Method and system for recovering filtered fluid retained in a filter

Abstract

The present invention relates to a method for aseptically recovering filtered fluid retained in a filter system, the filter system including a filter device comprising a housing having an inlet and an outlet defining a filtration flow path between the inlet and the outlet, and a porous filter medium across the filtration flow path, the porous medium having an upstream side and a downstream side, a filtered fluid receiving container arranged downstream of the outlet, the filtered fluid receiving container comprising an inlet and an outlet, a first fluid flow path between the outlet of the filter device and the inlet of the filtered fluid receiving container, a second fluid flow path between the first fluid flow path and the outlet of the filtered fluid receiving container, wherein the second fluid flow path is connected to the first fluid flow path by the connection between the second fluid flow path with the first fluid flow path, a pump positioned in or at the second fluid flow path, the pump being configured to pump fluid and / or gas from the filtered fluid receiving container to the first fluid flow path, the method comprising the steps of passing fluid in a fluid passing step via the filtration flow path through the filter device via the first fluid flow path into the filtered fluid receiving container, wherein a volume of filtered fluid is retained in the housing between the downstream side of the porous filter medium and the outlet; and moving in a filtered fluid removal step sterile gas comprised in the filtered fluid receiving container via the pump from the filtered fluid receiving container via the second fluid flow path into the first fluid flow path and through the outlet into the housing of the filter device, thereby displacing retained filtered fluid via the first fluid flow path into the filtered fluid receiving container.

Description

[0001] Method and System for Recovering Filtered Fluid retained in a Filter

[0002] Technical Field of the Invention

[0003] The present invention is concerned with a method for recovering filtered fluid retained in a filter. Furthermore, the present invention is concerned with a system for aseptically distributing a fluid comprising a target molecule. More specifically, the present invention is concerned with such a method or system, wherein the fluid, which resided for a certain time in a feeding line of the system, is automatically purged upon restart of the flow rate.

[0004] Background of the Invention

[0005] One example of a drug production method is a filtration step. When completing sterile filtration of a drug product, the system is typically provided with a filter having a membrane. Such membrane filters have an upstream cavity of the housing and a downstream cavity of the housing. From such configuration the problem is known that filtered fluid remains in the downstream cavity of the housing even after pushing pressurized sterile air through the filter.

[0006] Sterile filtered fluids, as inter alia used in the pharmaceutical industry, can be very expensive, and thus, the loss of this fluid volume (for example, during the manufacture of biological therapeutics) can be costly. Further, during clinical trials, non-recoverable product may prevent manufacturers from preparing an adequate quantity of product, adversely impacting the ability to generate critical data that could lead to beneficial treatment. Cumulatively, the loss of even a few milliliters of fluid per filtration can represent a significant amount of money.

[0007] Hence, there is the general need of recovering as much as possible of the filtered fluid from the system.

[0008] US 11 ,660,553 B2 and US 11 , 148,083 B2 disclose a system and a method, respectively, for recovering filtered fluid retained in a filter system using fluid flow paths having coaxially positioned hollow conduits. However, while this system or this method is able to recover filtered fluid from the filter, it provides a complex solution and limits the flexibility of the position of the filtered fluid receiving container.

[0009] US 11 ,498,023 B2 and US 11 ,498,024 B2 are also concerned with a system and a method, respectively, for removing filtered fluid from a volume in the filter housing downstream of the filter membrane by passive replacement with air. However, this method does not allow for fast removal of large quantities of fluid trapped in the filter. Summary of the Invention

[0010] Hence, it is an object of the present invention to provide a method and system for fast and efficient removal of large quantities of filtered fluid from the filter in a filtration process step of a drug production process.

[0011] It has now surprisingly been found that the above-mentioned object can be achieved by a method for aseptically recovering filtered fluid retained in a filter system, the filter system including a filter device comprising a housing having an inlet and an outlet defining a filtration flow path between the inlet and the outlet, and a porous filter medium across the filtration flow path, the porous medium having an upstream side and a downstream side, a filtered fluid receiving container arranged downstream of the outlet, the filtered fluid receiving container comprising an inlet and an outlet, a first fluid flow path between the outlet of the filter device and the inlet of the filtered fluid receiving container, a second fluid flow path between the first fluid flow path and the outlet of the filtered fluid receiving container, wherein the second fluid flow path is connected to the first fluid flow path by the connection between the second fluid flow path with the first fluid flow path, a pump positioned in or at the second fluid flow path, the pump being configured to pump fluid and / or gas from the filtered fluid receiving container to the first fluid flow path, the method comprising the steps of passing fluid in a fluid passing step via the filtration flow path through the filter device via the first fluid flow path into the filtered fluid receiving container, wherein a volume of filtered fluid is retained in the housing between the downstream side of the porous filter medium and the outlet; and moving in a filtered fluid removal step sterile gas comprised in the filtered fluid receiving container via the pump from the filtered fluid receiving container via the second fluid flow path into the first fluid flow path and through the outlet into the housing of the filter device, thereby displacing retained filtered fluid via the first fluid flow path into the filtered fluid receiving container.

[0012] It has further surprisingly been found that the above-mentioned object can be achieved by a filter system comprising a filter device comprising a housing having an inlet and an outlet defining a filtration flow path between the inlet and the outlet, and a porous filter medium across the filtration flow path, the porous medium having an upstream side and a downstream side, the system also including a filtered fluid receiving container arranged downstream of the outlet, the filtered fluid receiving container comprising an inlet and an outlet, a first fluid flow path between the outlet of the filter device and the inlet of the filtered fluid receiving container, a second fluid flow path between the first fluid flow path and the outlet of the filtered fluid receiving container, wherein the second fluid flow path is connected to the first fluid flow path, a pump positioned in or at the second fluid flow path, the pump being configured to pump fluid and / or gas from the filtered fluid receiving container to the first fluid flow path.

[0013] The present invention has the advantage that large quantities of fluid can be quickly and efficiently removed from the filter after the filtering system. This further has the advantage that the overall time of the filtering process can be reduced and thus, the overall efficiency of a filtering system be improved.

[0014] Brief Description of the Drawings

[0015] Figure 1 is a schematic drawing of a system according to the most general embodiment of the present invention.

[0016] Figure 2 is a schematic drawing of a system according to a preferred embodiment of the present invention including flow control devices.

[0017] Figure 3 is a schematic drawing of a system according to a preferred embodiment of the present invention including a third fluid flow path and a product receiving device.

[0018] Figure 4 is a schematic drawing of a system according to a preferred embodiment of the present invention including a preceding filter device.

[0019] Figure 5 is a schematic drawing of a system according to a preferred embodiment of the filtered fluid receiving container, formed as a bag.

[0020] Figure 6 is a schematic drawing of a system according to a preferred embodiment of the filtered fluid receiving container, formed as a bag and rotated about 30°.

[0021] Figure 7 is a schematic drawing of a system according to a preferred embodiment of the filtered fluid receiving container, formed as a bag, and rotated so that the connection between the outlet and the inlet is completely filled by a fluid.

[0022] Reference Signs

[0023] A Source of fluid

[0024] B Filtered fluid receiving container

[0025] C Product receiving device

[0026] 1 Filter device

[0027] 2 Pump

[0028] 3 Porous filter medium

[0029] 4 Inlet of the filter device

[0030] 5 Outlet of the filter device

[0031] 6 Connection between the second fluid flow path with the first fluid flow path 7 Connection between the third fluid flow path with the first fluid flow path

[0032] 8 Flow control device in the second fluid flow path

[0033] 9 Flow control device in the first fluid flow path

[0034] 10 Flow control device in the third fluid flow path

[0035] 11 Preceding filter device

[0036] Definitions

[0037] The term ‘sterilization’ as used herein preferably denotes a method to destroy all forms of living microorganisms from a substance. As there always can be a certain probability of at least one microorganism to survive such procedure, the aim of sterilization is the reduction of initially present microorganisms or other potential pathogens. Preferably, sterilization is accepted to be achieved if the bioburden load of the substance of object to be sterilized is lower than 10'6. The bioburden load can be measured i.e. , according to ISO 11737-1 :2018. Sterilization can be achieved using several methods. In one sterilization process, the object is heated up to at least 105 °C to achieve a sterile object. Thereby, the object should not be deformed by the elevated temperature. Preferably, the heating step is performed in an autoclave. In another sterilization process, the object is brought into contact with toxic gases, such as a mixture of ethylene oxide and carbon dioxide. Filtration methods are also used to sterilize liquids, i.e., by using membrane filters, Seitz filters, and / or candle filters. Finally, sterilization can be achieved by indirect energy import into or onto the object, e.g., by ultrasonic waves, ultraviolet light, as well as by high energy particles (such as electrons, gamma, or X-rays).

[0038] The term ‘sterile’ as used herein preferably denotes the status of an object having a significantly reduced number of bacteria and / or viruses on its surface to reduce the risk of an infection. In particular, the term ‘sterile’ preferably denotes an object or substance, which has a bioburden load of lower than 10-6. The bioburden load can be measured i.e., according to ISO 11737-1 :2018. A sterile substance or article is typically achieved by sterilization thereof.

[0039] The term ‘sterile air as used herein denotes air, which has been subjected to a sterilization process or which has been filtered by a sterile filter. The terms ‘sterile gas’ and ‘sterile air can be used equivalently, e.g., embodiments referring to sterile gas also encompass the use of sterile air, and vice versa.

[0040] The term ‘aseptically transporting’ as used herein denotes the transport of a sterile substance, preferably a sterile liquid, in a closed system, wherein the sterility of the substance is not decreased. The term ‘positive displacement pump’ as used herein denotes a pump, which moves a fluid by trapping a fixed volume of the fluid on a suction side and forcing the trapped volume into a discharge side. Some positive displacement pumps operate in a mode wherein the volume of the cavity decreases while traveling to the discharge side. Generally, a positive displacement pump creates a pressure gradient between the suction side and the discharge side in that the pressure on the suction side is lower than the pressure on the discharge side. Typical positive displacement pumps are rotary-type positive displacement pumps, such as internal and external gear pumps, screw pumps, lobe pumps, shuttle block, flexible vane and sliding vane, circumferential piston, flexible impeller, helical twisted roots, and liquid-ring pumps. Other typical positive displacement pumps are reciprocating-type positive displacement pumps, such as piston pumps, plunger pumps, and diaphragm pumps. Finally, linear-type positive displacement pumps are, for example, rope pumps and chain pumps. A common feature of positive displacement pumps is that they form a barrier for the liquid against the intended pumping direction of the positive displacement pump. Hence, once a fluid volume has been moved from the suction side to the discharge side, the positive displacement pump does not allow a flow back of said fluid volume. This also holds true in case the pump stops working.

[0041] The term ‘peristaltic pump’ as used herein denotes a specific embodiment of a positive displacement pump, in particular a specific embodiment of a rotary-type positive displacement pump. Thereby, it is a specific feature of the peristaltic pump that the fluid to be pumped is contained in a flexible tube. The flexible tube runs through the housing of the circular peristaltic pump. The peristaltic pump comprises a rotor, which comprises a means to put pressure on the flexible tube, such as wipers or rollers attached to the external circumference of the rotor. Thereby, the means to put pressure on the flexible tube compresses the flexible tube as they rotate, whereby the flexible tube is closed under compression. The closing of the flexible tube forces the fluid to move through the flexible tube during rotation of the rotor. Furthermore, the closing of the flexible tube prevents the fluid from flowing back. As the flexible tube opens to its natural state after the wipers or rollers have passed, more fluid is drawn into the flexible tube. This process is called peristalsis. Preferably, the peristaltic pump comprises two or more rollers for compressing the flexible tube, thereby trapping a volume of fluid between them.

[0042] The term ‘closed system’ as used herein denotes a system that allows the collection and processing (including filtration, and, if desired, the manipulation, e.g., separation of portions into components, storage, and preservation) of fluid, without exposing the contents of the system to the environment in which it is being used. Hence, in particular, a closed system is suitable for aseptically processing sterile fluids and components by shielding them from influences of the environment.

[0043] The term ‘flow control device’ as used herein is a device to manipulate the flow rate in a fluid connection line. Typically, flow control devices are selected from clamps, seals, valves, or transfer leg closures.

[0044] The use of the terms ‘a’ and ‘an’ and ‘the’ and ‘at least one’ and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0045] The use of the term ‘at least one’ followed by a list of one or more items (for example, ‘at least one of A and B’) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context.

[0046] The terms ‘comprising’ , ‘having’, ‘including’, and ‘containing’ are to be construed as open-ended terms (i.e., meaning ‘including, but not limited to’) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., ‘such as’) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any nonclaimed element as essential to the practice of the invention.

[0047] The term ‘controlling unit’ as used herein denotes any suitable equipment configured to control the operation of at least one component of the system described herein when carrying out the distribution operation. The controlling unit may comprise a processor, a non-transitory computer readable medium bearing a fluid distribution program, a data storage device, and a display device. The processor may be arranged with the computer readable medium to execute the fluid distribution program. The processor is in operable arrangement with the display device to selectively display output information from the fluid distribution program and / or to receive input information from a graphical user interface displayed by the display device. The processor can be configured to act as a controller to selectively operate at least one component of the system, such as the pump and the valve arrangements, for example. In embodiments, the processor is in electrical communication with the pump(s) and the valve arrangements to selectively operate the valves based upon instructions from the fluid distribution program. The controller and the processor can comprise separate devices, and the controller can be in operable communicative arrangement with the processor. The controller can include a user input and / or interface device having one or more user-actuated mechanisms (e.g., one or more push buttons, slide bars, rotatable knobs, a keyboard, and a mouse) adapted to generate one or more user actuated input control signals. In embodiments, the controller can be configured to include one or more other user-activated mechanisms to provide various other control functions for the system described herein. The controller can be associated with the display device which is adapted to display a graphical user interface. The graphical user interface can be configured to function as both a user input device and a display device in embodiments. The display device can comprise a touch screen device adapted to receive input signals from a user touching different parts of the display screen. The controller can be in the form of a smart phone, a tablet, a personal digital assistant (e.g., a wireless, mobile device), a laptop computer, a desktop computer, or other type of device.

[0048] The term ‘fluid’ as used herein denotes a liquid comprising a solvent and at least one target molecule. The fluid may comprise a small amount of solid particles, which are usually filtered out before distribution. Preferably, the solvent is sterile water.

[0049] Detailed Description

[0050] The present invention is concerned with a method for recovering filtered fluid retained in a filter system and a system for recovering filtered fluid retained in a filter system. The method and the system are described in more detail in the following with reference to Figures 1 to 7 using the reference signs as set out above.

[0051] Method

[0052] As set out above, the present invention is concerned with a method for aseptically recovering filtered fluid retained in a filter system, the filter system including: a filter device (1) comprising

[0053] ■ a housing having an inlet (4) and an outlet (5) defining a filtration flow path between the inlet (4) and the outlet (5), and

[0054] ■ a porous filter medium (3) across the filtration flow path, the porous medium (3) having an upstream side and a downstream side, a filtered fluid receiving container (B) arranged downstream of the outlet, the filtered fluid receiving container (B) comprising an inlet and an outlet, a first fluid flow path between the outlet of the filter device (1) and the inlet of the filtered fluid receiving container (B), a second fluid flow path between the first fluid flow path and the outlet of the filtered fluid receiving container (B), wherein the second fluid flow path is connected to the first fluid flow path by the connection between the second fluid flow path with the first fluid flow path (6), a pump (2) positioned in or at the second fluid flow path, the pump (2) being configured to pump (2) fluid and / or gas from the filtered fluid receiving container (B) to the first fluid flow path, the method comprising the steps of passing fluid in a fluid passing step via the filtration flow path through the filter device (2) via the first fluid flow path into the filtered fluid receiving container (B), wherein a volume of filtered fluid is retained in the housing between the downstream side of the porous filter medium (3) and the outlet (5); and, moving in a filtered fluid removal step sterile gas comprised in the filtered fluid receiving container (B) via the pump (1) from the filtered fluid receiving container (B) via the second fluid flow path into the first fluid flow path and through the outlet into the housing of the filter device (2), thereby displacing retained filtered fluid via the first fluid flow path into the filtered fluid receiving container (B).

[0055] In a preferred embodiment, the filter (1) is a membrane filter. Membrane filters are usually composed of materials such as polyethersulfone (PES), polyvinylidene fluoride (PVDF), or nylon and have typically a pore size ranging from 0.1 to 0.2 micrometers. Hence, they are suitable for removing bacteria, particulates, and endotoxins. The membrane structure provides high flow rates and low protein binding, ensuring efficient filtration without compromising the integrity of the drug solution.

[0056] Generally, the filter (1) comprises a housing having an inlet (4) and an outlet (5) defining a filtration flow path between the inlet (4) and the outlet (5), and a porous filtration medium (3) having an upstream side and a downstream side across the filtration flow path.

[0057] The filter (1) typically has at least a bacterial removal rated porous filtration medium (3) and can have a sterilizing grade porous filtration medium (3). The filtration medium (3) can have a variety of configurations, including planar, pleated and / or hollow cylindrical.

[0058] The housing of the filter (1) is typically a sterilizable, robust cartridge or capsule that can withstand the pressures and chemical environments of the filtering process. The design and materials of the filter ensure compatibility with various pharmaceutical formulations while maintaining sterility and filtration efficacy.

[0059] Typically, the filter (1) is vented during the initial filtration of liquid so that the maximum available filter medium surface is used, and to prevent build-up of air or gas in the system. After the filter housing is filled with liquid, the vent can be closed. Preferably, the filter (1) includes a vent, or vents can be arranged upstream and / or downstream of the filter (1), so that air or gas can be vented.

[0060] Preferably, the filter (1) is suitable for passing pressurized air therethrough subsequent to passing a liquid therethrough.

[0061] The fluid passing step can be an initial setup step or a filtering step. Usually, systems for sterile filtration are initially set up by passing sterile gas through the whole system, followed by passing sterile fluid therethrough. To set up a drug production filtering system, usually a sterile gas source is connected to the filter inlet, ensuring all connections are secured to prevent contamination. The sterile gas is then passed through the system to remove contaminants and / or to verify system integrity, i.e. check for leaks in the flow path. Once sterility and integrity are confirmed, the gas source is disconnected, and a sterile fluid source is connected to the filter inlet. The sterile fluid is gradually passed through the filter, displacing any remaining gas and ensuring the entire system is filled with the sterile fluid. A controlled flow rate is maintained to avoid damaging the filter, and it is confirmed that the effluent fluid meets sterility standards before commencing drug production. Nevertheless, such a process step can result in fluid retained in the filter, which needs to be removed, preferably recovered.

[0062] Hence, preferably, in one embodiment of the method as described herein, the fluid passing step comprises the steps of passing sterile gas in a gas initialization step through the outlet of the filter device (2) and via the first fluid flow path into the filtered fluid receiving container (B), and passing fluid in a fluid initialization step via the filtration flow path through the filter device (2) via the first fluid flow path into the filtered fluid receiving container (B), wherein the fluid in the fluid initialization step preferably does not comprise any solids.

[0063] In the actual filtering process of a drug production filtering system, the drug solution is introduced into the system, flowing towards the filter membrane. As it passes through, contaminants like particulates, bacteria, and endotoxins are trapped by the filter material. The now contaminant-free solution exits the filter and is collected in a sterile container. Throughout this process, pressure and flow rates are monitored and controlled to ensure consistent filtration and prevent damage to the filter. The filtered drug solution is then ready for further processing or packaging under sterile conditions.

[0064] Hence, in another preferred embodiment of the method as described herein the fluid passing step comprises the step of filtering fluid to be filtered in a fluid filtering step by passing the fluid via the filtration flow path through the filter device (1) and via the first fluid flow path into the filtered fluid receiving container (B), wherein the fluid in the fluid filtering step preferably comprises solids to be filtered off the fluid.

[0065] In the fluid removal step, it is important to control the level of liquid in the filtered fluid receiving container (B). If the level of fluid is too high, the risk increases of moving fluid instead of sterile air into the housing of the filter (1). Thus, it is important to control that during the fluid removal step, the outlet of the filtered fluid receiving container (B) is always in connection with a volume of sterile air. On the other hand, it is important to achieve a configuration in which most of the volume of the filtered fluid receiving container (B) is filled with fluid. This enhances the efficiency of the process.

[0066] Hence, preferably, in the method as described herein, the filtered fluid receiving container (B) is configured in that the outlet of the filtered fluid receiving container (B) is higher than or at the same height as the inlet of the filtered fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B), wherein the outlet of the filtered fluid receiving container (B) is not positioned at the lowest point of the fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B).

[0067] In a preferred embodiment, the filtered fluid receiving container (B) is a container or bag having a rectangular shape having a short edge and a long edge, wherein the filtered fluid receiving container (B) is positioned in that the short edge is oriented along the direction of the gravitational force and wherein the long edge is oriented perpendicular to the direction of the gravitational force.

[0068] In an even more preferred embodiment, the inlet of the filtered fluid receiving container (B) is positioned in a corner of a long edge and a short edge of the filtered fluid receiving container (B), wherein the corner is closer to the center of the gravitational force than another corner connected to the short edge, and wherein the outlet is positioned at said corner connected to the short edge. Hence, in such an embodiment, the short edge is not oriented along the direction of the gravitational force, but the filtered fluid receiving container (B) is rotated to allow the corner of the outlet to be at the highest point of the filtered fluid receiving container (B) with respect to the direction of the gravitational force.

[0069] These embodiments allow an efficient usage of the volume given by the filtered fluid receiving container (B). By achieving that the outlet is at the highest point, it can be ensured that the connection between the inlet and the outlet of the filtered fluid receiving container (B) comprises a volume of sterile gas while nearly the whole volume of the filtered fluid receiving container (B) is filled with fluid recovered from the filter.

[0070] Hence, preferably, in the fluid passing step, the filtered fluid receiving container (B) is filled with a volume of filtered fluid, whereby a volume of sterile gas remains in the filtered fluid receiving container (B) and wherein a connection between the inlet and the outlet via the filtered fluid receiving container (B) at least partially comprises the sterile gas.

[0071] Usually, the filtered fluid receiving container (B) is a flexible bag. The flexible bag typically used for storing the fluid in a drug production filtering system is typically made from multi-layered, medical-grade polymers such as polyethylene or ethylene-vinyl acetate (EVA). These bags are designed to be sterile, non-reactive, and resistant to punctures and tears. The multi-layer construction ensures a robust barrier against contamination while maintaining flexibility for easy handling and storage. The flexible bag often comes with integrated ports and connectors for secure, sterile transfer of fluids. Additionally, they are available in various sizes to accommodate different volumes of product fluid, ensuring versatility and scalability in drug production processes. Hence, more preferably the filtered fluid receiving container (B) is a flexible bag. Most preferably, the filtered fluid receiving container (B) is a flexible bag made from an air-tight film comprising a polymer, preferably from a multilayer polymer film.

[0072] In a post-filtration or post-fluid-passing step of the method as described herein, a sterile gas or additional sterile fluid can be used to press the remaining drug solution through the filter. This step ensures that a major part of the filtered fluid is collected and minimizes any residual fluid left within the filter system. The sterile gas or fluid is introduced at the filter inlet (4) under controlled pressure, effectively pushing the last traces of the filtered drug solution through the membrane and into the collection container. This method ensures maximum recovery of the drug solution and maintains the sterility and integrity of the final product.

[0073] Hence, preferably, the method as described herein further comprises after the fluid passing step and prior to the filtered fluid removal step the step of pushing in a filtered fluid pushing step filtered fluid retained in the housing between the inlet (4) of the filter device (1) and the porous filter medium (3) through the porous filter medium (3) and the outlet (5) of the filter device (1) into the filtered fluid receiving container (B) by means of forming an overpressure upstream or at the inlet (4) of the filter device (1), wherein a volume of filtered fluid is still retained in the housing between the downstream side of the porous filter medium (3) and the outlet (5).

[0074] In the method as described herein, typically more than one filter is used. A second filter used in the drug production filtering system is typically a depth filter, made from materials such as cellulose or glass fibers. This filter has a gradient density structure, providing a higher capacity for capturing larger particles and aggregates. Depth filters are used as a pre-filter to remove bulk contaminants and particulates, thereby protecting the final membrane filter from clogging and extending its life. These filters are often designed to handle high dirt loads and can operate under varying pressure conditions. By incorporating a depth filter, the system ensures an efficient, two-stage filtration process, enhancing the overall purity and quality of the drug solution.

[0075] Beside depth filters, bioburden filters can be used as second filters in the herein described method. Bioburden filters are specialized filtration devices designed to reduce the microbial load in a fluid by removing bacteria and other microorganisms. These filters typically have pore sizes ranging from 0.1 to 0.45 pm, which are effective in retaining and removing microbial contaminants while allowing the passage of the fluid. These filters are commonly constructed from materials such as polyethersulfone (PES), polyvinylidene fluoride (PVDF), or polypropylene (PP), chosen for their chemical compatibility, low extractables, and robust mechanical properties.

[0076] Hence, preferably, in the method as described herein, the filter system further comprises a preceding filter device (11) comprising

[0077] ■ a housing having an inlet and an outlet defining a filtration flow path between the inlet and the outlet, and

[0078] ■ a porous filter medium across the filtration flow path, the porous medium having an upstream side and a downstream side,

[0079] ■ wherein the outlet of the preceding filter device (11) is fluidly connected to the inlet of the filter device (1), wherein the method further comprises after the fluid passing step and prior to the filtered fluid pushing step the step of pushing in a preceding filtered fluid pushing step filtered fluid retained in the housing between the downstream side of the porous filter medium and the outlet of the preceding filter device (11) through said outlet of the preceding filter device (11) into the filter device (1) and / or the filtered fluid receiving container (B) by means of forming an overpressure at the inlet of the preceding filter device (11).

[0080] Nevertheless, either once the filter has been completely emptied or once the filtered fluid receiving container (B) has been filled shortly before completely filling the connection between the inlet and the outlet via the filtered fluid receiving container (B) with fluid, the fluid needs to be removed from the filtered fluid receiving container (B). As the fluid preferably comprises valuable product, the fluid should be recovered in a product receiving device (C).

[0081] Thus, preferably, in the method as described herein, the filter system further comprises a product receiving device (C) connected via a third fluid flow path to the first fluid flow path, and wherein the method further comprises after the filtered fluid removal step the step of moving in a final moving step the filtered fluid in the filtered fluid receiving container (B) via the third fluid flow path into the product receiving device (C).

[0082] As described above, in the filter fluid removal step, the filtered fluid receiving container (B) is filled up to a point before the connection between the inlet and the outlet via the filtered fluid receiving container (B) is completely filled with fluid. Hence, the connection still comprises a volume of sterile air. This sterile air can be problematic during the final moving step as it might interfere with means for moving the fluid, such as a pump.

[0083] Hence, preferably, as a first step in the final moving step, the connection between the inlet and the outlet via the filtered fluid receiving container (B) is completely filled with fluid. Therefore, the filtered fluid receiving container (B) preferably comprises means for adjusting the heights of the inlet and the outlet of the filtered fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B), and the final moving step comprises a first step of adjusting the heights of the inlet and the outlet of the filtered fluid receiving container (B) to achieve connection between the inlet and the outlet via the filtered fluid receiving container (B) is completely filled with fluid.

[0084] An efficient method for achieving this is to simply rotate the filtered fluid receiving container (B). Preferably the filtered fluid receiving container (B) is rotated so that the inlet and the outlet point towards the direction of the gravitational force. Furthermore, preferably, the filtered fluid receiving container (B) is fixed, i.e. hung, at the edge opposite of the inlet and the outlet of the filtered fluid receiving container (B).

[0085] Hence, preferably, the means for adjusting the heights of the inlet and the outlet of the filtered fluid receiving container (B) is a means to rotate the filtered fluid receiving container (B), and the final moving step comprises a first step of rotating the filtered fluid receiving container (B) to achieve connection between the inlet and the outlet via the filtered fluid receiving container (B) is completely filled with fluid.

[0086] In a preferred embodiment of the herein described method, the first fluid flow path comprises an associated flow control device (8) downstream of the connection between the second fluid flow path with the first fluid flow path (6) and downstream of the connection of the third fluid flow path and the first fluid flow path (7), wherein in the final moving step the flow control device (8) associated with the first fluid flow path is configured to reduce the flow rate in the first fluid flow path, preferably stops the flow through the first fluid flow path.

[0087] Preferably, the first fluid flow path comprises an associated flow control device (8) downstream of the connection between the second fluid flow path with the first fluid flow path (6) and downstream of the connection of the third fluid flow path and the first fluid flow path (7) and the filtered fluid receiving container (B) is a flexible bag as described above. This ensures that in the final moving step the fluid is efficiently removed from the filtered fluid receiving container (B) without producing a circular movement.

[0088] In this preferred embodiment, it is even more preferred if the connection between the second fluid flow path with the first fluid flow path (6) is positioned upstream to the connection of the third fluid flow path and the first fluid flow path (7).

[0089] Even more preferably, also the second fluid path comprises a flow control device (9) and / or the third fluid path comprises a flow control device (10). In a preferable embodiment of the method as described herein, prior to the fluid removal step, the method comprises a step of closing the flow control device (10) and opening the flow control devices (8) and (9). Furthermore, preferably, in the method as described herein, prior to the final removing step, the method comprises a step of closing the flow control device (9) and opening the flow control devices (8) and (10).

[0090] System

[0091] As set out above, the system as described herein comprises: a filter device (1) comprising ■ a housing having an inlet (4) and an outlet (5) defining a filtration flow path between the inlet (4) and the outlet (5), and

[0092] ■ a porous filter medium (3) across the filtration flow path, the porous medium (3) having an upstream side and a downstream side, the system also including a filtered fluid receiving container (B) arranged downstream of the outlet (5), the filtered fluid receiving container (B) comprising an inlet and an outlet, a first fluid flow path between the outlet of the filter device (1) and the inlet of the filtered fluid receiving container (B), a second fluid flow path between the first fluid flow path and the outlet of the filtered fluid receiving container (B), wherein the second fluid flow path is connected to the first fluid flow path at a connection (6), a pump (2) positioned in or at the second fluid flow path, the pump (2) being configured to pump (2) fluid and / or gas from the filtered fluid receiving container (B) to the first fluid flow path.

[0093] The system according to this embodiment is depicted in Figure 1.

[0094] The system usually has a source of a fluid (A) placed in communication with a feeding line to the inlet of the filter device (1). The source of a fluid (A) can be a source container comprising the fluid to be filtered but can also be a production process for a fluid. Hence the source of a fluid (A) could also be e.g. a bioreactor producing the fluid to be filtered.

[0095] As set out above for the method already, also in a preferred embodiment of the system, the filter (1) is a membrane filter.

[0096] The filter (1) typically has at least a bacterial removal rated porous filtration medium (3) and can have a sterilizing grade porous filtration medium (3). The filtration medium (3) can have a variety of configurations, including planar, pleated and / or hollow cylindrical.

[0097] The housing of the filter (1) is typically a sterilizable, robust cartridge or capsule that can withstand the pressures and chemical environments of the filtering process. The design and materials of the filter ensure compatibility with various pharmaceutical formulations while maintaining sterility and filtration efficacy.

[0098] Typically, the filter (1) is vented during the initial filtration of liquid so that the maximum available filter medium surface is used, and to prevent build-up of air or gas in the system. After the filter housing is filled with liquid, the vent can be closed. Preferably, the filter (1) includes a vent, or vents can be arranged upstream and / or downstream of the filter (1), so that air or gas can be vented. Preferably, the filter (1) is suitable for passing pressurized air therethrough subsequent to passing a liquid therethrough.

[0099] Preferably, the pump (2) is a positive replacement pump, more preferably, the pump (2) is a peristaltic pump.

[0100] Preferably, in the system as described herein, the filtered fluid receiving container (B) is configured in that the outlet of the filtered fluid receiving container (B) is higher than or at the same height as the inlet of the filtered fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B), wherein the outlet of the filtered fluid receiving container (B) is not positioned at the lowest point of the fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B).

[0101] In a preferred embodiment according to Figure 5 the filtered fluid receiving container (B) is a container or bag having a rectangular shape having a short edge and a long edge, wherein the filtered fluid receiving container (B) is positioned in that the short edge is oriented along the direction of the gravitational force and wherein the long edge is oriented perpendicular to the direction of the gravitational force.

[0102] In an even more preferred embodiment according to Figure 5, the inlet of the filtered fluid receiving container (B) is positioned in a corner of a long edge and a short edge of the filtered fluid receiving container (B), wherein the corner is closer to the center of the gravitational force than another corner connected to the short edge, and wherein the outlet is positioned at said corner connected to the short edge. Hence, in such an embodiment, the short edge is not oriented along the direction of the gravitational force, but the filtered fluid receiving container (B) is rotated to allow the corner of the outlet to be at the highest point of the filtered fluid receiving container (B) with respect to the direction of the gravitational force.

[0103] As already outlined for the method above, these embodiments allow an efficient usage of the volume given by the filtered fluid receiving container (B). By achieving that the outlet is at the highest point, it can be ensured that the connection between the inlet and the outlet of the filtered fluid receiving container (B) comprises a volume of sterile gas while nearly the whole volume of the filtered fluid receiving container (B) is filled with fluid recovered from the filter.

[0104] Hence, more preferably, the filtered fluid receiving container (B) according to Figure 5 is positioned in that the bag is rotated thereby achieving an angle between the long edge and a direction perpendicular to the direction of the gravitational force, thereby resulting in a short edge with a high position and a short edge with a low position with respect to the direction of the gravitational force, and wherein the inlet of the filtered fluid receiving container (B) is positioned in a corner of a long edge and the short edge with a high position of the filtered fluid receiving container (B), wherein the corner is closer to the center of the gravitational force than another corner connected to the short edge with a high position, and wherein the outlet is positioned at said corner connected to the short edge with a high position.

[0105] The angle is preferably in the range of from 10° to 80°, preferably from 20° to 70, more preferably from 30° to 60°, and most preferably from 40° to 50°.

[0106] Usually, the filtered fluid receiving container (B) is a flexible bag. The flexible bag typically used for storing the fluid in a drug production filtering system is typically made from multi-layered, medical-grade polymers such as polyethylene or ethylene-vinyl acetate (EVA). These bags are designed to be sterile, non-reactive, and resistant to punctures and tears. The multi-layer construction ensures a robust barrier against contamination while maintaining flexibility for easy handling and storage. The flexible bag often comes with integrated ports and connectors for secure, sterile transfer of fluids. Additionally, they are available in various sizes to accommodate different volumes of product fluid, ensuring versatility and scalability in drug production processes. Hence, more preferably the filtered fluid receiving container (B) is a flexible bag. Most preferably, the filtered fluid receiving container (B) is a flexible bag made from an air-tight film comprising a polymer, preferably from a multilayer polymer film.

[0107] Additionally, preferably, the filtered fluid receiving container (B) according to Figure 7 preferably comprises means for adjusting the heights of the inlet and the outlet of the filtered fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B). Preferably the filtered fluid receiving container (B) is rotatable so that the inlet and the outlet point towards the direction of the gravitational force. Furthermore, preferably, the filtered fluid receiving container (B) can be fixed, i.e. hung, at the edge opposite of the inlet and the outlet of the filtered fluid receiving container (B). Hence, preferably, the means for adjusting the heights of the inlet and the outlet of the filtered fluid receiving container (B) is a means to rotate the filtered fluid receiving container (B).

[0108] In a preferred embodiment of the system according to Figure 2, the first fluid flow path comprises an associated flow control device (8) downstream of the connection between the second fluid flow path with the first fluid flow path (6) and downstream of the connection of the third fluid flow path and the first fluid flow path (7) the second fluid path comprises a flow control device (9) and / or the third fluid path comprises a flow control device (10). In this preferred embodiment, it is even more preferred if the connection between the second fluid flow path with the first fluid flow path (6) is positioned upstream to the connection of the third fluid flow path and the first fluid flow path (7). The advantage of this system is that the flow paths can be controlled, and respective cycles enabled or not.

[0109] In another preferred embodiment of the system as described herein, the system further comprises a product receiving device (C) connected via a third fluid flow path to the first fluid flow path. In an even more preferable embodiment system comprises a flow control device (10) in the third fluid flow path.

[0110] The product receiving device (C) denotes any device or container, which is intended to receive the filtered fluid. Usually, the filtered fluid is collected after filtering either to be packaged and sold or to be directly used i.e. in medical application or in research. Hence, the type of the product receiving device (C) depends on the use case the system is intended to serve the filtered fluid for. In one embodiment, the product receiving device (C) is a filtered fluid container, which simply collects the filtered fluid. In another embodiment, the product receiving device (C) is a manifold, which distributes the filtered fluid to many containers or other devices such as syringes. Hence, in even another embodiment, the product receiving device (C) could be a syringe either for being packaged and sold or for being used in a subsequent treatment or method. Other product receiving devices (C) may be vials, ampoules, bottles, bioprocessing containers, and carbouys.

[0111] In another preferred embodiment of the system as described herein, the system further comprises a preceding filter device (11) comprising

[0112] ■ a housing having an inlet and an outlet defining a filtration flow path between the inlet and the outlet, and

[0113] ■ a porous filter medium across the filtration flow path, the porous medium having an upstream side and a downstream side,

[0114] ■ wherein the outlet of the preceding filter device (11) is fluidly connected to the inlet of the filter device (1),

[0115] A preceding filter used in the drug production filtering system is typically a depth filter, made from materials such as cellulose or glass fibers. This filter has a gradient density structure, providing a higher capacity for capturing larger particles and aggregates. Depth filters are used as a pre-filter to remove bulk contaminants and particulates, thereby protecting the final membrane filter from clogging and extending its life. These filters are often designed to handle high dirt loads and can operate under varying pressure conditions. By incorporating a depth filter, the system ensures an efficient, two-stage filtration process, enhancing the overall purity and quality of the drug solution.

[0116] Beside depth filters, bioburden filters can be used as second filters in the herein described system. Bioburden filters are specialized filtration devices designed to reduce the microbial load in a fluid by removing bacteria and other microorganisms. These filters typically have pore sizes ranging from 0.1 to 0.45 pm, which are effective in retaining and removing microbial contaminants while allowing the passage of the fluid. These filters are commonly constructed from materials such as polyethersulfone (PES), polyvinylidene fluoride (PVDF), or polypropylene (PP), chosen for their chemical compatibility, low extractables, and robust mechanical properties.

Claims

Claims:

1. A method for aseptically recovering filtered fluid retained in a filter system, the filter system including: a filter device (1) comprising■ a housing having an inlet (4) and an outlet (5) defining a filtration flow path between the inlet (4) and the outlet (5), and■ a porous filter medium (3) across the filtration flow path, the porous medium (3) having an upstream side and a downstream side, a filtered fluid receiving container (B) arranged downstream of the outlet (5), the filtered fluid receiving container (B) comprising an inlet and an outlet, a first fluid flow path between the outlet (5) of the filter device (1) and the inlet of the filtered fluid receiving container (B), a second fluid flow path between the first fluid flow path and the outlet of the filtered fluid receiving container (B), wherein the second fluid flow path is connected to the first fluid flow path, a pump (2) positioned in or at the second fluid flow path, the pump (2) being configured to pump (2) fluid and / or gas from the filtered fluid receiving container (B) to the first fluid flow path, the method comprising the steps of passing fluid in a fluid passing step via the filtration flow path through the filter device (1) via the first fluid flow path into the filtered fluid receiving container (B), wherein a volume of filtered fluid is retained in the housing between the downstream side of the porous filter medium (3) and the outlet (5); and, moving in a filtered fluid removal step sterile gas comprised in the filtered fluid receiving container (B) via the pump (2) from the filtered fluid receiving container (B) via the second fluid flow path into the first fluid flow path and through the outlet (5) into the housing of the filter device (1), thereby displacing retained filtered fluid via the first fluid flow path into the filtered fluid receiving container (B).

2. The method according to claim 1 , wherein the fluid passing step comprises the steps ofpassing sterile gas in a gas initialization step through the outlet (5) of the filter device (1) and via the first fluid flow path into the filtered fluid receiving container (B), and passing fluid in a fluid initialization step via the filtration flow path through the filter device (1) via the first fluid flow path into the filtered fluid receiving container (B), wherein the fluid in the fluid initialization step preferably does not comprise any solids.

3. The method according to claim 1 , wherein the fluid passing step comprises the step of filtering fluid to be filtered in a fluid filtering step by passing the fluid via the filtration flow path through the filter device (1) and via the first fluid flow path into the filtered fluid receiving container (B), wherein the fluid in the fluid filtering step preferably comprises solids to be filtered off the fluid.

4. The method according to any of the preceding claims 1 to 3, wherein the filtered fluid receiving container (B) is configured in that the outlet of the filtered fluid receiving container (B) is higher than or at the same height as the inlet of the filtered fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B), wherein the outlet of the filtered fluid receiving container (B) is not positioned at the lowest point of the fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B).

5. The method according to any of the preceding claims 1 to 4, wherein the filtered fluid receiving container (B) comprises means for adjusting the heights of the inlet and the outlet of the filtered fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B).

6. The method according to claim 5, wherein the means for adjusting the heights of the inlet and the outlet of the filtered fluid receiving container (B) is a means to rotate the bag.

7. The method according to any of the preceding claims 1 to 6, wherein in the fluid passing step the filtered fluid receiving container (B) is filled with a volume of filtered fluid, whereby a volume of sterile gas remains in the filtered fluid receiving container (B) and wherein a connection between the inlet and the outlet via the filtered fluid receiving container (B) at least partially comprises the sterile gas.

8. The method according to any of the preceding claims 1 to 7, wherein the method further comprises after the fluid passing step and prior to the filtered fluid removal step the step ofpushing in a filtered fluid pushing step filtered fluid retained in the housing between the inlet (4) of the filter device (1) and the porous filter medium (3) through the porous filter medium (3) and the outlet (5) of the filter device (1) into the filtered fluid receiving container (B) by means of forming an overpressure upstream or at the inlet (4) of the filter device (1), wherein a volume of filtered fluid is still retained in the housing between the downstream side of the porous filter medium (3) and the outlet (5).

9. The method according to claim 8, wherein the filter system further comprises a preceding filter device (11) comprising■ a housing having an inlet and an outlet defining a filtration flow path between the inlet and the outlet, and■ a porous filter medium across the filtration flow path, the porous medium having an upstream side and a downstream side,■ wherein the outlet of the preceding filter device (11) is fluidly connected to the inlet of the filter device (1), wherein the method further comprises after the fluid passing step and prior to the filtered fluid pushing step the step of- pushing in a second filtered fluid pushing step filtered fluid retained in the housing between the inlet of the preceding filter device (11) and the porous filter medium (3) through the porous filter medium (3) and the outlet of the preceding filter device (11) into the filter device (1) and / or the filtered fluid receiving container (B) by means of forming an overpressure at the inlet of the preceding filter device (11).

10. The method according to any of the preceding claims 1 to 9, wherein the filter system further comprises a product receiving device (C) connected via a third fluid flow path to the first fluid flow path, and wherein the method further comprises after the filtered fluid removal step the step of- moving in a final moving step the filtered fluid in the filtered fluid receiving container (B) via the third fluid flow path into the product receiving device (C).

11. The method according to claim 10, wherein the first fluid flow path comprises an associated flow control device (8) downstream of the connection between the second fluid flow path with the first fluid flow path (6) and downstream of the connection of the third fluid flow path and the first fluid flow path (7),- wherein the in the final moving step the flow control device (8) associated with the first fluid flow path is configured to reduce the flow rate in the first fluid flow path, preferably stops the flow through the first fluid flow path.

12. A filter system comprising: a filter device (1) comprising■ a housing having an inlet and an outlet defining a filtration flow path between the inlet and the outlet, and■ a porous filter medium across the filtration flow path, the porous medium having an upstream side and a downstream side, the system also including a filtered fluid receiving container (B) arranged downstream of the outlet, the filtered fluid receiving container (B) comprising an inlet and an outlet, a first fluid flow path between the outlet of the filter device (1) and the inlet of the filtered fluid receiving container (B), a second fluid flow path between the first fluid flow path and the outlet of the filtered fluid receiving container (B), wherein the second fluid flow path is connected to the first fluid flow path at a connection (a), a pump (2) positioned in or at the second fluid flow path, the pump (2) being configured to pump (2) fluid and / or gas from the filtered fluid receiving container (B) to the first fluid flow path.

13. The filter system according to claim 12, wherein the filtered fluid receiving container (B) is configured in that the outlet of the filtered fluid receiving container (B) is higher than the inlet of the filtered fluid receiving container (B) with respect to the level of a fluid in the filtered fluid receiving container (B).

14. The filter system according to claim 13, wherein the filtered fluid receiving container (B) is a bag having a rectangular shape having a short edge and a long edge, wherein the bag is positioned in that the short edge is oriented via the direction of the gravitational force and wherein the long edge is oriented perpendicular to the direction of the gravitational force.

15. The filter system according to any of the preceding claims 12 to 14, wherein the system further comprises a product receiving device (C) connected via a third fluid flow path to the first fluid flow path.

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