Procedure for preparing a filling process

Abstract

The present invention relates to a method (100) for preparing a filling process, comprising the following steps: providing (S102) a filling system (10) comprising a liquid source (12), a barrier system (14), in particular an isolator, 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 conveying the pharmaceutical liquid from the liquid source (12) to the filling device (16), and a filter assembly (20) arranged in the fluid path (18) comprising at least one filter housing (22) and a filter element (24) arranged in the respective filter housing (22); introducing (S104) the pharmaceutical liquid from the liquid source (12) into the fluid path (18);Passing (S106) a defined quantity of the introduced pharmaceutical liquid through the filter assembly (20) to wet each filter element (24) of the filter assembly (20); performing (S108) an integrity check of each filter element (24) wetted with the pharmaceutical liquid; and passing (S110) the passed pharmaceutical liquid to the filling device (16) to at least partially flush the fluid path (18).

Description

[0001] The present invention relates to a method for preparing a filling process. Furthermore, the present invention relates to a method for producing a pharmaceutical product.

[0002] Filter integrity testing is a fundamental requirement for process filtration applications in the pharmaceutical industry, particularly in pharmaceutical manufacturing processes. In particular, various guidelines for quality assurance of production processes in pharmaceutical production (e.g., the production of medicinal products and active ingredients) stipulate that a filter system must be subjected to an integrity check or integrity test before and after use. Examples include the so-called GMP guidelines (GMP stands for "Good Manufacturing Practice"), which require the integrity testing of such filter systems before and after use in the manufacture of medicinal products.

[0003] A pre-use filter integrity test ensures the integrity of the filter element before processing a batch, thus preventing the use of a non-integral filter element. A filter integrity test after filtration of a production batch can determine whether the integrity of a filter was maintained throughout the filling process. If a defect is detected immediately after processing the production batch, immediate action can be taken, avoiding delays and quickly repeating the processing step.

[0004] Particular attention is paid to filter integrity testing prior to use in the manufacture of pharmaceutical products. 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 be tested for integrity after installation and before use (i.e., before the filter system is used to filter the final product).

[0005] In the area of ​​sterile manufacturing or filling processes, so-called PUPSIT filter tests, for example, can be used. These are a regulatory requirement in pharmaceutical production for European markets, for example. The abbreviation PUPSIT stands for "Pre-Use Post-Sterilization Integrity Testing," which indicates that the filter system, especially disposable filter systems, must be tested for integrity after installation and sterilization and before use. In addition, a filter used to sterilize a liquid should be subjected to a non-destructive integrity test after use, before the filter is removed from its housing or the disposable filter system is removed. The integrity test procedure should be validated, and the test results should correlate with the microbial retention capacity of the filter determined during validation.Examples of tests used are the bubble point test, the diffusion test, the water intrusion test or the pressure holding test.

[0006] Testing methods are generally divided into two classes: destructive and non-destructive, i.e. non-destructive and non-destructive.

[0007] Since destructive filter integrity tests such as the bacterial retention test (Bacterial Challenge Test) generally preclude further use of the filter elements, non-destructive testing methods are preferred in pharmaceutical production. A non-destructive filter integrity test thus paves the way for in-process filter integrity testing, meaning that the filters can remain in the fluid path while the filter integrity test is performed. Examples of non-destructive filter integrity tests that can be considered include a bubble pressure test, a diffusion test, and / or a pressure retention test, which are preferred methods for filtration processes in pharmaceutical production.

[0008] The bubble pressure test, also known as the bubble point test, is one of the most commonly used test methods in the pharmaceutical industry. The process utilizes the capillary forces and surface tension of a liquid applied to the filter. Before the test begins, the filter element to be tested must be exposed to a wetting liquid in order to wet the filter surface or filter membrane, especially completely. Pressure, particularly gas pressure, is then 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 pressure test appear on the opposite side of the filter element, indicating 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 falls below a certain limit (depending on the wetting fluid, this is either specified by the filter manufacturer or determined product-specifically during filter validation), this indicates that the filter is not intact. In this case, the filter cannot be used in the filling process and must be replaced. The bubble pressure test is a highly reliable test method for determining the maximum pore size of a filter surface as well as for critical damage to the filter surface.

[0009] The diffusion test utilizes the natural diffusion of gas molecules according to Fick's law. Similar to the bubble pressure test, the respective filter element must be wetted with a wetting fluid before the test begins. A pressure is then applied, preferably corresponding to approximately 70% to 80% of the specified bubble point pressure. Due to the desire to achieve 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 flowing the same amount of gas on the non-sterile side. This way, the differential pressure remains constant throughout the entire test, and only the small pressure drops are measured.The pressure hold test, also known as the pressure drop test, is a variant of the diffusion test. However, in the pressure hold test, no additional gas is added. Instead, the total pressure drop is measured once, specifically using 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, it is likely that the filter element is damaged.

[0010] The wetting fluid is typically pure water or the pharmaceutical liquid to be filtered, i.e., the original product. Using the original product as the wetting fluid has the advantage over water that the fluid path extending between the product source and the filling point, where the filter elements are located, does not need to be cleared of water residues after the filter integrity test. This can improve the quality of the subsequent filling process and reduce downtime of the filling system.

[0011] In addition, in pharmaceutical filtration processes, particularly 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 arrangement arranged in the fluid path, must be completely rinsed before the actual filling process can take place. The reason for flushing is that undesirable residues that need to be removed may be present in components of the filling system, such as lines, in particular hoses, connections, seals or the like. The residues can be, for example, so-called "extractables" and "leachables". The term "extractables" here refers to chemical compounds that can be extracted from a material, e.g. 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, e.g., a pharmaceutical liquid.

[0012] A method for filtering a liquid raw material in a process stream to obtain a pharmaceutical product is known, for example, from document EP 2 925 420 B1.

[0013] 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.

[0014] In addition, an automated disposable filtration device is known from the document DE 10 2017 127 017 A1.

[0015] In conventional filling systems, the fluid path is usually flushed separately from the filter integrity test. In particular, the wetting liquid used to perform the filter integrity test (e.g., the pharmaceutical product or water) is conventionally removed from the fluid path after the filter has been wetted via a fluid outlet branched off from the fluid path, before it enters a barrier system (e.g., an isolator). In conventional filling systems, the fluid path is flushed in a separate process by introducing a flushing liquid, preferably the pharmaceutical product, into the fluid path and using it to flush it. In addition, during conventional flushing, the flushing medium, in particular the pharmaceutical product, is usually filled into the original packaging (e.g., vials, syringes, etc.), which then have to be removed from the barrier system.

[0016] However, the existing methods still leave room for improvement. Since the filter integrity test and the flushing of the fluid path are performed independently in conventional pharmaceutical filling processes, a high level of product loss is observed, as neither the wetting medium nor the flushing medium can be used for final production. Performing the flushing and filter integrity test separately also proves to be detrimental to the filling system's downtime, as the processes are time-consuming.

[0017] It is therefore an object of the present invention to provide an improved method for preparing a filling process for producing a pharmaceutical product, as well as an improved method for producing a pharmaceutical product. In particular, it is an object of the present invention to provide an efficient method for preparing a filling process for producing a pharmaceutical product, as well as an efficient method for producing a pharmaceutical product, which minimizes product loss.

[0018] According to a first aspect of the invention, a method for preparing a filling process is proposed, comprising the following steps: - Providing a filling system comprising 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; - 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; and - Passing the pharmaceutical liquid through to the filling device to at least partially flush the fluid path.

[0019] A barrier system is a system that provides a physical and aerodynamic barrier, e.g., by means of positive air pressure, between an external environment, such as an external cleanroom environment, and a work process. Various barrier systems are known in the art. A barrier system can, for example, be an isolator or a barrier with restricted access, a so-called RABS (Restricted Area Barrier System). The RABS can be an open RABS or a closed RABS.

[0020] The present invention primarily concerns aseptic isolators as barrier systems. However, the present invention can also be applied to other barrier systems. The term "isolator" generally refers to a container that is hermetically and gas-tightly sealed from the surrounding work space. A defined atmosphere can be created within an isolator for processing sensitive or hazardous products. In this context, isolators are typically used in biopharmaceutical process engineering, for example, as part of a filling system with multiple processing stations, to create a highly clean or sterile, i.e., germ-free environment.

[0021] "Pharmaceutical liquid" refers to a pharmaceutical product liquid. Accordingly, wetting of the filter element and flushing of the fluid path are not carried out with water, but with the "original product."

[0022] A filling operation is understood to mean a 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 final pharmaceutical product. Whether the filling operation is actually carried out depends preferably on the result of the filter integrity test.

[0023] The fluid path ensures fluid transport, in particular liquid transport, between the product source and the filling device arranged in the barrier system and can, for example, comprise one or more hoses or one or more pipes. In particular, a fluid path is understood to be a route taken by the pharmaceutical liquid from the liquid source to the filling device. Various components such as valves, filter elements, connecting elements, and / or the like can be integrated into the fluid path and are preferably part of the fluid path.

[0024] Preferably, the fluid path is at least partially designed as a one-way filling path or disposable filling path. In other words, the fluid path or parts of the fluid path can be designed as disposable parts. In the conventional sense, a disposable part is a component designed for single use only. Disposable parts are generally inexpensive to manufacture and are used particularly in the medical field because the cleaning costs and effort, particularly for filling devices, often exceed the cost of the individual components. Cleaning is particularly complex in the pharmaceutical field because the purity and cleanliness, for example of filling systems, are of great importance. Even the smallest residues of liquids from previous use can lead to contamination in the filling process.

[0025] A filling device is understood to mean means for filling liquids into containers, in particular vials, cartridges, bottles, syringes, and / or the like. The filling device can, for example, comprise one or more filling devices. A filling device can, for example, be or comprise a filling needle, a particularly open end of a line or hose, a dosing unit, and / or the like. The filling device can also be designed as a disposable part.

[0026] The filter assembly has at least one filter housing. For example, the filter assembly can have one filter housing or a plurality of filter housings. In the case of multiple filter housings, the filter housings can, for example, be arranged in series in the fluid path. The filter housing can be understood as a structure that contains and protects the filter element. It preferably has inlet and outlet connections to enable the flow of the pharmaceutical liquid to be filtered. The filter element can have one or more filters or filter media designed to filter out impurities, particles, solids, and / or other undesirable substances from the pharmaceutical liquid. The filter element can be a sterile filter element, which preferably has one or more sterile filters. The pore size of the membranes used for this purpose is preferably approximately ≤ 0.22 µm.The filter element can be available in various shapes and designs, such as a membrane filter or depth filter, depending on the specific requirements of the application.

[0027] The pharmaceutical liquid is preferably introduced from the product source into the fluid path. The product source can, for example, be a container containing or having the pharmaceutical liquid, which is in fluid communication with the fluid path. The pharmaceutical liquid can be introduced, for example, using a pump or a valve, particularly on the product source side.

[0028] Pumps, for example, can be used to convey the pharmaceutical liquid through the fluid path. Alternatively or additionally, the pharmaceutical liquid can be conveyed through the fluid path at least in sections by applying a gas, in particular one under pressure or overpressure. Alternatively or additionally, it can be provided that the pharmaceutical liquid is conveyed through the fluid path at least in sections using gravity.

[0029] The step of passing the defined amount of the introduced pharmaceutical liquid through the filter assembly ensures the wetting of the filter element of each filter housing. "Passing" here means that a defined amount is passed into the filter assembly and downstream out of the filter assembly. Preferably, the amount of liquid passed out of the filter assembly is smaller than the amount of liquid passed into the filter assembly. Passing the defined amount of the introduced pharmaceutical liquid through the filter assembly ensures wetting on the one hand, and on the other hand, guarantees a reliable filter integrity test, particularly if this is carried out on the basis of or by means of a bubble pressure test, a diffusion test, and / or a pressure retention test.

[0030] Preferably, the fluid path is flushed exclusively by means of the pharmaceutical liquid passing through it. This can be achieved, for example, by closing a (first) valve located upstream of the filter element in the fluid path after a sufficiently large amount of the introduced pharmaceutical liquid has already entered the filter assembly to wet the filter or each filter, and by keeping the (first) valve closed while the pharmaceutical liquid is passed through.

[0031] Rinsing is part of the cleaning and validation process, particularly to ensure that the filling system meets the required cleanliness and sterility standards.

[0032] In other words, a portion of the pharmaceutical liquid introduced into the fluid path, which is used to wet the filter element(s), is also used to flush the section of the fluid path downstream of the filter assembly by forwarding the pharmaceutical liquid passed through 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 to ensure that the final product meets safety and quality requirements. Furthermore, since the fluid path is flushed using the pharmaceutical liquid passed through, significant product savings can be achieved.

[0033] The steps of introducing and / or passing and / or wetting and / or passing and / or forwarding can be carried out with computer support. This can be done, for example, by controlling corresponding valves, filter testing devices, pumps, and / or sensors, which are preferably connected to a control device for data exchange.

[0034] According to a second aspect, a method for producing a pharmaceutical product is proposed, comprising the following steps: - carrying out a method for preparing a filling operation according to the first aspect; and - Performing the filling process in the filling system based on a result of the filter integrity test.

[0035] The step of performing the filling process preferably occurs (in time) after the step of performing the method for preparing the filling process. To perform the filling process, pharmaceutical liquid from the product source can be passed 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.

[0036] The integrity test is usually carried out using automatic filter testing devices that are connected to a pressurised gas source and the respective filter element via pressure lines. Such automatic filter testing devices are available on the market. To determine the result of the filter integrity test, i.e. to determine the intactness of the or each filter element, a bubble pressure test, a diffusion test and / or a pressure holding test can be used, for example. For example, the bubble pressure can be determined using a control device, i.e. the pressure at which the first bubbles begin to form in the wetted filter element while the wetted filter element, in particular on the raw side, is pressurised with a gas at a test pressure. The bubble pressure can be recorded, for example, using pressure sensors arranged in a connected filter testing device.The assessment of filter integrity is based on a comparison of the determined pressure with a permitted limit value. If a deviation is detected between the determined bubble pressure and the reference pressure, this is an indication that the filter element is not intact. Alternatively or additionally, the control device can determine a gas volume that passes through the wetted filter element while the wetted filter element, particularly on the raw side, is pressurized with a gas under a test pressure. The gas volume passing through the filter element can, for example, be measured using 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 permitted limit value. If the control device, for example,If the system detects that the measured flow rate is higher than an approved limit, 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 time 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 automatic filter testing devices that are connected to a pressurized gas source and the respective filter element via pressure lines. Such automatic filter testing devices are available on the market.

[0037] Preferably, the filling process is carried out when each filter element is intact. If the filter integrity test reveals that at least one filter element is not intact, this may result in the filling process not being carried out. In this case, the defective filter element or filter assembly can be replaced and the procedure repeated.

[0038] The task posed at the beginning is thus completely solved.

[0039] According to a first embodiment of the aspects, it can 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.

[0040] Sterilization serves to eliminate or reduce microbial contamination to ensure a sterile environment and safeguard the quality and safety of the manufactured pharmaceutical products. Examples of possible methods include steam sterilization, dry sterilization, and / or radiation sterilization. This allows for a PUPSIT-compliant filter integrity test to be performed. Preferably, the filter assembly is sterilized before the filter integrity test and / or before the wetting of each filter element.

[0041] According to a further embodiment of the aspects, it can 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.

[0042] In other words, the transferred pharmaceutical liquid is removed or discharged from the fluid path. In this way, any contaminants and / or residues that could compromise the quality or safety of the pharmaceutical products being manufactured are transferred in a controlled manner to a reject container. The reject container is preferably a bottle rather than a finished product container such as a vial, cartridge, syringe, and / or the like.

[0043] Optionally, it can be provided that at least a portion 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.

[0044] One advantage of this design is that any contaminants and / or residues that could compromise the quality or safety of the pharmaceutical products being manufactured are transferred to a reject container in a controlled manner. Furthermore, proper disposal can be ensured.

[0045] According to a further embodiment of the aspects, it can be provided that the at least one reject container is removed from the barrier system, in particular with the assistance of a robot.

[0046] The removal of at least one reject container from the barrier system can be done manually, for example, particularly using glove ports. Such glove ports allow isolated access to 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 can pose an increased contamination and / or safety risk, e.g., due to leaks.

[0047] Alternatively or additionally, the removal of at least one reject container from the barrier system can be carried out robotically, in particular by means of one or more handling robots.

[0048] The removal of the at least one reject container can be carried out, for example, via a transfer system of the barrier system, which serves to transfer objects into or out of the barrier system. A transfer system can have 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 can be designed, for example, as a port system, in particular as an alpha-beta port system. Such transfer systems have an alpha port and a beta container. The beta container serves as a transfer lock. The beta container has a beta port. The alpha port is preferably arranged on a wall of the barrier system that surrounds an interior space of the barrier system.The Alpha port and the Beta port can be coupled to connect the interior of the isolator with an internal volume of the Beta container. When coupled, 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 containing the "rinsing liquid" can be removed from the barrier system (temporarily) before the start of a filling process or a production cycle. Alternatively, the at least one reject container can remain in the barrier system until the end of production and be removed after a cleaning process with the barrier system doors open.

[0049] Removing the "rinsing fluid" from the barrier system prevents any contaminants from entering the further production process and compromising the quality or safety of the manufactured pharmaceutical products. At the same time, the "wetting fluid" is removed from the barrier system.

[0050] According to a further embodiment of the aspects, it can be provided that the at least one reject container containing the forwarded pharmaceutical liquid is closed, in particular with the assistance of a robot.

[0051] By closing the reject container containing the "rinsing liquid," the risk of contamination in the barrier system can be reduced. The respective reject container can be closed, for example, using 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 on the respective reject container to securely seal it. The closing of at least one reject container preferably takes place within the barrier system.

[0052] According to a further embodiment of the aspects, it can be provided that the at least one reject container is removed, in particular discharged, from the barrier system by means of one or more handling robots.

[0053] The respective handling robot can have an end effector, with a gripping device arranged on the end effector. The end effector can have the gripping device or carry the gripping device. The handling robot preferably has 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. Drive means, such as one or more drive devices, can be provided to move the arm. The arm can be attached to a support structure arranged in or on the handling station. The range of the arm is preferably such that the end effector can be moved between a filling location where the reject containers are filled and a port that enables the reject containers to be discharged.

[0054] According to a further embodiment of the aspects, it can be provided that the filling system further comprises an intermediate container, in particular an intermediate bag, which is arranged between the filter assembly and the filling device in the fluid path 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.

[0055] The intermediate container serves for the temporary storage of the pharmaceutical liquid passed through the filter assembly and is preferably arranged near the filling location. The intermediate container can be arranged, for example, outside the barrier system. In order to realize multi-point filling within the barrier system, the intermediate container can be in fluid communication with the filling device by means of a plurality of fluid paths. For this purpose, the intermediate container preferably has a plurality of outlets corresponding to the plurality of fluid paths. Each outlet of the intermediate container can be assigned a fluid path. To transport 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. Preferably, a pump is arranged in each of the plurality of fluid paths. The intermediate container may, for example, be an intermediate bag made of a flexible material.

[0056] Optionally, the intermediate container can be used to eliminate any gas pockets in the pharmaceutical liquid. This process is equivalent to "deaeration" or "degassing" and serves to ensure that the liquid is free of air bubbles, as these could potentially have undesirable effects on the production process or the quality of the final product.

[0057] The pharmaceutical liquid is introduced into the intermediate bag. The liquid flows through the inlet port into the bag. As the liquid flows into the bag, the air or gas contained within the liquid rises to the top. This allows air pockets to accumulate in the upper chamber of the bag, while the liquid collects in the lower chamber. To remove the air pockets, the intermediate container can have a venting mechanism. This could be, for example, a special valve or a filtration medium that allows air to pass through but retains the liquid. This allows the air pockets to escape, and the liquid is gradually freed of air bubbles.

[0058] According to a further embodiment of the aspects, it can be provided that, in order to carry out the integrity test, each filter element of the filter assembly is checked for its integrity by means of a filter integrity test, in particular a non-destructive one.

[0059] In other words, the filter integrity test is performed by subjecting each filter element wetted with the pharmaceutical liquid to a filter integrity test.

[0060] Various types of filter integrity tests are considered, including destructive and non-destructive (i.e., non-destructive) filter integrity tests, to check the integrity of the filters before the filling process or before a production cycle. Since destructive filter integrity tests, such as the bacterial retention test, generally preclude further use of the filter elements, the integrity test is preferably performed using a non-destructive filter integrity test.

[0061] A non-destructive filter integrity test is particularly suitable for in-process filter integrity testing, meaning the filter element can remain in the fluid path while the filter integrity test is performed. If the integrity or intactness of the filter element is determined, the filling process can proceed without prior removal or removal of the filter element from the fluid path. In-process filter integrity testing is particularly relevant for sterile filling processes in the pharmaceutical industry to reduce the risk of contamination.

[0062] According to a further embodiment of the aspects, it can be provided that in order to carry out the integrity test, each filter element is subjected to a bubble pressure test, a diffusion test and / or a pressure holding test.

[0063] These are meaningful and proven test methods to demonstrate filter integrity.

[0064] According to a further embodiment of the aspects, it can be provided that the filter assembly is part of a disposable filter system.

[0065] Unlike reusable filter systems, where filter elements can be cleaned, validated, and reused, disposable filter systems are considered a closed unit and are not reused after use. Rather, a disposable filter system is completely disposed of after use.

[0066] A disposable filter system is a unit consisting of filter housings and filter elements that are considered a single unit and are completely disposed of after use. The disposable filter system preferably has inlet and outlet ports for connecting the filter assembly to the fluid path. These ports allow the fluid to be filtered to enter the system and the filtered fluid to exit the system.

[0067] According to a further embodiment of the aspects, it can be provided that the fluid path has 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.

[0068] According to a further embodiment of the aspects, it can be provided that a first valve is arranged in the fluid path upstream of the filter assembly, which valve delimits the first section and the second section from one another.

[0069] In other words, the first section of the fluid path extends between the product source and a first valve located upstream of the filter assembly in the fluid path. The first valve serves to regulate or interrupt the flow of pharmaceutical liquid in the fluid path, depending on the process requirements. This enables precise liquid dosing or delivery. The first valve can also serve to regulate the pressure in the second section of the fluid path. It can increase or decrease the pressure to achieve the desired operating conditions. Preferably, the first valve can be controlled by an electronic control device.

[0070] According to a further embodiment of the aspects, it can 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.

[0071] By opening the first valve, the pharmaceutical fluid introduced into the fluid path, particularly 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, further fluid flow from the first section can be prevented. In this way, a quantity of the pharmaceutical fluid used to wet the filter element and / or a quantity of the pharmaceutical fluid used to flush the fluid path can be metered, thus reducing product loss.

[0072] According to a further embodiment of the aspects, it can be provided that the step of passing through the defined amount of the introduced pharmaceutical liquid further comprises a step of wetting, in particular when the first valve is open, each filter element with or by means of the pharmaceutical liquid flowing 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 to wet each filter element from the filter assembly, in particular into the third section of the fluid path.

[0073] For example, it can be provided that the first valve is closed again only after the pharmaceutical liquid used to wet each filter element has been completely discharged from the filter assembly, in particular completely. Alternatively, it can be provided, for example, that the first valve is closed again before the pharmaceutical liquid used to wet the or each filter element is discharged from the filter assembly, but after the or each filter element has been sufficiently wetted, so that the step of discharging from the filter assembly takes place with the first valve closed.

[0074] The filter element is "sufficiently wetted" when the requirements for the degree of wetting specified by the respective filter integrity test method are met. For example, in the bubble pressure test, the filter membrane should be completely wetted with the liquid, which is achieved by a longer wetting time. Incomplete wetting can potentially lead to an incorrect measurement and should therefore be avoided.

[0075] According to a further embodiment of the aspects, it can be provided that the step of discharging from the filter assembly takes place with the first valve closed.

[0076] In other words, the first valve is closed before the pharmaceutical liquid used to wet each filter element is discharged from the filter assembly, but after the respective filter element(s) is sufficiently wetted.

[0077] To remove the liquid used to wet the filter element(s) from the filter assembly, an air supply can be provided 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 can be provided, for example, via a gas supply path that opens into the fluid path upstream of the filter element of each filter housing. The liquid can then be removed, for example, using gravity and / or a pump and / or by supplying a pressurized gas.

[0078] An advantage of this design is that the filter assembly or the second section of the fluid path is now essentially free of liquid—apart from the pores of the filter element, which are wetted or filled with pharmaceutical liquid. This provides ideal test conditions for conducting the filter integrity test, especially when the respective filter element is exposed to a gas under test pressure on the downstream side for integrity testing. The absence of liquid in the filter assembly particularly reduces the risk of falsifying the measurement results.

[0079] According to a further embodiment of the aspects, it can be provided that the step of carrying out the filter integrity test takes place with the first valve closed.

[0080] The first valve is preferably closed before performing the filter integrity test. This ensures that no fluid flows into the respective filter housing or filter assembly during the filter integrity test. Furthermore, with the first valve closed, the test pressure required for the bubble pressure test, the diffusion test, and the pressure retention test can be applied, i.e., the respective filter element can be pressurized with a gas at test pressure on the downstream side for integrity testing.

[0081] According to a further embodiment of the aspects, it can be provided that the second section of the fluid path is limited by the first valve and by a second valve which is arranged downstream of the filter assembly in the fluid path.

[0082] In other words, the first valve separates the first portion of the fluid path from the second portion of the fluid path, and the second valve separates the second portion of the fluid path from the third portion of the fluid path.

[0083] The second valve serves to regulate or interrupt the flow of pharmaceutical liquid in the fluid path, depending on the process requirements. This enables precise liquid dosing or delivery. The second valve can also be used to regulate the pressure in the second section of the fluid path. It can increase or decrease the pressure to achieve the desired operating conditions. Preferably, the second valve can be controlled by an electronic control device.

[0084] According to a further embodiment of the aspects, it can be provided that the wetting of the or each filter element takes place when the first valve is open and when the second valve is closed.

[0085] Opening the first valve ensures that the pharmaceutical liquid flows into the respective filter housing to wet the filter element. Since the second valve is closed during wetting, the wetting process can be carried out safely.

[0086] According to a further embodiment of the aspects, it can be provided that the filter integrity test is carried out with the first valve closed and the second valve open.

[0087] An advantage of this design is that a gas used for filter integrity testing can flow from the second section of the fluid path into the third section of the fluid path.

[0088] According to a further embodiment of the aspects, it can be provided that the discharge of the pharmaceutical liquid used to wet the or each filter element from the filter assembly, in particular into the third section of the fluid path, takes place when the first valve is closed and when the second valve is open.

[0089] In this way, the pharmaceutical liquid used for wetting can be removed from the filter assembly or the respective filter housing without "pushing" additional liquid from the first section of the fluid path. This creates ideal test conditions for conducting the filter integrity test, especially when the respective filter element is pressurized with a gas at test pressure on the downstream side for integrity testing. The absence of liquid in the filter assembly particularly reduces the risk of distorting the measurement results.

[0090] According to a further embodiment of the aspects, it can be provided that, in order to carry out the filter integrity test, each filter element, in particular on the raw side, is subjected to a gas under a test pressure, wherein the first valve is closed and the second valve is open while the respective filter element is subjected to the gas under the test pressure.

[0091] The gas used for filter integrity testing can therefore flow into the third section of the fluid path.

[0092] According to a further embodiment of the aspects, it can be provided that, in order to carry out 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 to carry out the filter 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 has a third valve, in particular wherein, during the exposure of 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.

[0093] The third valve can be used to regulate the pressure in the second section of the fluid path. Preferably, the third valve can be controlled by 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 in the second section of the fluid path.

[0094] According to a further embodiment of the second aspect, it can be provided that carrying out the filling process comprises filling at least one container, in particular a pharmaceutical container, arranged in the barrier system.

[0095] The respective container can be, for example, a vial, a cartridge, a bottle, a syringe, a package, and / or the like. The respective container is preferably different from the reject containers.

[0096] According to a further embodiment of the second aspect, it can be provided that the filling process is carried out using the filter element subjected to the filter integrity test when the filter integrity of the or each filter element of the filter assembly has been determined.

[0097] 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 between the filter assembly and the product source in the fluid path for blocking or releasing a liquid supply;a gas source comprising a gas, in particular nitrogen or an inert gas, and in fluid communication 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, which has 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 a quantity of gas passing 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.

[0098] It is understood that the features mentioned above and those to be explained below can be used not only in the combination specified in each case, but also in other combinations or on their own, without departing from the scope of the present invention.

[0099] Embodiments of the invention are illustrated in the drawings and explained in more detail in the following description. They show: Fig. 1 a schematic representation of an embodiment of a filling system; Fig. 2 shows a flow diagram of an embodiment of a method for preparing a filling operation according to a first aspect; and Fig. 3 a flow diagram of an embodiment of a method for producing a pharmaceutical product according to a second aspect.

[0100] Fig. 1 shows a schematic representation of an embodiment of a filling system, designated overall by the reference numeral 10. The filling system 10 has a liquid source 12, which can be designed, 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) can be arranged in the fluid path 18 between the liquid source 12 and the filter assembly 20.

[0101] In the illustration shown, one filter housing 22 is shown as an example. However, it is understood that the filter assembly 20 may also comprise a plurality of filter housings 20, which may, for example, be arranged in series in the fluid path 18.

[0102] The filling system 10 may further include a gas source 26 for storing and / or providing a gas for the filter integrity test, which gas is fluidly connected to a raw side (i.e., an upstream side) of the filter 24 via a gas supply path 28. The gas may be, for example, air or nitrogen.

[0103] Furthermore, the filling system 10 includes, by way of example, a filter testing device 27 for performing the integrity test. In the illustration shown, the filter testing device 27 is connected to the compressed gas source 26 on the one hand and to the filter housing 22 via the gas supply path 28 on the other hand.

[0104] Furthermore, the filling system 10 can have 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.

[0105] The valves 30 and 32 arranged in the fluid path 18 delimit a second region 40 of the fluid path 18. A first section 38 of the fluid path 18 extends between the liquid source 12 and the first valve 30 and borders the second section 40 of the fluid path 18. A third section 42 of the fluid path 18 extends between the second valve 32 and the filling device 16 and borders the second section 40 of the fluid path 40.

[0106] Furthermore, the filling system 10 can have an optional gas discharge path 44 that 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 can be arranged in the gas discharge path 44 to regulate the gas outflow.

[0107] The gas source 26 is preferably in fluid communication with the gas discharge path 46, for example, to remove a gas supplied to the filter element 22 for checking the filter integrity from the fluid path. Alternatively, however, the gas can also be discharged via the fluid path 18. Furthermore, the filling system 10 has an optional intermediate container 33, which is arranged between the filter assembly 20 and the filling device 16 in the fluid path 18, in particular in the third section 42 of the fluid path 18, and is in fluid communication with the filter assembly 18 and the filling device 16. In this way, the pharmaceutical liquid passed through the filter assembly 20 can be fed to the intermediate container 33 for intermediate storage before the pharmaceutical liquid is fed 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, which is configured to convey pharmaceutical liquid from the intermediate container to the filling device 16. The intermediate container 33 can, for example, be an intermediate bag made of a flexible material.

[0108] Furthermore, the filling system 10 can have a control device 34 for controlling the first valve 30, the second valve 32, the third valve 46, a gas supply line via the gas supply path 28, a gas discharge line via the gas discharge path 44, and / or a liquid introduction into the fluid path 18. Alternatively or additionally, at least one of the valves 30, 32, 46 can also be manually actuated. Optionally, the control device (34) can be configured to control the first pump 25 and / or the second pump 35.

[0109] Fig. 2 shows a flowchart of a method 100 for preparing a filling process according to the first aspect of the invention.

[0110] In a first step S102 of the method 100, the filling system 10 is provided.

[0111] In a second step S104 of the method 100, the pharmaceutical liquid is introduced from the liquid source 12 into the fluid path 18.

[0112] In a third step 106 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.

[0113] In a fourth step 108 of the method 100, each filter element 24 wetted with the pharmaceutical liquid is subjected to a filter integrity test.

[0114] In a fifth step 110 of the method 100, the pharmaceutical liquid passed through is forwarded to the filling device 16 in order to at least partially flush the fluid path 18.

[0115] Fig. 3 shows a flow diagram of a method 200 for producing a pharmaceutical product according to the second aspect

[0116] In a first step 202 of the method 200, the method 100 is carried out according to the first aspect.

[0117] In a second step 204 of the method 200, the filling process in the filling system 10 is carried out based on a result of the filter integrity test. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] EP 2 925 420 B1

[0012] EP 1 849 484 B1

[0013] DE 10 2017 127 017 A1

[0014]

Claims

[1] Method (100) for preparing a filling operation, comprising the following steps: - Providing (S102) a filling system (10) comprising a liquid source (12), a barrier system (14), in particular an isolator, 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); - introducing (S104) the pharmaceutical liquid from the liquid source (12) into the fluid path (18); - passing (S106) a defined amount of the introduced pharmaceutical liquid through the filter assembly (20) in order to wet each filter element (24) of the filter assembly (20); - performing (S108) an integrity check of each filter element (24) wetted with the pharmaceutical liquid; and - forwarding (S110) the pharmaceutical liquid passed through to the filling device (16) in order to at least partially flush the fluid path (18). [2] The method (100) of claim 1, wherein each filter element (24) is sterilized prior to the step of performing the filter integrity test and / or prior to the step of wetting each filter element (24). [3] Method (100) according to claim 1 or 2, wherein the forwarded pharmaceutical liquid is dispensed, in particular filled, via the filling device (16) into at least one reject container (36) arranged in the barrier system (14). [4] Method according to claim 3, wherein the at least one reject container containing the forwarded pharmaceutical liquid is closed, in particular by robot support. [5] Method (100) according to claim 3 or 4, wherein the at least one reject container (36) is removed from the barrier system (14), in particular robot-assisted. [6] Method (100) according to claim 5, wherein the at least one reject container (36) is removed, in particular discharged, from the barrier system (14) by means of one or more handling robots. [7] Method (100) according to one of the preceding claims, wherein the filling system (10) further comprises an intermediate container, in particular an intermediate bag, which is arranged between the filter assembly (20) and the filling device (16) in the fluid path (18) and is in fluid communication with the filter assembly (18) and the filling device (16), wherein the pharmaceutical liquid passed through the filter assembly (20) is fed to the intermediate container for intermediate storage before the pharmaceutical liquid is fed to the filling device (16). [8] Method (100) according to one of the preceding claims, wherein, in order to carry out the integrity test, each filter element (24) of the filter assembly (20) is tested for its integrity by means of a filter integrity test, in particular a non-destructive one. [9] Method (100) according to claim 8, wherein to carry out the integrity test each filter element (24) is subjected to a bubble pressure test, a diffusion test and / or a pressure holding test. [10] Method (100) according to one of the preceding claims, wherein the filter assembly (20) is arranged outside the barrier system (14). [11] Method (100) according to one of the preceding claims, wherein the filter assembly (20) is part of a disposable filter system. [12] The method (100) of any preceding claim, wherein the fluid path (18) comprises a first portion (38), a second portion (40) in which the filter assembly (20) is disposed, and a third portion (42), the first portion (38) extending between the product source (12) and the second portion (40), and the third portion (42) extending between the second portion (40) and the filling device (16). [13] The method (100) of claim 12, wherein a first valve (30) is disposed in the fluid path (18) upstream of the filter assembly, said first valve (30) separating the first portion (38) of the fluid path (18) and the second portion (40) of the fluid path (18) from one another. [14] The method (100) 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 (30) until an amount of the pharmaceutical liquid introduced into the fluid path (18) flows from the first portion (38) of the fluid path (18) into the second portion (40) of the fluid path (18), and a step of closing the first valve (30). [15] Method (100) according to claim 13, wherein the step of passing the defined amount of the introduced pharmaceutical liquid further comprises a step of wetting, in particular when the first valve (30) is open, each filter element (24) with or by means of the pharmaceutical liquid flowing into the second section (40), the step of closing the first valve (30) when each filter element (40) is sufficiently wetted, and a step of discharging the pharmaceutical liquid used to wet each filter element (24) from the filter assembly (20), in particular into the third section (42) of the fluid path (18). [16] The method (100) of claim 15, wherein the step of discharging from the filter assembly (20) occurs with the first valve (30) closed. [17] The method (100) of any one of claims 12 to 16, wherein the step of performing the filter integrity test occurs with the first valve (30) closed. [18] The method (100) of any one of claims 12 to 17, wherein the second portion (40) of the fluid path (18) is defined by the first valve (30) and by a second valve (32) disposed downstream of the filter assembly (20) in the fluid path. [19] The method (100) of claim 18, wherein wetting of each filter element (24) occurs with the first valve (30) open and the second valve (32) closed. [20] Method (100) according to claim 18 or 19, wherein the filter integrity test is carried out with the first valve (30) closed and the second valve (32) open. [21] Method (100) according to one of claims 18 to 20, wherein, in order to carry out the filter integrity test, each filter element (24), in particular on the raw side, is subjected to a gas under a test pressure, wherein during the exposure of the respective filter element (24) to the gas under test pressure, the first valve (30) is closed and the second valve (32) is open. [22] Method (100) according to claim 18 or 19, wherein, in order to carry out the filter integrity test, each filter element (24), in particular on the raw side, is subjected to a gas under a test pressure, wherein the gas used to carry out the filter integrity test is discharged from the fluid path (18) via a gas discharge path (46) which branches off from the second section (40) of the fluid path (18) in a region of the fluid path located downstream of the filter assembly (20) and upstream of the second valve (32) and has a third valve (46), in particular wherein, during the respective filter element (24) being subjected to the gas under the test pressure, the first valve (30) and the second valve (32) are closed and the third valve (46) is open, in particular wherein the third valve (46) is a check valve. [23] A process (200) for the manufacture of a pharmaceutical product, comprising the following steps: - carrying out (S202) a method (100) for preparing a filling process according to one of claims 1 to 22; and - performing (S204) the filling process in the filling system (10) based on a result of the filter integrity check. [24] Method (200) according to claim 23, wherein carrying out the filling process comprises filling at least one container (48), in particular a pharmaceutical container, arranged in the barrier system (14). [25] A method according to claim 23 or 24, wherein the filling operation is carried out using the filter element (24) subjected to the filter integrity test when the filter integrity of the or each filter element (24) of the filter assembly (20) has been determined.

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