in the second section of the fluid path. The air supply is intended to prevent the pressure within the second section of the fluid path from falling below atmospheric pressure. The air supply may, for example, take place via a gas supply path that opens into the fluid path upstream of the filter element of each filter housing. The liquid may then be discharged, for example, by utilizing gravity and / or by using a pump and / or by supplying a gas under pressure.

[0087] An advantage of this configuration is that the filter assembly or the second section of the fluid path—apart from the pores of the filter element, which are wetted or filled with pharmaceutical liquid—is now substantially free of liquid. In this way, ideal test conditions for performing the filter integrity test can be provided, in particular when the respective filter element is subjected on the raw side to a gas under test pressure for the integrity test. The absence of liquid in the filter assembly particularly reduces the risk of falsification of the measurement results.

[0088] According to a further embodiment of the aspects, it may be provided that the step of performing the filter integrity test is carried out with the first valve closed.

[0089] The first valve is preferably closed before performing the filter integrity test. In this way, it is ensured that no liquid flows into the respective filter housing or into the filter assembly during testing of filter integrity. In addition, with the first valve closed, the test pressure relevant for the bubble point test, the diffusion test and the pressure hold test can be applied, that is to say the respective filter element can be subjected on the raw side to a gas under test pressure for the integrity test.

[0090] According to a further embodiment of the aspects, it may be provided that the second section of the fluid path is delimited by the first valve and by a second valve, which is arranged downstream of the filter assembly in the fluid path.

[0091] In other words, the first valve separates the first section of the fluid path from the second section of the fluid path, and the second valve separates the second section of the fluid path from the third section of the fluid path.

[0092] The second valve serves to regulate or interrupt the flow of the pharmaceutical liquid in the fluid path, depending on the requirements of the process. This enables precise liquid dosing or supply. The second valve may also serve to regulate the pressure in the second section of the fluid path. It can increase or decrease the pressure in order to achieve the desired operating conditions. Preferably, the second valve can be actuated by means of an electronic control device.

[0093] According to a further embodiment of the aspects, it may be provided that wetting of the filter element or each filter element is carried out with the first valve open and with the second valve closed.

[0094] Opening the first valve ensures inflow of the pharmaceutical liquid into the respective filter housing in order to wet the filter element. Since the second valve is closed during wetting, the wetting process can be carried out reliably.

[0095] According to a further embodiment of the aspects, it may be provided that performing the filter integrity test is carried out with the first valve closed and with the second valve open.

[0096] An advantage of this configuration is that a gas used for the filter integrity test can flow from the second section of the fluid path into the third section of the fluid path.

[0097] According to a further embodiment of the aspects, it may be provided that discharging the pharmaceutical liquid used for wetting the filter element or each filter element from the filter assembly, in particular into the third section of the fluid path, is carried out with the first valve closed and with the second valve open.

[0098] In this way, the pharmaceutical liquid used for wetting can be removed from the filter assembly or the respective filter housing without “pushing” further liquid from the first section of the fluid path. In this way, ideal test conditions for performing the filter integrity test can be provided, in particular when the respective filter element is subjected on the raw side to a gas under test pressure for the integrity test. The absence of liquid in the filter assembly particularly reduces the risk of falsification of the measurement results.

[0099] According to a further embodiment of the aspects, it may be provided that, for performing the filter integrity test, each filter element, in particular on the raw side, is subjected to a gas under a test pressure, wherein during subjecting the respective filter element to the gas under the test pressure the first valve is closed and the second valve is open.

[0100] The gas used for the filter integrity test can thus flow into the third section of the fluid path.

[0101] According to a further embodiment of the aspects, it may be provided that, for performing the filter integrity test, each filter element, in particular on the raw side, is subjected to a gas under a test pressure, wherein the gas used for performing the filter integrity test is discharged from the fluid path via a gas discharge path that branches off from the second section of the fluid path in a region of the fluid path located downstream of the filter assembly and upstream of the second valve and comprises a third valve, in particular wherein during subjecting the respective filter element to the gas under the test pressure the first valve and the second valve are closed and the third valve is open, in particular wherein the third valve is a check valve.

[0102] The third valve may serve to regulate the pressure in the second section of the fluid path. Preferably, the third valve can be actuated by means of an electronic control device. Accordingly, the gas used for the filter integrity test does not flow into the third section of the fluid path, but is discharged from the system while still in the second section of the fluid path.

[0103] According to a further embodiment of the second aspect, it may be provided that performing the filling operation comprises filling at least one container, in particular a pharmaceutical container, arranged in the barrier system.

[0104] The respective container may, for example, be a vial, a cartridge, a bottle, a syringe, a package and / or the like. The respective container is preferably different from the reject containers.

[0105] According to a further embodiment of the second aspect, it may be provided that performing the filling operation is carried out using the filter element subjected to the filter integrity test when the filter integrity of the filter element or of each filter element of the filter assembly has been determined.

[0106] According to a further aspect, a filling system is proposed, comprising: a liquid source with a pharmaceutical liquid; a barrier system, in particular an isolator, for providing a controlled environment; a filling device arranged in the barrier system for filling the pharmaceutical liquid; a fluid path extending between the liquid source and the filling device and means, in particular a pump, for conducting the pharmaceutical liquid from the liquid source to the filling device; a filter assembly arranged in the fluid path with at least one filter housing and a filter element arranged in the respective filter housing; a first valve arranged in the fluid path between the filter assembly and the product source for blocking or releasing a supply of liquid; a gas source comprising a gas, in particular nitrogen or an inert gas, and being in fluid connection with the respective filter housing; at least one gas supply device for regulating a gas flow from the gas source to the respective filter housing; a sensor device arranged in the respective filter housing and comprising at least one pressure sensor for measuring a pressure, in particular at which first bubbles begin to form in the wetted filter element, and / or a flow sensor for measuring an amount of gas that passes through the wetted filter element; and a control device configured to carry out the method according to the first aspect and / or the second aspect.

[0107] It is understood that the features mentioned above and those yet to be explained below may be used not only in the respective combination indicated, but also in other combinations or individually, without departing from the scope of the present invention.DRAWINGS

[0108] Embodiments of the present application are illustrated in the drawings and are explained in more detail in the following description. In the drawings:

[0109] FIG. 1 shows a schematic representation of an embodiment of a filling system;

[0110] FIG. 2 shows a flow diagram of an embodiment of a method for preparing a filling operation according to a first aspect; and

[0111] FIG. 3 shows a flow diagram of an embodiment of a method for producing a pharmaceutical product according to a second aspect.DETAILED DESCRIPTION

[0112] FIG. 1 shows a schematic representation of an embodiment of a filling system, designated overall by reference sign 10. The filling system 10 comprises a liquid source 12, which may be configured, for example, as a pharmaceutical product bag, a barrier system 14 for providing a controlled environment, a filling device 16 arranged in the barrier system 14 for filling a pharmaceutical liquid, a fluid path 18 extending between the liquid source 12 and the filling device 16 for conducting the pharmaceutical liquid from the liquid source 12 to the filling device 16, and a filter assembly 20 arranged in the fluid path 18 with at least one filter housing 22 and a filter element 24 arranged in the respective filter housing 22. In order to introduce the pharmaceutical liquid from the liquid source 12 into the fluid path 18 and / or to supply it to the filter assembly 20, a first pump 25 (e.g. a peristaltic pump) may, for example, be arranged in the fluid path 18 between the liquid source 12 and the filter assembly 20.

[0113] In the representation shown, one filter housing 22 is illustrated by way of example. However, it is understood that the filter assembly 20 may also comprise a plurality of filter housings 22, which may, for example, be arranged in series in the fluid path 18.

[0114] The filling system 10 may further comprise a gas source 26 for storing and / or providing a gas for the filter integrity test, which is in fluid connection via a gas supply path 28 with a raw side (i.e. an inflow side) of the filter 24. The gas may, for example, be air or nitrogen.

[0115] Furthermore, the filling system 10 exemplarily comprises a filter test device 27 for performing the integrity test. In the representation shown, the filter test device 27 is connected on the one hand to the pressurized gas source 26 and on the other hand via the gas supply path 28 to the filter housing 22.

[0116] Furthermore, the filling system 10 may comprise a first valve 30 and an optional second valve 32. The first valve 30 is configured to regulate or interrupt the flow of the pharmaceutical liquid in the fluid path 18. The same applies to the second valve 32.

[0117] The valves 30 and 32 arranged in the fluid path 18 delimit a second section 40 of the fluid path 18. Between the liquid source 12 and the first valve 30 extends a first section 38 of the fluid path 18, which adjoins the second section 40 of the fluid path 18. Between the second valve 32 and the filling device 16 extends a third section 42 of the fluid path 18, which adjoins the second section 40 of the fluid path 18.

[0118] Furthermore, the filling system 10 may comprise an optional gas discharge path 44, which branches off from the fluid path 18 downstream of the filter assembly 20 and upstream of the barrier system 14, for example via a three-way valve not shown. Preferably, the gas discharge path 44 branches off from the fluid path 18 between the filter assembly 20 and the second valve 32. An optional third valve 46 may be arranged in the gas discharge path 44 in order to regulate gas outflow.

[0119] The gas source 26 is preferably in fluid connection with the gas discharge path 44 in order, for example, to remove a gas supplied to the filter element 22 for checking filter integrity from the fluid path. Alternatively, however, the gas may also be discharged via the fluid path 18. Furthermore, the filling system 10 comprises an optional intermediate container 33 arranged in the fluid path 18 between the filter assembly 20 and the filling device 16, in particular in the third section 42 of the fluid path 18, and being in fluid communication with the filter assembly 20 and the filling device 16. In this way, the pharmaceutical liquid passed through the filter assembly 20 can be supplied to the intermediate container 33 for intermediate storage before the pharmaceutical liquid is supplied to the filling device 16. A second pump 35 is arranged in the fluid path 18 between the intermediate container 33 and the filling device 16 and is configured to forward pharmaceutical liquid from the intermediate container to the filling device 16. The intermediate container 33 may, for example, be an intermediate bag made of a flexible material.

[0120] Furthermore, the filling system 10 may comprise a control device 34 for controlling the first valve 30, the second valve 32, the third valve 46, a gas supply via the gas supply path 28, a gas discharge via the gas discharge path 44 and / or a liquid introduction into the fluid path 18. Alternatively or additionally, however, at least one of the valves 30, 32, 46 may also be manually actuatable. Optionally, the control device 34 may be configured to control the first pump 25 and / or the second pump 35.

[0121] FIG. 2 shows a flow diagram of a method 100 for preparing a filling operation according to the first aspect of the invention.

[0122] In a first step S102 of the method 100, the filling system 10 is provided.

[0123] In a second step S104 of the method 100, the pharmaceutical liquid is introduced from the liquid source 12 into the fluid path 18.

[0124] In a third step S106 of the method 100, a defined amount of the introduced pharmaceutical liquid is passed through the filter assembly 20 in order to wet each filter element 24 of the filter assembly 20, in particular with the pharmaceutical liquid.

[0125] In a fourth step S108 of the method 100, each filter element 24 wetted with the pharmaceutical liquid is subjected to a filter integrity test.

[0126] In a fifth step S110 of the method 100, the passed pharmaceutical liquid is forwarded to the filling device 16 in order to at least partially flush the fluid path 18.

[0127] FIG. 3 shows a flow diagram of a method 200 for producing a pharmaceutical product according to the second aspect.

[0128] In a first step S202 of the method 200, the method 100 according to the first aspect is carried out.

[0129] In a second step S204 of the method 200, the filling operation is carried out in the filling system 10 based on a result of the filter integrity test.

[0130] It is to be understood that the foregoing is a description of one or more preferred exemplary embodiments of the invention. The invention is not limited to the particular embodiment(s) disclosed herein, but rather is defined solely by the claims below. Furthermore, the statements contained in the foregoing description relate to particular embodiments and are not to be construed as limitations on the scope of the invention or on the definition of terms used in the claims, except where a term or phrase is expressly defined above. Various other embodiments and various changes and modifications to the disclosed embodiment(s) will become apparent to those skilled in the art. All such other embodiments, changes, and modifications are intended to come within the scope of the appended claims.

[0131] As used in this specification and claims, the terms “for example,”“e.g.,”“for instance, “such as,” and “like,” and the verbs “comprising,”“having,”“including,” and their other verb forms, when used in conjunction with a listing of one or more components or other items, are each to be construed as open ended, meaning that the listing is not to be considered as excluding other, additional components or items. Other terms are to be construed using their broadest reasonable meaning unless they are used in a context that requires a different interpretation.

Claims

1. A method for preparing a filling operation, comprising the following steps:providing a filling system, which comprises a liquid source, a barrier system for providing a controlled environment, a filling device arranged in the barrier system for filling a pharmaceutical liquid, a fluid path extending between the liquid source and the filling device for conducting the pharmaceutical liquid from the liquid source to the filling device, and a filter assembly arranged in the fluid path with at least one filter housing and a filter element arranged in the respective filter housing;introducing the pharmaceutical liquid from the liquid source into the fluid path;passing a defined amount of the introduced pharmaceutical liquid through the filter assembly in order to wet each filter element of the filter assembly;performing an integrity test of each filter element wetted with the pharmaceutical liquid; andforwarding the passed pharmaceutical liquid to the filling device in order to at least partially flush the fluid path.

2. The method according to claim 1, wherein each filter element is sterilized prior to the step of performing the integrity test and / or prior to the step of wetting each filter element.

3. The method according to claim 1, wherein the forwarded pharmaceutical liquid is dispensed via the filling device into at least one reject container arranged in the barrier system.

4. The method according to claim 3, wherein the at least one reject container containing the forwarded pharmaceutical liquid is closed.

5. The method according to claim 3, wherein the at least one reject container is removed from the barrier system.

6. The method according to claim 5, wherein the at least one reject container is removed from the barrier system using one or more handling robots.

7. The method according to claim 1, wherein the filling system further comprises an intermediate container which is arranged in the fluid path between the filter assembly and the filling device and is in fluid communication with the filter assembly and the filling device, wherein the pharmaceutical liquid passed through the filter assembly is supplied to the intermediate container for intermediate storage before the pharmaceutical liquid is supplied to the filling device.

8. The method according to claim 1, wherein, for performing the integrity test, each filter element of the filter assembly is tested for integrity using a non-destructive filter integrity test.

9. The method according to claim 8, wherein, for performing the integrity test, each filter element is subjected to a bubble point test, a diffusion test and / or a pressure hold test.

10. The method according to claim 1, wherein the filter assembly is arranged outside the barrier system.

11. The method according to claim 1, wherein the filter assembly is part of a single-use filter system.

12. The method according to claim 1, wherein the fluid path comprises a first section, a second section, in which the filter assembly is arranged, and a third section, wherein the first section extends between a product source and the second section, and wherein the third section extends between the second section and the filling device.

13. The method according to claim 12, wherein a first valve is arranged upstream of the filter assembly in the fluid path, which separates the first section of the fluid path from the second section of the fluid path.

14. The method according to claim 13, wherein the step of passing the defined amount of the introduced pharmaceutical liquid comprises a step of opening the first valve until an amount of the pharmaceutical liquid introduced into the fluid path flows from the first section of the fluid path into the second section of the fluid path, and a step of closing the first valve.

15. The method according to claim 13, wherein the step of passing the defined amount of the introduced pharmaceutical liquid further comprises a step of wetting each filter element with or using the pharmaceutical liquid that has flowed into the second section, the step of closing the first valve when each filter element is sufficiently wetted, and a step of discharging the pharmaceutical liquid used for wetting each filter element from the filter assembly.

16. The method according to claim 15, wherein the step of discharging from the filter assembly is carried out with the first valve closed.

17. The method according to claim 12, wherein the step of performing the integrity test is carried out with the first valve closed.

18. The method according to claim 12, wherein the second section of the fluid path is delimited by the first valve and by a second valve, which is arranged downstream of the filter assembly in the fluid path.

19. The method according to claim 18, wherein wetting each filter element is carried out with the first valve open and with the second valve closed.

20. The method according to claim 18, wherein performing the integrity test is carried out with the first valve closed and with the second valve open.

21. The method according to claim 18, wherein, for performing the integrity test, each filter element is subjected to a gas under a test pressure, wherein during subjecting the respective filter element to the gas under test pressure the first valve is closed and the second valve is open.

22. The method according to claim 18, wherein, for performing the integrity test, each filter element is subjected to a gas under a test pressure, wherein the gas used for performing the integrity test is discharged from the fluid path via a gas discharge path, which branches off from the second section of the fluid path in a region of the fluid path located downstream of the filter assembly and upstream of the second valve and comprises a third valve, wherein during subjecting the respective filter element to the gas under the test pressure the first valve and the second valve are closed and the third valve is open.

23. A method for producing a pharmaceutical product, comprising the following steps:performing the method for preparing a filling operation according to claim 1; andperforming the filling operation in the filling system based on a result of the integrity test.

24. The method according to claim 23, wherein performing the filling operation comprises filling at least one container arranged in the barrier system.

25. The method according to claim 23, wherein performing the filling operation is carried out using the filter element subjected to the integrity test when the filter integrity of the filter element or of each filter element of the filter assembly has been determined.

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