Filtration device for bioprocessing

Abstract

To provide systems and methods for overcoming the drawbacks associated with current depth filtration devices to permit closed processing operations.SOLUTION: The present invention provides an apparatus for treating a biological fluid, including a plurality of filtration devices. In some embodiments, each of the plurality of filtration devices includes at least one inlet and at least one outlet. A first insert plate and a second insert plate that faces the first insert plate are provided, and the plurality of filtration devices is disposed therebetween. In some embodiments, each filtration device has a vent port. A manifold for each of the inlet, the outlet, and the vent port is optionally fluidly connected. In another embodiment, hose barb connectors or the like may be protected from damage and / or exposure by being embedded in the device or disposed at the periphery of the device. Embodiments include apparatuses and methods to achieve dripless connection / disconnection and to reduce the number of sterile-to-sterile connections.SELECTED DRAWING: Figure 2A

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 114,623, filed November 17, 2020, the entire disclosure of which is incorporated herein by reference.

[0002] Embodiments of the present disclosure relate to the treatment of body fluids. More specifically, the embodiments disclosed herein relate to filtration devices for bioprocessing. In some embodiments, the filtration device may include, for example, a depth filter, a virus clearance filter, a TFF filter, a membrane including a membrane adsorber or chromatography membrane, a chromatography resin, or other filters known to those skilled in the art.

Background Art

[0003] Conventionally, depth filtration devices are disposable modular depth filtration devices used for primary and secondary clarification of the feed stream of biopharmaceuticals. To enable pilot and process scale clarification (e.g., 200L to 3,000L) of unpurified cell cultures used in the large-scale manufacture of recombinant biological therapeutics such as monoclonal antibodies (mAbs), multiple devices are stacked and loaded into stainless steel filter holders. The assembly of stacked devices is compressed using a hydraulic pump attached to the holder (e.g., about 1,000 psi), creating a liquid-tight seal between adjacent devices. The device can reach an internal pressure of up to 50 PSI (pounds per square inch) during operation. Current device formats include disposable adapters and / or ports along with gaskets, fittings, and / or tubes, which are installed individually prior to the start of the clarification operation. These current device formats are not suitable for closed processing operations because the connection ports are open to the surrounding environment and serve as vectors for compromising sterility even in a sterile environment. These device formats pose a risk of cross-contamination of products and a risk of operator exposure to biological substances.

[0004] Bioprocess operations where process fluids, including biological products and biopharmaceuticals, may be exposed to the environment within the manufacturing space require preventive measures to ensure process cleanliness and avoid product contamination. Therefore, such bioprocess operations need to be carried out in a controlled classified space (i.e., a "cleanroom") to minimize the risk of contamination of the product supply stream. Classified spaces are very costly to construct, operate, and maintain. Despite taking preventive measures to avoid contamination, contamination events can still occur. Contamination can require stoppage, cleaning, and revalidation, each of which is costly and time-consuming. Therefore, to minimize the risk of contamination, bioprocess equipment and materials need to be sterilized prior to use. Given the cost and time involved in building, operating, and maintaining a controlled environment, biopharmaceutical manufacturers have a desire to move bioprocess operations to a controlled unclassified space (i.e., a "gray space") to enable manufacturing flexibility and potential cost savings. Existing bioprocess filters, particularly depth filtration, tangential flow filtration, and virus filtration devices, can be sterilized prior to use, but when these devices are used in a gray space, the sterility is immediately compromised upon removal from a bag or other packaging container due to one or more open fluid ports present in the device. These fluid ports are necessary to enable modularity, i.e., the ability to change the total filtration area, media grade, or other functions according to batch size, product attributes, etc., so eliminating these ports is not a viable option.

[0005] Therefore, there is a need for a fully enclosed sterilizable filtration device having a sterile connection that can be connected to other bioprocess operations.

[0006] Current industry trends in biopharmaceutical manufacturing are moving towards the development of multi-product production facilities. To operate such facilities efficiently, it is necessary to use a fully enclosed filtration device to reduce or eliminate potential causes of product contamination. It is desirable to be able to connect and disconnect the device from the process fluid without exposing the production facility or its operators to the process fluid. Other recent industry trends include enhanced batch mode and continuous bioprocesses. "Continuous mode" operations often occur over much longer periods (such as several days or weeks) compared to conventional "batch mode" operations, which typically occur within a few hours or a day. In continuous processing applications, perfusion bioreactors designed to operate for several days or weeks are often used to maintain high productivity of cell culture. In a batch process, after maintaining the cell culture for a set period, the entire culture within the batch is harvested. In a continuous harvest system, such as a perfusion process where spent cell culture medium is removed and replaced, the permeate containing the product is continuously collected from the cell culture over a long period, resulting in an increase in product titer and an increase in the amount of waste and dead cells removed in the downstream process. Therefore, the upstream and downstream processes need to balance processing time, product concentration, and quality.

[0007] There are several methods and devices for retaining cells within a perfusion bioreactor. These include TFF-based cell retention devices sold under the trade name Cellicon® by EMD Millipore, alternating tangential flow XCell® ATF, or tangential flow depth filtration TFDF™ (both sold by Repligen). In some embodiments of these perfusion processes, the perfusion fluid generated by these devices may require a secondary depth filtration step to further reduce turbidity and / or soluble impurities, rendering the feed stream suitable for subsequent sterile-grade filtration, i.e., filtration through a 0.22 μm pore size membrane and capture chromatography steps. The depth filters employed in these applications are likely to require longer operating times (days or weeks), so the depth filters are sterilized (or bioburden reduced) to minimize the risk of upstream contamination of the bioreactor. Also, since they can be utilized in a fully enclosed device format, the replacement of used / expired filters during operation can be performed more easily and efficiently (i.e., “hot swapped”) and can be carried out in a controlled non-classified (CNC) or “gray space” / ballroom production facility. Further, in other embodiments of continuous or semi-continuous processes, one or more secondary depth filtration steps may be required further downstream, for example, after protein A capture chromatography and / or low pH virus inactivation steps. Depth filtration can also be used as a pre-filtration step prior to the virus filtration step. Similarly, in these downstream applications, enclosed sterile depth filters are used to minimize the risk of contamination during long-term operation.

[0008] At least one drawback of prior art attempts is that the sterility of the internal flow paths within a depth filter device comprising multiple filters / filter devices is not maintained after sterilization of the filter device (e.g., by gamma irradiation, X-rays, electron beam (e-beam), ethylene oxide, or autoclaving). The connection ports (inlets, outlets, vents, etc.) of the filter device are directly exposed to the ambient environment when mounting the filter device onto a holder upon unpacking, and also while connecting multiple pods / filter devices, and / or associated adapters / connectors, and / or tubes thereto. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0009] Accordingly, it is an advancement in the art to provide a system and method that overcome the drawbacks associated with current depth filtration devices and enable a closed processing operation. It is also an advancement in the art to provide a system that eliminates or significantly reduces the risk of cross-contamination of products and manual labor exposure to biological substances. It is a further advancement to provide a pre-sterilized or reduced bioburden depth filter device that can be used within these closed processing facilities. It is a further advancement to provide an apparatus and method that enable aseptic installation of these devices, maintain the sterility of the devices, and reduce the need for expensive cleanroom facilities during biological processing. In some embodiments, certain features provide for drip-free removal of these devices, ensure operator safety, maintain the cleanliness of the manufacturing environment, and facilitate the replacement of filter devices for continuous manufacturing processes in an efficient manner. MEANS FOR SOLVING THE PROBLEMS

[0010] An apparatus for treating body fluids, comprising a plurality of filtration devices, each comprising a filtration medium, at least one inlet, and at least one outlet; and a first insert plate and a second insert plate on the opposite side of the first insert plate, wherein the plurality of filtration devices are arranged between the first and second insert plates. Optionally, a manifold is connected to each of the inlet, outlet, and vent port. Substantially as fully described by the claims, as shown and / or described in relation to at least one of the drawings.

[0011] In another embodiment, an apparatus for chromatographic purification of body fluids using membrane adsorption devices comprises a plurality of membrane adsorption devices, each comprising at least one inlet and at least one outlet, and a first insert plate and a second insert plate on the opposite side of the first insert plate, between which the plurality of membrane adsorption devices are arranged. Optionally, a manifold is connected to each of the inlet and outlet. In this embodiment, the apparatus does not have a vent port.

[0012] The embodiments disclosed herein relate to an apparatus that enables so-called "downstream processing", e.g., a closed bioprocessing such as a process (e.g., depth filtration) for removing or reducing contaminants from a material collected in a bioreactor. In certain embodiments, the apparatus enables aseptic fluid transfer. In some embodiments, the apparatus is pre-sterilized and is a single-use disposable device. In certain embodiments, the apparatus is a series of pre-assembled individual filtration packets, each including a filtration medium and / or one or more membranes. In certain embodiments, the series of pre-assembled packets are under tension by a specific force, e.g., tie rods each having a load of 300 pounds. The packets and end caps can be interconnected to form a module, and one or more modules can be held together with a manifold end cap to form a module assembly that can prevent unwanted ingress through one or more fluid ports. The fully assembled apparatus can be sterilized, e.g., by gamma rays, X-rays, autoclaving, steam treatment, ozone or ethylene oxide treatment, to make the interior of the apparatus aseptic. Since aseptic connection can be made to the process piping, aseptic fluid transfer such as a filtration operation can be enabled without contaminating the filtration medium or the process fluid.

[0013] In some embodiments, a modular filtration device is disclosed for use in a fully enclosed or functionally enclosed processing application that reduces the risk of product contamination and maintains product integrity. In some embodiments, the modular filtration device includes one or more filtration devices, particularly those commercially available under the names Millistak+(R) HC, Millistak+(R) HC Pro, Clarisolve(R) (or Pod depth filter devices or pods, etc.), which may be pre-sterilized and may include, for example, media suitable for primary and secondary clarification of a biopharmaceutical feed stream or virus filtration. Multiple filtration devices or pods can be stacked in parallel and loaded into a suitable holder. The stack can be horizontal, vertical, or both. In certain embodiments, to achieve a closed processing operation in which the filtration device is isolated from the environment throughout the device's use cycle, the aseptic connection points (inlets, outlets, vent ports, etc.) and internal passages are provided and maintained in a sterile, sealed environment to protect against contamination, enabling the filtration device to be aseptically connected to and disconnected from the process fluid without exposing the production facility or operator to the process fluid. The embodiments disclosed herein provide alternative ways to achieve this.

[0014] For example, in some embodiments, one or more insert plates can be assembled into the pod, each insert plate having one or more ports and / or slots that align with, for example, a hose barb connection component extending from the pod and receive the hose barb connection component within the thickness of the plate (e.g., such that the connection component is fully or partially recessed), accommodating the component (which may include a tube) and protecting it from exposure to the environment. Using insert plates allows for an organized arrangement of tubes and manifolds and is reusable. In other embodiments, insert plates are not used, but hose barb connection components, etc., extend from the outer peripheral side of the pod rather than from the front face of the pod or are embedded within the body of the pod itself, such that they do not protrude from the pod body.

[0015] In some embodiments, multiple pods can be pre - combined and loaded onto a cart for easy transportation and / or can be encapsulated or enclosed with a sterilization barrier. The sterile barrier can include one or more rigid or rigid - based, and polymer / plastic films welded thereto. The rigid or hard base can be hard enough to support the polymer / plastic film welded thereto, including bases made of LDPE, HDPE, ABS, and / or nylon. The sterilization - sterilization connector can be used to connect to, for example, a hose barb fitting, either before or after the pod assembly is enclosed and sterilized. In another embodiment, the pod assembly can be enclosed within a plastic bag, the pods compressed to form a liquid - tight seal between adjacent pods, and then the plastic bag opened to expose a pre - assembled sterilization - sterilization connector. One or more manifolds can be used to connect multiple pods. For example, a connector plate with a Lynx® S2S - style female coupling can be used to make connections between sterile pods between deep - filter devices.

[0016] Accordingly, in some embodiments, an apparatus for treating body fluid is disclosed, which includes a plurality of filtration devices, each including a filtration medium, at least one inlet, and at least one outlet; and a first insert plate and a second insert plate on the opposite side of the first insert plate, with a plurality of filtration devices disposed therebetween. Each of the plurality of filtration devices can further include at least one vent port. The at least one inlet can further include a sterile-sterile connector. The at least one outlet can further include a sterile-sterile connector. The at least one vent port can terminate with a vent filter. At least one inlet from each of the plurality of devices can be connected to communicate with each other via a manifold. At least one outlet from each of the plurality of devices can be connected to communicate with each other via a manifold. At least one vent port from each of the plurality of devices can be connected to communicate with each other via a manifold. Any or all of the manifolds can include a sterile-sterile connector.

[0017] The filtration medium can include a medium effective for virus filtration, depth filtration, or adsorption filtration. The filtration medium may include a chromatography membrane.

[0018] The plurality of filtration devices can be combined and loaded into a cart having a holder hardware including side A and side B. The device holder hardware can include a pressure gauge, a hydraulic pump, a clamp rod, a frame, and one or more of two platens.

[0019] In some embodiments, an apparatus for sealing a sterilizing filtration device is disclosed, including a container that includes two rigid bases and a plastic film, with a plurality of filtration devices disposed therebetween, one of the rigid bases having a protruding hose barb fitting connected to a tube and a sterilization-sterilization connector, the plastic film sealing the plurality of filtration devices between the rigid bases. The plastic film may be joined to at least a portion of the perimeter of the rigid base by heat welding, adhesion, or other means. There may be two plastic films, and the plastic films may extend beyond the perimeter of the rigid base. At least one of the rigid bases may include an alignment key. Each end plate may be able to have at least one groove for holding a binding band. There may be at least one hose barb adapter or at least one blind end cap, and each hose barb adapter or blind end cap adapter may further include a gasket and a snap fit connection.

[0020] In some embodiments, the assembly includes a filtration module that includes a filtration medium and one or more fluid ports; and an insert plate having a thickness and configured to be attached to a face of the filtration module, the insert plate having at least one recess configured and arranged to receive a connection component fluidly connectable to one of the fluid ports, such that when the insert plate is attached to the face of the filtration module, the connection component is received within the thickness of the insert plate. The filtration module may be enclosed within a sterilization barrier that includes a plastic bag.

[0021] In some embodiments, the assembly includes a filtration module that includes a filtration medium and one or more fluid ports, the filtration module having an end face that has at least one recess configured and arranged to receive a connection component fluidly connectable to one of the fluid ports, such that the connection component is received within the recess. The filtration module may be enclosed within a sterilization barrier that includes a plastic bag.

[0022] In some embodiments, a method of deploying a seal within a filtration device including a filter medium, an inlet, and an outlet is disclosed, the method including inserting an applicator into each of the inlet and the outlet and introducing a seal material through each applicator. The sealing material can include cotton, rayon, foam, polyurethane, polyether, polyester, or cellulose.

[0023] In some embodiments, an apparatus for treating a body fluid is disclosed that includes: a plurality of filtration devices, each including a filter medium, at least one inlet, and at least one outlet. Two of the inlets of the plurality of filtration devices are fluidly connected by a first Y-connector. Two of the outlets of the plurality of filtration devices can be fluidly connected by a second Y-connector. Each of the plurality of filtration devices can further include a vent, and two of the vents of the plurality of filtration devices can be fluidly connected by a third Y-connector. Any or all of the Y-connectors can be fluidly connectable or connected to a manifold.

[0024] The various advantages, aspects, novel and inventive features, and details of the exemplary embodiments of the present disclosure will be more fully understood from the following description and the drawings. [Brief Description of the Drawings]

[0025]

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DETAILED DESCRIPTION OF THE INVENTION

[0026] To enable a more detailed understanding of the features disclosed herein, a more specific description of the embodiments of the present disclosure briefly summarized above can be understood by referring to the accompanying drawings. However, it should be noted that the accompanying drawings show only typical embodiments of the present disclosure, and thus, the described and shown embodiments are not considered to limit the scope of the present disclosure because other equally effective embodiments may be allowed. It should also be understood that elements and features of one embodiment may be found in other embodiments without further explanation, and the same reference numbers may be used to indicate equivalent elements common to the drawings.

[0027] The term "cell culture" refers to cells grown in suspension, roller bottles, flasks, etc., as well as the components of the suspension itself, which includes, but is not limited to, cells, cell debris, cell contaminants, colloidal particles, biomolecules, host cell proteins (HCP) and DNA, mAb, antibody-drug conjugates (ADC), viral vectors, and / or aggregating agents. Large-scale approaches such as bioreactors containing adherent cells growing attached to microcarriers in stirred fermenters are also included within the meaning of the term "cell culture".

[0028] The terms "cell culture medium / media" and "culture medium / media" refer to nutrient solutions used to grow animal cells, such as mammalian cells. Such nutrient solutions generally contain various factors necessary for cell attachment, growth, and maintenance of the cell environment. For example, a typical nutrient solution may contain a basal medium formulation, various supplements depending on the cell type, and optionally antibiotics. In some embodiments, the nutrient solution may contain at least one component from one or more of the following categories: 1) an energy source, usually in the form of a carbohydrate such as glucose; 2) one or more essential amino acids and / or cysteine; 3) vitamins and / or other organic compounds; 4) free fatty acids; 5) trace elements (trace elements are defined as inorganic compounds).

[0029] The terms "filter device", "pod", "pod", "process scale pod", and the acronym "PSP" are used interchangeably in the present disclosure and are intended to denote any filter module.

[0030] A "depth filter" is a filter that achieves filtration by the depth of the filter material. Particle separation in a depth filter occurs by capture or adsorption by the fibers and filter aid matrix that make up the filter material.

[0031] The terms "bioreactor", "bag", and "container" are generally used interchangeably within the present disclosure. As used herein, the terms bioreactor, bag, and container refer to any manufactured or designed device or system that supports a biologically active environment. In some cases, a bioreactor is a container having an internal volume in which a cell culture process is performed that includes an organism or a biochemically active substance derived from such an organism. A flexible bioreactor, bag, or container means a flexible container that can, for example, hold body fluids, fold, crush, and expand. A disposable bioreactor, bag, or container is typically flexible and is a container that is discarded once used.

[0032] The terms "sterile" and "sterilized" are defined as a state in which no contaminants are present, particularly in the bioprocessing industry, a state in which no unwanted pathogens such as viruses, bacteria, bacteria, and other microorganisms are present. In this context, the terms "bioburden reduced" and "bioburden reduction" (e.g., by non-sterilizing doses of gamma or X-ray radiation less than 25 kGy) may be substituted in certain embodiments that do not require a sterility claim.

[0033] The term "upstream" is defined as the first step process in the treatment of biological materials (including microorganisms / cells, mAbs, ADCs, proteins including therapeutic proteins, viral vectors, etc.) that are grown or inoculated in a bioreactor within a cell culture medium under controlled conditions to produce a particular type of biological product.

[0034] The term "downstream" refers to the process by which, following growth and proliferation within a bioreactor, a biological product is harvested, tested, purified, concentrated, and packaged.

[0035] As used herein, the term "monoclonal antibody" (mAb) refers to an antibody obtained from a substantially homogeneous population of antibodies (i.e., the individual antibodies comprising the population are identical except for naturally occurring mutations that may be present in minor amounts). Monoclonal antibodies may further include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chains is identical or homologous to the corresponding sequences of antibodies derived from a particular species or belonging to a particular antibody class or subclass.

[0036] The term "continuous process" refers to a process for purifying a target molecule that includes two or more process steps (or unit operations), such that the output from one process step flows directly to the next process step in the process without interruption, and two or more process steps can be carried out simultaneously for at least a portion of the duration. In other words, in the case of a continuous process as described herein, it is not necessary to complete a process step before the next process step is initiated, but a portion of the sample is always moving through the process steps.

[0037] The term "semicontinuous process" refers to a generally continuous process for purifying a target molecule in which the input or output of fluid material in any single process step is discontinuous or intermittent. In some embodiments, the processes and systems described herein are "semicontinuous" in nature in that they include unit operations that are operated intermittently while other unit operations within the process or system can be operated continuously.

[0038] The term "clarification" is defined as a downstream process where whole cells, cell debris, soluble impurities (HCP and / or DNA), suspended particles, and / or turbidity are reduced and / or removed from the cell culture feed stream using centrifugation and / or depth filtration. The terms "clarifying", "clarification", "clarification step", and "harvest" generally refer to one or more steps first used in the purification of biomolecules. The clarification step generally involves removing whole cells and / or cell debris during the recovery operation from the bioreactor, but may also include reducing the turbidity of the downstream process intermediate or prefilter to protect other sensitive filtration steps such as virus filtration.

[0039] The term "purification" is defined as a downstream process where large amounts of contaminants and impurities, including host cell proteins, DNA, and process residues, are removed from the product stream.

[0040] The term "polishing" is defined as a downstream process where trace contaminants or impurities that are similar to the product in physical and chemical properties are removed from the purified product stream.

[0041] The term "chromatography" is defined as a downstream separation process suitable for biological chromatography techniques, including but not limited to: Protein A chromatography, affinity chromatography, hydrophobic interaction chromatography, capture chromatography, column chromatography, and ion exchange chromatography, such as anion exchange chromatography and cation exchange chromatography. "Chromatography" also refers to any type of technique that separates the analyte of interest (e.g., the target molecule concentrated as the product) from other molecules present in the mixture. Usually, as a result of the difference in the rates at which the individual molecules of the mixture move through the stationary medium, the analyte of interest is separated from other molecules.

[0042] The term "affinity chromatography matrix" refers to a chromatography matrix that bears a ligand suitable for affinity chromatography. Typically, the ligand (e.g., Protein A or a functional variant or fragment thereof) is covalently bound to the chromatography matrix material and is accessible to target molecules in the solution when the solution contacts the chromatography matrix. An example of an affinity chromatography matrix is a Protein A matrix. Affinity chromatography matrices typically bind to target molecules with high specificity based on a lock / key mechanism such as antigen / antibody or enzyme / receptor binding. The described processes and systems can include affinity chromatography steps that can be used as binding and elution chromatography steps in a purification process.

[0043] The terms "ion exchange" and "ion exchange chromatography" refer to chromatography processes in which a target solute or analyte in a mixture (e.g., a target molecule during purification) interacts with a charged compound bound (e.g., by covalent bond) to a solid phase ion exchange material, whereby the target solute or analyte interacts more or less nonspecifically with the charged compound than solute impurities or contaminants in the mixture. Contaminant solutes in the mixture elute from the column of the ion exchange material faster or slower than the target solute, or bind to or are excluded from the resin compared to the target solute.

[0044] "Ion exchange chromatography" specifically includes cation exchange chromatography, anion exchange chromatography, and mixed-mode ion exchange chromatography. Ion exchange chromatography methods are generally separations based on charge. For example, cation exchange chromatography can bind to a target molecule (e.g., an Fc region containing a target protein) and then be eluted (e.g., using cation exchange binding and elution chromatography or "CIEX"), or the target molecule can mainly bind to impurities while "passing through" the column (cation exchange flow by chromatography FT-CIEX). Anion exchange chromatography can bind to and elute a target molecule (e.g., an Fc region containing a target protein), or the target molecule can mainly bind to impurities while "passing through" the column, and is also called negative chromatography. In some embodiments, anion exchange chromatography is performed in a flow-through mode.

[0045] As used herein, the terms "impurity" or "contaminant" refer to any foreign or unwanted molecule, including DNA, RNA, biopolymers such as one or more host cell proteins, endotoxins, lipids, aggregated polymers, surfactants, antifoam additives, and one or more additives that may be present in a sample containing a target molecule (which is separated from one or more foreign or unwanted molecules using the processes described herein). Further, such impurities can include any reagent used in steps that may occur prior to the methods of the present invention. Impurities can be soluble or insoluble.

[0046] The term "adjuvant" in the present disclosure is defined, for example, as a substance that enhances the body's immune response to an antigen.

[0047] As used herein, the term "(fully) closed system" is a process system that is designed and operated so that the product is never exposed to the surrounding environment.

[0048] The term "functionally closed system" refers to a process that may be opened routinely but is returned to a closed state through a disinfection or sterilization step prior to use of the process. For example, a process vessel that can be washed in a predetermined location and steam-treated in a predetermined location between uses.

[0049] The term "sterilization" refers to a state free of bioburden (sterile), for example, created by methods of heat sterilization (121 °C / 15 minutes or more); aseptic filtration (membrane with a pore size of 0.2 μm or more), chemical sterilization (e.g., VHP, chlorine dioxide, ozone), or radiation irradiation (gamma rays, X-rays, UV).

[0050] Figures 1A - 1F show diagrams of a modular deep - filter device including an insert plate, a connector, and a process - scale pod according to an embodiment of the present disclosure. The illustrated modular deep - filter device 100 is a process - scale pod 102 having one or more add - on components 104 (such as those shown in Figure 1A). The modular deep - filter device 100 is enclosed from the environment throughout the usage cycle of the device, enabling aseptic connection and disconnection of the device in closed - process applications. Figure 1A shows a blind - end component 104a and a 90° elbow hose barb connection component 104b. In some embodiments, rims 105a, 105b exist for each component (the back side shown in Figure 1A). In Figure 1B, the blind - end component 104a is attached to a pod 102 having a total of six port openings 108 (108a, 108b, 108c, etc.). (As shown, the three ports on the back side (not shown) are in fluid communication and are on the opposite side of the three ports on the front face 110). Three hose barb fittings or connectors 112 at the end of the hose barb connection component 104b are attached to the three front - facing openings, and the blind - end component 104b is attached to the three rear - facing openings by any suitable plastic joining method. The blind - end component can be attached on either side. For example, instead of placing three hose barbs on one side and three blind components on the other side, two hose barbs and one blind component can be placed on one side and one hose barb and two blind components on the other side. If all the blind components are placed on one side, one side may appear flat. For example, plastic joining methods include, but are not limited to, solvent bonding, vibration welding, laser welding, and induction welding techniques. The 90° elbow hose barb connection component 104b can also be attached by spin welding due to the circular geometry of the interface surface.A tube 114b (e.g., silicone or C-Flex® (Saint Gobain)) is attached to each hose barb connection, and a sterile-sterile connector 114a (e.g., AseptiQuik® G (Colder Products), ReadyMate™ disposable sterile connector (Cytiva), LYNX® S2S connector (manufactured by EMD Millipore), KLEENPAK® Presto sterile connector (Pall), and PURE-FIT® SC (Saint Gobain)) is attached to the end of the tube 114b as shown in FIG. 1C (the sterile connector 114a is shown as a cube). The type of sterile connector component can be selected according to the application, tube size, compatibility with the sterilization method, etc. Alternatively, the blind end component 104a and the 90° elbow hose barb connection component 104b can be integrated into each end plate during the injection molding of these components (see FIGS. 5 and 6 below). Alternatively, instead of the hose barb fittings of FIGS. 1, 5, and 6, a tri-clover or tri-clamp sanitary fitting can also be used. Further, instead of 90° in the elbow hose barb fitting of the component 104b, other angles such as 135° or 180° (or a straight hose barb) can be used. The filter device 100 with the tube 114b and the sterile connector 114a is considered as one module and should be packaged and sterilized (or the bioburden reduced) before use (e.g., gamma irradiation, X-ray irradiation, electron beam / beta ray irradiation, ethylene oxide, vaporized hydrogen peroxide, nitrogen dioxide, vaporized peracetic acid, or autoclave).

[0051] As shown in FIG. 1C, the orientation of each of the 90° elbow hose barb connectors 112 can be changed. For example, the hose barb connector 112 can face downward with respect to any of the port openings 108a, 108b, 108c, which can be an inlet (e.g., 108a), can face upward with respect to the vent port (e.g., 108b), and can face rightward with respect to the outlet port (e.g., 108c). Other orientations of the hose barb connector are also possible (see FIGS. 3 and 4). Typically, the vent port includes an upward-facing barb connector 104b to facilitate air removal. FIG. 1D shows the insert plate 116, and the positions and geometric shapes of the respective slots 118a, 118b, 118c of the insert plate correspond to each of the hose barb connectors 104b. The insert plate 116 shown in FIG. 1D has one port on each side and helps the end user easily identify which port each tube component and its associated sterilization connector exits from. The insert plate 116 can be made of plastic, metal, ceramic, or a combination thereof. The insert plate 116 is a disposable or reusable separate component and is not adhered to the filter device 100 as shown in FIG. 1E. The insert plate 116 has a thickness suitable for accommodating and protecting the hose barb connectors and the tubes associated therewith. That is, when the insert plate 16 is in the assembled state attached to the surface of the pod 102, due to the respective positions and configurations of the slots 118a, 118b, and 118c of the insert plate 116, the hose barb connectors and the associated tubes can be recessed within the thickness of the insert plate 116. The insert view 120 of FIG. 1E shows the hose barb connector 104b at the outlet position when the insert plate 116 is arranged in contact with the end plate of the adjacent filter device. Depending on the size of the hose barb connector 104b and / or the weight of each insert plate 116, an additional insert plate 116 (not shown) can be placed between the two filter devices 102 to create space for the hose barb connector 104b.The purpose of the insert plate 116 is to house and protect the hose barb connector 104b and the pipes 114 (114a, 114b, 114c, etc.) when multiple filter devices are stacked together for full-scale operation. Without the insert plate 116, when the device 102 is compressed together within the holder hardware using a press machine, for example a hydraulic pump, the hose barb connector 104 and the attached tubes 114 could be damaged, pinched, or not operate as intended.

[0052] Figures 2A - 2E show a plurality of modular deep filter devices comprising an insert plate, connectors, and a manifold, according to embodiments of the present disclosure. In Figure 2(A), the filter device 102 and the insert plate 116 are arranged such that all the hose barb connectors 114a are aligned with respective slots 118a, 118b, and 118c of the insert plate 116. As an example, a configuration including three filter devices 102 is shown in Figure 2B. The plurality of filter devices 102 are stacked together with a plurality of insert plates 116 adjacent to the filter devices 102. For visual clarity, the holders are not shown here. Then, a plurality of sets of pre - sterilized (or bio - burden reduced) filter devices 102 can be placed in a pod holder rack (not shown). A corresponding number of insert plates 116 are placed between each of the sterilized filter devices 102. Each insert plate 116 includes alignment key mechanisms on both sides that match the corresponding opposite - side pattern of the adjacent holder plate or filter device 102, so that it can be arranged in only one direction / orientation as described above. A pre - sterilized manifold tube 122 assembly is introduced. A sterilized connector 124 is attached to the pre - sterilized manifold tube 122. The sterilized connector 124 of the manifold assembly 122 is connected to a corresponding sterilized connector 114a attached to the sterilized filter device 102, as shown in Figure 2C. The manifold tube 122 can be shaped or constructed using tubes, tees, reducers, and / or 90° elbow connectors (Figure 2E).

[0053] In some embodiments, only one manifold tube 122 is disposed on each side of the filter device 102, but it should be understood that additional modifications are possible depending on the length of the tubes connected to each port of the filter device 102 and the layout of the slots in the insert plate 116. For example, the length of the pipe 114b attached to the inlet port may be long enough such that the connected manifold assembly 122 is disposed on the upper side of the filter device 102 alongside the manifold assembly (described above) connected to the vent port. A plurality of deep filter devices that have been pre-sterilized or have reduced bioburden (e.g., gamma or X-ray irradiated, or ethylene oxide exposed) can be aseptically connected and / or removed. Other modes having pre-attached filter devices are also described below.

[0054] For non-dripping cutting / disassembly, an irreversible pinch-pipe type crimping solution 126 (e.g., NovaSeal (trademark) from EMD Millipore), a reversible pinch clamp 128, and / or heat welding can be implemented (the pinch pipe and pinch clamp are shown in FIG. 2(D)). Alternatively, other cutting devices can also be used (QuickSeal (registered trademark) disconnect (Sartorius), Clipster (registered trademark) aseptic disconnect (Sartorius), AseptiQuik (registered trademark) DC (Colder Products), HFC39 (Colder Products), HFC disconnect (Colder Products), Kleenpak (trademark) sterile disconnect (PALL), SeriesLock (trademark) (Eldon James), and Lynx (registered trademark) CDR (EMD Millipore), etc.). In previous pod designs, in order to create a liquid-tight seal between two adjacent flat seal gaskets and also to structurally support multiple pressurized pod filter devices (e.g., up to 50 PSI) during operation, it was necessary to apply a compressive force of up to 1000 PSI from a hydraulic pump attached to the pod holder. However, in the novel embodiments presented herein, there is no flat seal gasket, and an external pipe manifold is used to provide a liquid-tight seal between adjacent pod devices. As a result, the compression from the hydraulic pump is only used to provide structural support to the pressurized filter device 102, and thus, advantageously, there is no need to form a liquid-tight seal between two adjacent filter devices 102.

[0055] Figures 3A - 3C show a plurality of modular deep filter devices including alternative insert plates and alternative connectors according to embodiments of the present disclosure. Instead of the 90° elbow hose barb connector 104b, as shown in FIG. 3A, a straight hose barb connector 304a on a circular base portion 304b can be used. In some embodiments, the thickness of one insert plate 316 (or the total thickness of multiple insert plates 316) appropriately prevents kinking of a tube (not shown) connected to the straight hose barb connector 304a when the insert plate 316 is oriented upward, as shown in FIG. 3B. That is, in some embodiments, all or part of the tube is recessed within the through slot 318 of the insert plate 316, protecting the tube from contact with other components or materials that could cause damage. As shown in FIGS. 3B and 3C, various configurations of the insert plate 316 are possible by changing the layout of the slots 318. In FIG. 3B, the slots 318 direct the tube upward from all three ports. In FIG. 3C, as long as sufficient tube length is provided for each port, the end user is provided with several options for the tube layout from each port. For example, using slot 318d, the end user can direct the tube in three different directions. As shown, the tube can cross the plate 316 upward, leftward, and / or rightward.

[0056] Figures 4A - 4E show perspective views of a modular deep filter device including a second alternative insert plate, connectors, and blind end components according to embodiments of the present disclosure. Three 90° hose barb connectors 404b (FIG. 4B) and three blind end components 404a (FIG. 4E) are attached to a process scale pod (PSP). The PSP has an annular space 409 recessed around each opening 408 (FIG. 4A). The hose barb connector 404b or the blind end component 404a is attached to each opening 408, such as by spin welding. The backs of these components have rims 405a, 405b shaped to form a "butt weld" configuration for spin welding (as shown in FIG. 4E). Devices capable of spin welding these components include the VORTEX® PRECEDENCE™ servo - driven spin welder (Extol, Zeeland, Michigan) and the Servo Weld™ Plus Spin Welder (Dukane, St. Charles, Illinois). When the components are connected, other components are connected: a discharge filter (e.g., Gamma Phobic Opticap® XL50Express® SPG0.2 and Gamma Phobic Opticap® XL300Express® SPG0.2), a pre - cut tube (e.g., silicone or C - Flex®), a sterilization - sterilization connector (e.g., AseptiQuik® G (Colder Products), ReadyMate™ disposable sterilization connector (Cytiva), LYNX® S2S connector (EMD Millipore), KLEENPAK® Presto sterilization connector (Pall), and Pure - Fit® SC (Saint - Gobain)). The size (tube inner diameter) of the hose barb fitting 412 can range from 0.25 to 1 inch (about 6.3 to 25.4 cm). An insert plate 416 is also shown (FIG. 4D) and serves to stack a plurality of pods 402 within a pod holder rack (not shown).

[0057] Example of a Process Scale Pod (PSP) integrated with a hose barb connector Figures 5A and 5B each show at least one embodiment of a PSP 500 with an end plate 516a having three hose barb connectors 112 in fluid communication via a tube 114 for an inlet 508c, a vent 508b, and an outlet 508a, according to embodiments of the present disclosure. The PSP also includes a sterilization-sterilization connector 524 on the inlet 508c, a vent filter 510 on the vent 508b, and a sterilization-sterilization filter 524 on the outlet 508a. The second end plate 516b on the opposite side of the first end plate has no opening. In FIG. 4, an insert plate was utilized to protect the hose barb and tube connections from damage while the PSP device was compressed within a steel holder. Unlike the foregoing example of FIG. 4, since the hose barb connectors are located outside the end plate 516a, an insert plate 116 is not necessary, thereby reducing the installation area. In this embodiment, the hose barb and tube connections are not located in an area that would be damaged when the PSP device is compressed within a steel holder, and as a result, an insert plate between PSP devices is not required. Thus, during assembly, the holder approaches from a plane perpendicular to the plane of the face of the end plate 516a and avoids contact with the hose barb (or other) connectors attached on the outside as shown in FIGS. 5A and 5B. Instead of the hose barb connectors, a triclover or triclamps sanitary fitting can be placed on the end plate 516a.

[0058] Figures 6A - E show two embodiments of an end plate according to some embodiments of the present disclosure. Figure 6A shows an end plate 600 having a plurality of tube hose barb connectors 604a having an inner diameter of, for example, 0.5 inches, about 1.27 cm (according to embodiments of the present disclosure, other sizes such as inner diameters of 0.25 - 1.0 inches can be used). Figure 6B is an insert view of Figure 6C and shows a plate 602 having a hose barb connector 604b arranged to be in fluid communication with an integral port region 606, the hose barb connector 604b protruding from the plate 602. The hose barb connector 604b may be threaded into the end plate 602 or may be an integral part (i.e., cannot be removed without destroying the end plate 602). As shown in Figures 6D and 6E, the hose barb connector 604c is within a recessed region 608. The recessed region 608 protects the hose barb connector 604c. In some embodiments, the integrated hose barb connector 604b is permanently adhered, heat adhered, or injection molded as a single component to the recessed region 606. Some embodiments include both forms of hose barb connectors 604a, 604b. Instead of a hose barb connector, a triclover or triclammp sanitary fitting can be placed on the end plate 602.

[0059] To increase the area of the depth filter, a plurality of PSPs can be removably or permanently coupled using a manifold assembly. FIGS. 7A - 7C show some embodiments of three PSPs 102, 500 coupled using a manifold assembly according to embodiments of the present disclosure. The plurality of PSPs 102 can be coupled or pre - connected as shown in FIG. 7A and sterilized. The plurality of PSPs 500 can be coupled or pre - coupled and sterilized as shown in FIG. 7B, with three PSPs coupled as shown. In practice, two PSPs 102, 500 can be coupled, or more than 10 PSPs 102, 500 can be coupled. FIG. 7A shows a PSP 102 between a first insert plate 116 and a second insert plate (not shown) on the opposite side of the first insert plate 116 as described above. The three PSPs 102, 500 have an inlet 108a, an outlet 108c, and a vent 108b as described above. The inlet 108a terminates with a sterile - sterile connector 524, the vent port 108b terminates with a vent filter 510, for example, and the outlet port 108c terminates with a sterile - sterile connector 524. Each inlet from each of the plurality of PSPs 102, 500 is connected via a manifold 702. Similarly, each of the respective vent ports 108b and outlet ports 108c is connected via two separate manifolds 702. Each of the three manifolds can also terminate with a sterile - sterile connector 524. The embodiment shown in FIG. 7B is similar to the embodiment of FIG. 7(A), but further shows that an insert plate, such as insert plate 116, is not required. The hose barb protrudes from the side of the PSP 500. Alternatively, the individual PSPs 102, 500 having sterile - sterile connectors 524 can be sterilized, in which case the operator couples them to a separate sterilized manifold 722 assembly as shown in FIG. 7C. In general, it should be understood that the end plate is an integral part of the PSP. The insert plate is a separate component removably coupled to the PSP and functions as a spacer.

[0060] Some embodiments within the present disclosure enable a closed process for clarification using a pre-sterilized or bio-burden reduced depth filter device. Some embodiments within the present disclosure enable a closed process for other unit operations such as virus filtration or purification. Some embodiments provide individual filter device units or modules (modular depth filter devices) with pre-attached tubes and connectors; individual filter device modules that can be shipped, handled, and sterilized; multiple filter device modules that can be aseptically connected and disconnected using sterilization connectors, cutting devices, insert plates, and manifolds; and / or easy placement of tubes and manifolds with various insert plate designs. Practical advantages for manufacturers include minimal or no changes to currently available process scale pods; reusable insert plates; and use of existing pod holders.

[0061] Multi-part holder hardware with a handcart for a pre-assembled filter device The pre-connected pod filter format involves a relatively small number of sterile-sterile connections performed by an operator. The pre-connected format is heavy (e.g., >50 pounds, about 23 kg). FIGS. 8A and 8B show an assembly of at least one approach for coupling a plurality of filter devices according to some embodiments of the present disclosure. FIG. 8A shows an embodiment in which a pre-connected pod device is loaded onto a handcart and the holder hardware has two separate parts, side A and side B. Using this cart enables short-distance transport within the biomanufacturing suite without using a forklift, crane, or hoist. The holder hardware 800 is shown in FIG. 8(A) and is designed to individually load each process scale pod as described herein. The holder hardware 800 includes a pressure gauge 802, a hydraulic pump 804, a clamp rod 808, a frame 810, and platens 812a, 812b, with a space S disposed therebetween to accommodate a plurality of filter devices for compression. The plurality of filter devices can be the device 102, 500, 820, and all other filter devices described herein. In FIG. 8B, according to an embodiment of the present disclosure, the holder hardware 800 has two platens 812a, 812b, and a plurality of pre-connected PSP devices are loaded onto an empty cart 816a to form a full cart 816b. The number of pre-connected PSPs 820 depends on the desired application and / or the layout of the facility. For example, if the depth of the material airlock in a biopharmaceutical production facility is 44 inches (e.g., the depth range of the airlock is 44 inches to 72 inches (about 111 cm to 183 cm); see, e.g., https: / / www.terrauniversal.com / cleanroom-airlocks.html) and the thickness of each filter device is about 4.8 inches (12.2 cm), for example, up to 10 devices can be combined and introduced into the biomanu facturing suite. When a multi-rack approach is used, more PSPs 102, 500, 820 can be pre-combined and loaded onto the cart 816b. FIGS. 9A and 9B show multi-racks of process scale pods according to some embodiments of the present disclosure.For example, as shown in FIG. 9A, a single rack (A) of PSPs 102, 500, 820 is shown in an exploded view on cart 816b between pressure platens 812a and 812b. In FIG. 9B, a double rack (B) consisting of two stacks of PSPs 102, 500, 820 is shown on cart 816b between two higher platens 812a, 812b. In some embodiments, three or four stacks of PSPs 102, 500, 820 are stacked on cart 816b, i.e., a total of 30 - 40 PSPs 102, 500, 820 are loaded on a single cart 816b. The PSPs 102, 500, 820 can be of laboratory scale configuration, i.e., one PSP 102, 500, 820; pilot scale, e.g., two to ten PSPs 102, 500, 820 coupled to be in fluid communication with each other; process scale configuration, i.e., fifteen to forty PSPs 102, 500, 820 in fluid communication (five to ten PSPs 102, 500, 820 are coupled and in fluid communication, i.e., in a pilot scale configuration and stacked with other similar pilot scale configurations). Such a modular and flexible format allows for pre - filtration and / or clarification of fluids, for example, from 5L to 15,000L, while reducing the installation area and as required by the process.

[0062] Filter device pre-assembled in a container made of a rigid base and a plastic film In some embodiments, a plurality of filter devices 102, 500, 820 form a pre - coupled configuration, and the sterile barrier can be created using a rigid base (e.g., a base made of LDPE, HDPE, ABS, nylon) and a polymer / plastic film (e.g., LDPE, a copolymer of LDPE, a composite film such as a PureFlex™ film and / or an ULTIMUS® film (both sold by EMD Millipore of Billerica, Massachusetts, USA, and are laminated films with a woven or non - woven substrate), and a layer of LDPE, ethylene vinyl acetate, ethylene vinyl alcohol, and / or other polymers suitable for bioprocesses). FIG. 10 shows at least one embodiment of a container 1000 including two rigid bases A, B and a plastic film 1008, and only one hose barb of the pod is shown for illustration. The plastic film 1008 seals the PSPs 102, 500, 820 from the environment, e.g., air - tightly. In some embodiments, the plastic film 1008 seals the rigid bases A and B at both of its ends as shown in FIG. 10. These seals can be formed by means known in the art such as heat welding. One of the rigid bases (side A) has a protruding hose barb fitting 1012, which is connected to a tube 1014 and a connector 1016, e.g., a sterile - sterile connector. The plurality of PSPs 102, 500, 820 have seals 1006 disposed between each of the PSPs 102, 500, 820.

[0063] Figure 11 shows a container 1100 having a plastic film 1108 joined by heat welding, adhesion, or other means to at least a portion of the perimeter of rigid bases A and B, optionally including an overhang 1110. Rigid base A includes alignment keys 1106 and a hose barb connector 1104. Rigid base B includes alignment keys 1106. Each PSP 102, 500, 820 has at least one alignment key mechanism 1106 on an end plate (see the "L" or "R" side in FIGS. 6A - 6B), and the stainless - steel end plates of the holder hardware also have at least one alignment key function, as described above. The alignment key mechanism 1106 is present on both the front and back sides of each rigid base A and B so as to be aligned with the end plates of the pod and the holder. FIG. 11 shows the location of the alignment keys 1106 present on both sides of each rigid base. The plurality of sterilization - sterilization connectors 1112 of FIG. 12 are attached at three locations of the hose barb connector 1104. The container 1100 is heat - sealed by folding the overhang 1110 to the top of the assembly and forming a pre - joined pod 1200, for example, using an impulse heat sealer having PSPs 102, 500, 820. Alternatively, the sterilization - sterilization connectors 1112 can be releasably joined or attached after the container 1100 has been heat - sealed by the film 1108. Further, straps or banding 1114 can be used to further stabilize or hold the contents within the container 1100. The rigid bases A and B may further include grooves (not shown) to facilitate the placement of the strap bands.

[0064] FIG. 12 shows a plurality of PSPs 102, 500, 820 enclosed within a container 1200 according to some embodiments of the present disclosure. The plastic film overhang 1110 of FIG. 11 is heat sealed after a plurality of filter devices or PSPs 102, 500, 820 are loaded. FIG. 13 shows a plurality of PSPs 102, 500, 820 enclosed within a container 1200 disposed on a cart 816a according to some embodiments of the present disclosure. The plastic film overhang 1110 is heat sealed after a plurality of filter devices or PSPs 102, 500, 820 are loaded. The pre-coupled pod 1200 can be loaded onto the handcart 816a. Optionally, the loading of the pre-coupled pod 1200 into the container 1100 can be performed after the container 1100 is pre-loaded onto the cart 816a. The handle 818 can be disposed after the container 1100 is sealed and secured with straps. The cart 816a and the container 1100 can be integrated to make the entire assembly disposable, or, for example, if the container 1100 is separated from the cart 816a after use, the cart 816a can be reusable. Next, the cart 816a having the PSPs 102, 500, 820 can be delivered between a pressure platen 812a and a pressure platen 812b to provide pressure during operation (FIG. 14A).

[0065] In some embodiments, multiple aseptic connections are made between the depth filter devices 102, 500, 820. The depth filter devices include, but are not limited to, other flat sheet filtration cassette devices such as MILLISTAK+(R) HC Pods, MILLISTAK+(R) HC Pro Pods, CLARISOLVE(R) Pods from EMD Millipore, or SARTOCLEAR(R) Depth Filters from Sartorius Stedim. The aseptic connection can be made using a "connector plate" component. For example, the connector plate may include a female coupling. In some embodiments, the female coupling is of the LYNX(R) S2S style from EMD Millipore. Each pod or depth filter device may have male couplings, such as LYNX(R) S2S style male couplings, at six openings (two for inlets, two for venting, and two for outlets). A sterilization-sterilization connection device, such as a connector of the type described in U.S. Patent No. 7,137,974, the entire disclosure of which is incorporated herein by reference, and, for example, the connector shown in FIGS. 3, 4, and / or FIG. 5 of U.S. Patent No. 7,137,974, may be used.

[0066] FIGS. 14A and 14B show the rigid bases A, B of FIGS. 12-13, further including a clamp rod, according to an embodiment of the present disclosure. The rigid base A includes an alignment key 1106 and a hose barb connector 1104. The hard base B includes an alignment key 1106. As shown in FIG. 12, a plurality of filter devices or PSPs 102, 500, 820 are loaded. The alignment key mechanism 1106 is present on both sides of each rigid base A, B so as to be aligned with the end plates of the pod and the holder. A plurality of sterilization-sterilization connectors 1112 are attached at three locations of the hose barb connector 1104.

[0067] In some embodiments, a cart 816a and two platens 812a, 812b are provided, with a space therebetween for compressing a plurality of filter devices disposed therebetween. The platens 812a and 812b include rails 1406a, 1406b. The rails 1406a, 1406b facilitate alignment with the cart 816a. The two platens 812a, 812b are brought together and aligned with the cart 816a sandwiched therebetween. Optionally, the cart 816a includes grooves (not shown) for disposing the rails 1406a, 1406b. Also optionally, the platens 812a, 812b optionally include casters 1410. The clamp rod knob 1402 and the clamp rod 1404 are installed separately. The hydraulic pump 804 is installed within or on one side of the platens 812a, 812b and is used to compress the device and optionally the gasket within the assembly to establish a seal between the gaskets. Each of the two platens 812a, 812b has three, for example, circular openings 1412 for an inlet connector, a vent connector, and an outlet connector. For example, a sterilization-sterilization connector and a tube pass through the opening 1412. Alternatively, the shape of each opening 1412 may be a slot (similar to those shown in FIGS. 1-4) such that only the tube, rather than the entire cross-section of the sterilization-sterilization connector, needs to pass through the slot. The pre-coupled pod described in the present disclosure can be sterilized or have its bioburden reduced, for example, by gamma irradiation, X-rays, or electron beam (e-beam) / beta ray irradiation. However, when using a gas-based sterilization method such as ethylene oxide, vaporized hydrogen peroxide, nitrogen dioxide, vaporized peracetic acid, or steam (under controlled conditions), the container requires a vented area through which the sterilizing gas / vapor can penetrate and be quickly discharged.

[0068] Figures 15A and 15B respectively show a schematic view and a perspective view of a container 1100 further including a spacer between pods 102, 500, 820 according to an embodiment of the present disclosure. FIG. 15A is a simplified schematic view showing the main features of the embodiment. These include a plurality of PSP devices, an outer plastic film, an end plate (rigid base), an adapter, and the seals described. FIGS. 15A-15B show a container system 1500, where a plastic film 1108 (e.g., LDPE, PureFlex (trademark) film, and ULTIMUS (registered trademark) film manufactured by EMD Millipore) is arranged on three sides, a TYVEK (registered trademark) film 1506 is arranged on one side (e.g., the upper surface), and a clip 1502 is removably coupled to a rigid base A via a spacer or cushion component 1504, attached therebetween, creating a space 1512 for the entry and exit of sterilizing gas / vapor. For example, two rigid bases A, B and a plastic film 1008, a tube 1014 and a connector 1016, such as a sterilization-sterilization connector, a container including the same, and the PSPs 102, 500, 820 shown in FIG. 10 can be used with the container system 1500. The clip 1502 is typically removable, arranged during sterilization, and removed during the attachment of two platens 812a, 812b. A sealed pod with a piping manifold according to some embodiments is shown. The sealed pod / filter device can be seen, for example, as FIG. 15 from International Publication No. WO 2020 / 036869, the entire disclosure of which is incorporated herein by reference.

[0069] In some embodiments, rigid bases A, B and polymer film 1008 (e.g., LDPE, PureFlex™ film, and ULTIMUS® film from EMD Millipore) are used to construct a container as shown in FIG. 10. In some embodiments, the container can be made of a polymer film with other components including a hose barb adapter, a blind end cap adapter, and an end plate as shown in FIG. 16. FIG. 16 shows a container system 1500 as described above, enclosed in a polyfilm 1008 that further includes at least one hose barb 1602 and one blind end cap adapter 1604. FIG. 17 shows an exploded view of a plurality of PSPs 102, 500, 820, two support plates, connectors, and snap fit adapters. As shown in FIG. 17, each end plate 1702, 1704 has at least one groove 1706 for receiving a tie band as described above. The groove 1706 has a function similar to that of the rigid bases A, B as shown in FIG. 11. Each hose barb 1712 / blind end cap adapter 1710 has a gasket 1708 and a snap fit connection 1714 to facilitate placement within each opening 1718 of a filter device, e.g., PSPs 102, 500, 820. An optional tube 1716 for connecting the hose barb 1712 to a sterile connector 1720 is also shown.

[0070] Figure 18 shows the assembled container 1800 of the exploded view of FIG. 17 according to some embodiments of the present disclosure, further including a strap 1814. The assembled container 1800 is typically sterilized and maintained in a sterile state while inside the polybag 1808. As shown in FIG. 18, all three hose barb adapters 1712 are disposed on one side of the end plate 1702, and three blind end cap adapters are disposed on the opposite side of the end plate 1704 (not shown). In some embodiments, two hose barb adapters (for inlet and vent) and one blind end cap adapter (for outlet) are disposed on one side, while one hose barb adapter (for outlet) and two blind end cap adapters are disposed on the other side.

[0071] In FIG. 18, a plastic or polyfilm 1008 as a sterilization barrier surrounds all components including the sterilization-sterilization connector 1720. As described above, when the handcart is loaded with the filter device pre-assembled in the polybag container 1808 as shown, it can be combined with the two platens 812a, 812b as in FIG. 14. As described above, when the handcart is loaded with the filter device pre-assembled in the polybag container 1808 as shown, it can be combined with the two platens 812a, 812b as in FIG. 14. As described above, two clamp rods can be installed to engage the two platens 812a, 812b and the cart (not shown). When the device is compressed using a hydraulic pump, the gasket components engage to form a liquid-tight seal between two adjacent PSPs 102, 500, 820 and between the adapter components and the PSPs 102, 500, 820. At some point, three protruding regions in the polybag container 1808 are cut open to expose the sterilization-sterilization connector. Opening the polybag container 1808 at this point does not compromise the sterility of the PSP assembly because a liquid-tight seal has already been formed by the compression of the PSP generated by the hydraulic pump.

[0072] Figures 19A, 19B, and 19C show front views of three embodiments of pods 102, 500, 820 contained in plastic bags. Three different embodiments of plastic bags or containers 1808 according to embodiments of the present disclosure are shown in FIGS. 19A - 19C. FIG. 19A is the same as that of FIG. 16, that is, the container system 1500 is completely enclosed within the plastic bag 1808. FIG. 19B shows a second embodiment in which support plates such as end plates 1702, 1704 are outside the plastic bag 1808. FIG. 19C shows an embodiment of the container system 1500 without a support plate. For ease of explanation, only one hose barb 1602 of each container constituting the PSPs 102, 500, 820 is shown. Cushioning materials and foaming materials (e.g., polyethylene closed-cell foam, expanded polyethylene (EPE) foam, polystyrene foam, polyurethane foam, other continuous-cell and / or closed-cell foamed polymer materials, etc.) are optionally placed at locations where the plastic film contacts the hard surfaces of the device to prevent film breakage and damage.

[0073] Cart with a filter device and a manifold assembly pre-assembled The above-described pre-assembled filter device may be enclosed in a container and loaded onto a cart. Some embodiments according to the present disclosure are shown in FIG. 20, and a device configuration having the five PSPs 102, 500, 820 and manifold 722 described above is loaded onto a cart 816b having a handle 818. The individual devices are connected by a manifold set. To disconnect / decompose these devices without dripping, an irreversible pinch pipe type crimping solution (such as NovaSeal™), a reversible pinch clamp, and / or thermal tube welding can be implemented (an example of a pinch pipe and a pinch clamp is shown in FIG. 2(D)). Alternatively, other cutting devices (such as QuickSeal (Sartorius), Clipster Asetic Disconnector (Sartorius), AseptiQuik DC (Colder Products), HFC39 (Colder Products), HFC Disconnect (Colder Products), Kleenpak Sterile Disconnector (PALL), SeriesLock (Eldon James), and Lynx® CDR (EMD Millipore)) can also be used. With these functions, each device can be individually discarded in a way that is free of droplets. The manifold assembly is made of sterilizable-sterile connectors, tubes, tees, reducers, and / or 90° elbow connectors.

[0074] For operations where the maximum operating pressure is limited to less than 30 PSI, a simplified holder device 2100 with end support plates 1702, 1704 can be used without a hydraulic pump (as described above). FIGS. 21A - 21D show a plurality of pods in various installed states within the holder device according to some embodiments of the present disclosure. For example, in FIGS. 21A - D, carts such as cart 816b are loaded with pre - coupled filter devices 102, 500, 820. Cart 816b has side walls 2102a, 2102b, 2102c that can be opened (or removed) by hinges or living hinges 2104, a portion of which is open during the attachment of end support plates 1702, 1704 and clamp rod 808. Side walls 2102a and 2102c can be closed during the filtration operation. For clarity, the upper wall is not shown. Optionally, it is to be understood that an upper part may be included and may be closed by side walls 2102a, 2102b, and 2102c. When the filtration operation is complete, end support plates 1702, 1704 and clamp rod 808 are removed and filter devices 102, 500, 820 can be discarded. Cart 816b may be disposable or reusable multiple times. FIG. 21A shows cart 816b with filter devices 102, 500, 820 placed thereon. As shown, there are five filter devices 102, 500, 820, but any suitable number of filter devices 102, 500, 820 can be used. The manifold 722 coupled to the filter devices or pods 102, 500, 820 as described above can extend through side wall 2102b at window 2106. Then, the simplified holder device 2100 can be moved to, for example, a clean room or other suitable location. Optionally, two stoppers 2108 are also shown, which are disposed between the filter devices and side walls 2102a and 2102b and hold filter devices 102, 500, 820 in place during transportation. FIG. 21B shows the simplified holder device 2100 with filter devices 102, 500, 820 housed therein, with side walls 2102a and 2102c open. At this step, stoppers 2108 are removed.Figure 21C shows a simplified holder device 2100 that includes filter devices 102, 500, 820 inside, with side walls 2102a and 2102c open and end support plates 1702, 1702 and clamp rod 808 attached. Figure 21D shows a simplified holder device 2100 that includes filter devices 102, 500, 820 inside and has end support plates 1702, 1702 and clamp rod 808 attached, where side walls 2102a, 2102b, and 2102c are closed and ready for the filtering operation.

[0075] Connector plate approach Figures 22 - 26 show the steps for making a sterile connection between filter devices or pods. The process of making a sterile connection between a pod and a filter device using a fluid transfer device 2200, such as a connector or a sterilizing connector, is described in Figures 22 - 26 below. These figures show how the connector plate 2250 and the pods 102, 500, 820 are connected step by step. In Figures 22A and 22B, the connectors 2250 and two coupling devices 2256, 2258 are shown in an unassembled closed state. The coupling devices may already be connected to another component (not shown) via a second opening 2270 and a stem 2266 (shown below in Figure 27) and may be sterilized, for example, by gamma or X-ray irradiation, ethylene oxide, steam, or a gas such as a gas.

[0076] A connector plate 2250 is provided. The connector plate 2250 has three handles 2280 (only one handle is shown for ease of explanation, see FIG. 22B). Each connector plate 2250 can accommodate six sterilization plugs 2260 that are loaded into the recesses of the connector plate 2250. The pods 102, 500, 820 and the connector plate 2250 are aligned, and male couplings, such as coupling devices 2256, 2258 and sleeve components, are introduced into each recess within the connector plate 2250. Then, any lock tabs / sleeve covers can be removed (FIGS. 23A, 23B). The male couplings are further inserted into the recesses until each sterilization plug is fully engaged within the hollow space in the handle (FIGS. 24A, 24B). Each handle has two hollow spaces for receiving the sterilization plugs. An example of a handle is described in FIG. 4 of U.S. Patent No. 7,137,974 and is also shown at the lower left of FIG. 24B. When the sterilization plugs occupy the hollow spaces, as shown in FIGS. 25A, 25B, each handle is pushed down to move the sterilization plugs away from the sterile fluid path. Then, as shown in FIGS. 26A, 26B, the male couplings within the pod engage with the female couplings within the connector plate to establish a sterile fluid path. At this point, the pod and the connector plate are in contact with each other. In FIG. 22B, male connectors, such as blind end connectors and LYNX® S2S style connectors, are disposed at the ends of the connector plate, respectively. In some embodiments, both sides have male connectors for establishing a flow path with an external sterilization system, such as the piping manifold described above.

[0077] In FIG. 23A, the coupling devices 2256, 2258 are attached to the connector 2250 by fitting the first ends of the coupling devices 2256, 2258 into the first and second openings 2290 (FIG. 22) of the connector 2250, respectively. This can be a friction fit or an interference fit. Alternatively, there may be a more secure fitting between the components to ensure that the components stay together and the sterile state is maintained. To make such a secure connection, fitting screws, snap connections, movable claws, etc. can also be used. As shown in FIG. 27, the coupling device uses a plurality of nubs 2291 that lock into corresponding grooves 2292 to make this connection. Optionally, the connector 2250 and the coupling devices 2256, 2258 are locked to each other so as not to accidentally come off. In some embodiments, the mutual locking of the components is irreversible to ensure single use.

[0078] In FIGS. 24A and 24B, each stem 2266 (also shown in FIG. 27 below) is moved towards the connector 2250 to move the sterile plug 2260 of each coupling device 2256, 2258 into the first opening 2274 of the port 2272. In FIGS. 25A and 25B, the port 2272 (see FIG. 27) is moved to a second position, and a fluid path and fluid communication are formed between the two connecting devices 2256, 2258. In FIGS. 26A and 26B, the stem 2266 is moved to a fully open position and seals with each other.

[0079] Figure 27 shows a fluid transfer device 2200 including a connector 2250 for making connections between pods, according to some embodiments of the present disclosure. Connector 2250 has a first opening 2252 and a second opening 2254, and two coupling devices 2256 and 2258, respectively. Each of these coupling devices includes a sterilization plug 2260 within a first opening 2262 of a coupling body 2264, and a stem 2266 that extends outside a second opening 2268 of the body 2264 within the body 2264. Each stem 2260 extending from the second opening of the body 2264 has a second opening 2270 that is connected to another component that can already be sterilized. Figure 27 shows a representative type of sterilization-sterilization connector technology described in U.S. Patent No. 7,137,974, the disclosure of which is incorporated herein by reference.

[0080] Port 2272 is in the form of a slide that fits within the body of connector 2250. Port 2272 can be in at least two positions, a closed position and an open position. This also includes a first opening 2274 and a second opening 2276. To ensure sterility, a surrounding seal 2278 is disposed around opening 2276. The illustrated port 2272 also has an actuating device 2280 in the form of a handle in some embodiments. The handle 2280 in this embodiment also includes a latch 2282 that is used to lock port 2272 in the open position when actuated. As illustrated, the actuating device 2280 is a push handle, but in some embodiments, the actuating device is a pull handle.

[0081] The first opening 2274 of port 2272 in this embodiment is formed by two recesses 2284, 2286, each recess having a wall 2288 between the two recesses 2284, 2286 and facing each of the first and second openings of connector 2250. Optionally, some embodiments of connector 2250 in this embodiment include a sterilization barrier plug.

[0082] In some embodiments, a sealed pod may be provided that allows for droplet-free decomposition. For example, FIG. 28 shows a pod having end caps modified to have one or more holes or eyelets 2800 (four are shown at the top of each end cap and one is shown on the side of each end cap) configured and arranged to receive respective tie rods 2802. A gasket 2803 that seals each port needs to be compressed symmetrically to avoid accidental breakage of the closed device.

[0083] As shown in FIGS. 29A and 29B, a deployable plug or seal 2810, such as expanded foam or a foam (e.g., expanded insulation foam), can be inserted into the T-port 2805 of the pod using one or more applicators 2811 (two are shown in FIG. 30). Geometric features (not shown) may be molded or otherwise introduced into the T-port 2805 to assist in the placement and alignment of the applicators. Thus, in certain embodiments, the filtration system includes two or more depth filtration devices (each depth filtration device including an inlet port, a vent port, a filtration media region or zone, and an outlet port); a midplate between each pair of depth filtration devices to provide appropriate spacing for radial seal components such as TC tees and gaskets; a fluid inlet line and a sterilization-to-sterilization (S2S) connector that can be connected adjacent to the tee of the inlet radial seal TC adjacent to the two depth filtration devices, or is connected; a fluid discharge line and a sterilization-to-sterilization (S2S) connector that can be connected adjacent to the T-adjacent of the discharge radial seal TC adjacent to the two depth filtration devices, or is connected; a fluid outlet line and a sterilization-to-sterilization (S2S) connector that can be connected adjacent to the tee of the outlet radial seal TC adjacent to the two depth filtration devices, or is connected; and one or more tie rods 2802 and / or straps for holding the depth filtration devices together and maintaining the integrity of the environmental seal between the devices. After the filtration operation is complete and before disassembling the system, the fluid inlet / vent / outlet lines can be removed from adjacent to the tee of the corresponding radial seal TC, and a foam, rayon, foam / sponge (e.g., polyurethane, polyether, polyester, and / or cellulose), or other absorbent plug / sealing material 2810 can be deployed into each radial seal TC tee via compressed air, aerosol, propellant, and / or mechanical operation, and the depth filtration ports can be plugged / sealed using one or more applicators 2811 as shown in FIGS. 29B and 30. The volume of the plugging / sealing material 2810 is from 1 to 5 cubic inches (about 16.4 to 81.9 cm 3) forms the range. The applicator 2811 can be molded or constructed from a thermoplastic material such as polyethylene, polypropylene, polyamide, and / or polycarbonate. The double applicator 2811 can be used to simultaneously deploy the plug / seal material 2810 to both deep filtration devices (Figure 30). The radial seal TC tee can include features to assist with the placement and / or alignment of the applicator. After the plug / seal 2810 has been properly deployed and the individual devices are fully plug / sealed, the radial seal TC tee can be removed and the disassembly of the system can proceed without dripping.

[0084] As illustrated in FIGS. 31 and 32, by using an integrated valve, droplet-free decomposition of a closed pod can also be provided. Thus, in certain embodiments, the filtration system includes two or more depth filtration devices (each depth filtration device includes an inlet port with an integrated valve, a discharge port with an integrated valve, a filtration media region or zone, and an outlet port with an integrated valve); an intermediate plate between each pair of depth filtration devices to provide appropriate spacing for radial seal components such as TC tees and gaskets; a fluid inlet line and a sterilization-to-sterilization (S2S) connector that can be connected to or are connected to an inlet radial seal TC tee adjacent to two deep filtration devices; a fluid discharge line and a sterilization-to-sterilization (S2S) connector that can be connected to or are connected to a discharge radial seal TC tee adjacent to two deep filtration devices; a fluid outlet line and a sterilization-to-sterilization (S2S) connector that can be connected to or are connected to an outlet radial seal TC tee adjacent to two deep filtration devices; and one or more tie rods and / or straps for holding the two deep filtration devices together and maintaining the integrity of the environmental seal between the devices. The inlet port / vent port / outlet port can incorporate an integrated valve device such as a butterfly valve 2820, a backdraft / damper valve 2825, and / or a check valve 2830 as shown in FIGS. 31 and 32. The backdraft / damper and check valves are automatically operated and close at the end of the filtration operation when the fluid pressure and flow rate are gone, sealing the ports of the device. The butterfly valve can be manually operated via an external actuation (lever, switch, dial, etc.) to seal the ports of the device after the filtration operation is complete and before disassembling the system. After all valves are properly closed and the individual devices are fully sealed, the radial seal TC tees can be removed and the system can be disassembled in a droplet-free manner.

[0085] The number of sterilization connectors and sterilization connectors can be significantly reduced. For comparison, FIG. 33 shows a closed three-pod system that requires 24 sterilization-sterilization connectors. A filtration system 3000 is shown comprising three depth filtration devices 3001, 3002, 3003 and three piping manifolds 3010, 3011, 3012, each filtration device including an inlet port (i), a vent port (v), a filtration media zone, and an outlet port (o). The inlet port (i) is fluidly connected to the vent port (v). A fluid inlet line 3005 and a sterilization-sterilization (S2S) connector 3007 are connectable or connected to the respective inlet ports 3005 of the three depth filtration devices. A fluid discharge line 3004 and a sterilization-sterilization (S2S) connector 3007 are connectable or connected to the respective vent ports (v) of the three depth filtration devices. A fluid outlet line 3008 and a sterilization-sterilization (S2S) connector 3007 are connectable or connected to the respective outlet ports (o) of the three depth filtration devices. The piping manifolds 3010, 3011, 3012 include tubes and four sterilization-sterilization connectors 3017. The first piping manifold 3010 is connectable or connected to the supply flow process piping by an S2S connector 3017.The fluid inlet line 3005 of the first depth filtration device 3001 can be connected to or is connected to the first pipe manifold 3010 by an S2S connector; the fluid inlet line of the second depth filtration device 3002 can be connected to or is connected to the first pipe manifold 3010 by an S2S connector; the fluid inlet line 3005 of the third depth filtration device 3003 can be connected to or is connected to the first pipe manifold 3010 by an S2S connector; the fluid discharge line 3004 of the first depth filtration device 3001 can be connected to or is connected to the second pipe manifold 3011 by an S2S connector; the fluid discharge line 3004 of the second depth filtration 3002 device can be connected to or is connected to the second pipe manifold 3011 by an S2S connector; the fluid discharge line 3004 of the third depth filtration device 3003 can be connected to or is connected to the second pipe manifold 3011 by an S2S connector; the second pipe manifold 3011 can be connected to or is connected to a ventilation device (for example, a Millipak+(registered trademark) barrier filter) not shown by an S2S connector; the fluid outlet line 3008 of the first depth filtration device 3001 can be connected to or is connected to the third pipe manifold 3012 by an S2S connector; the fluid outlet line 3008 of the second depth filtration device 3002 can be connected to or is connected to the third pipe manifold by an S2S connector; the fluid outlet line of the third depth filtration device 3003 can be connected to or is connected to the third pipe manifold 3012 by an S2S connector; and the third pipe manifold 3012 can be connected to or is connected to a feed stream collection bag (not shown) by an S2S connector. This closed filtration system of this figure requires 24 sterile connectors.

[0086] Figure 34 shows an embodiment in which the number of sterilization-to-sterilization (S2S) connectors can be reduced to save costs. Although three pod manifolds are illustrated, those skilled in the art will understand that different numbers of pods can be used. In the illustrated embodiment, there is a filtration system 4000 that includes three depth filtration devices 4001, 4002, 4003 and one piping manifold 4010. Each of the filtration devices includes an inlet port (i), a vent port (v), a filtration media zone, and an outlet port (o), and the inlet port (i) is in fluid communication with the vent port (v). There are sterilization-to-sterilization (S2S) connectors that can be connected to or are connected to the inlet port (i) of each of the three depth filtration devices and the fluid inlet lines 4005, 4005', 4005". The fluid discharge lines 4004, 4004', 4004" and the sterilization-to-sterilization (S2S) connector 4007 are connected to the vent port (v) of each of the three depth filtration devices. The fluid outlet lines 4008, 4008', 4008" and the sterilization-to-sterilization (S2S) connector 4007 are connected to the outlet port (o) of each of the three depth filtration devices 4001, 4002, 4003. The piping manifold 4010 includes a tube and four sterilization-to-sterilization connectors 4017. The fluid inlet line 4005 of the first depth filtration device 4001 can be connected to or is connected to the supply flow process tube 4020 by the S2S connector 4007. The supply flow process tube 4020 is connected to the first depth filtration device 4001 through the fluid inlet line 4005 by the sterilization-to-sterilization connector 4007.The fluid inlet line 4005’ of the second depth filtration device 4002 is attached to the fluid discharge line 4004 of the first depth filtration device 4001 by an S2S connector 4007; the fluid inlet line 4005” of the third depth filtration device 4003 is attached to the fluid discharge line 4004’ of the second depth filtration device 4002 by an S2S connector 4007; the fluid discharge line 4004” of the third depth filtration device 4003 can be or is attached by an S2S connector 4007 to an air discharge device (e.g., Millipak+(registered trademark) barrier filter) (not shown); the fluid outlet line 4008 of the first depth filtration device 4001 is attached to an outlet piping manifold 4010 by an S2S connector; the fluid outlet line 4008’ of the second depth filtration device 4002 is attached to the outlet piping manifold 4010 by an S2S connector; and the fluid outlet line 4008” of the third depth filtration device 4003 is attached to the outlet piping manifold 4010 by an S2S connector; the outlet piping manifold 4010 can be or is attached by an S2S connector 4017 to a supply flow collection bag (not shown); the illustrated closed filtration system requires 16 sterile connectors.

[0087] Figure 35 shows another embodiment that can save costs by reducing the number of sterilization-sterilization (S2S) connectors. Although three pod manifolds are illustrated, those skilled in the art will understand that different numbers of pods can be used. In the illustrated embodiment, a filtration system 5000 is shown that includes three depth filtration devices 5001, 5002, 5003, each device including an inlet port (i), a vent port (v), a filtration media zone, and an outlet port (o). The inlet port (i) is fluidly connected to the vent port (v); the fluid inlet lines 5005, 5005', 5005" and the sterilization-sterilization (S2S) connectors are connectable to or are connected to the respective inlet ports of the three depth filtration devices; the fluid vent lines 5004, 5004', 5004" and the sterilization-sterilization (S2S) connector 5007 are connected to the respective vent ports of the three depth filtration devices; the fluid outlet lines 5008, the T-connector (t) having a first connection point and a second connection point, are attachable to or are attached to the respective outlet lines 5008 of the three depth filtration devices, and at the respective outlet ports of the three depth filtration devices, two sterilization-sterilization (S2S) connectors 5007 are connectable to or are connected to the T-connector (t). The fluid inlet line 5005 of the first depth filtration device 5001 is connected to or is connectable by an S2S connector 5007 to the supply flow process tube 5002. The supply flow process tube 5020 is connected by a sterilization-sterilization connector 5007 to the first depth filtration device 5001 via the fluid inlet line 5005. The fluid inlet line 5005' of the second depth filtration device 5002 is attached by an S2S connector 5007 to the fluid discharge line 5004 of the first depth filtration device 5001. The fluid inlet line 5005" of the third depth filtration device 5003 is attached by an S2S connector 5007 to the fluid discharge line 5004' of the second depth filtration device 5002; and the fluid discharge line 5004" of the third depth filtration device 5003 is connectable to or is connected by an S2S connector 5007 to an air discharge device (e.g., a Millipak+(registered trademark) barrier filter) (not shown).The first connection point of the T-connector (t) of the first depth filtration device 5001 is attached to the dead-end plug 5030. The second connection point of the T-connector (t) of the first depth filtration device 5001 is attached to the first connection point of the T-connector (t) of the second depth filtration device 5002 by the S2S connector 5007; the second connection point of the T-connector (t) of the second depth filtration device 5002 is attached to the first connection point of the T-connector (t) of the third depth filtration device 5003 by the S2S connector; and the second connection point of the T-connector (t) of the third depth filtration device 5003 is attached to a supply flow collection bag (not shown) by the S2S connector. The exemplary closed filtration system requires 16 sterile connectors.

[0088] In some embodiments, the closed processing device can be achieved by using angled barb fittings. For example, FIGS. 36A and 36B show a depth filtration device with an inlet port, a vent port, and an outlet port, and angled fittings 125, 126, and 127 fluidly connected to each port (in FIG. 36B, to each sterile connector 130). FIGS. 37A and 37B show a similar embodiment in a membrane adsorption chromatography device that does not require a vent port. The appropriate angle of the angled fitting forms an angle of from about 0 degrees to about 90 degrees, preferably from about 20 degrees to about 60 degrees.

[0089] FIGS. 38A, 38B, and 38C show an embodiment in which the inlets of each filtration device (pod 1, pod 2, pod 3) are fluidly connected (i.e., connected in fluid communication) to a multi-branched manifold 6010 having branches 6011, 6012, 6013 of different lengths. In some embodiments, as shown, the lengths of the branches gradually decrease as 6011, 6012, 6013 towards the free end 6015 of the manifold. The stepwise decrease can be linear or non-linear.

[0090] FIG. 39A shows an embodiment that minimizes the thickness of a plurality of stacked pods. In the illustrated embodiment, there are three locations on the right side (R) of the pod where hose barb fittings 125, 126, 127 are present. When a plurality of filtration devices are stacked, the right side (R) contacts the left side (L) of the opposite side of the adjacent pod. On the right side (R) of the pod, each region 135 around the hose barb fitting is configured convexly and can be received or is received by the corresponding region 136 on the left side (L) configured concavely (FIG. 38B). These convex and concave regions create a mating strategy, reducing the thickness of the right side (R) cap compared to an assembly where such a mating strategy is not employed. As the thickness of the end cap decreases, the overall thickness of the device decreases, allowing more filter devices to be used within the limited space of the holder hardware.

[0091] Figures 40A - E illustrate an embodiment in which the number of sterilization connectors is reduced by half, thereby reducing the opportunity for sterilization failure. Thus, the Y - connector 6000 is used to fluidly connect the inlet ports, outlet ports, and / or vent ports of a plurality of filtration devices. For example, FIGS. 40A and 40B show the inlet port (i), vent port (v), and outlet port (o) of adjacent filtration devices having 90° TC - to - barb connectors 6010 (FIG. 40C) attached to each port. The Y - connector 6000 is then connected to the barb connectors 6010 to be in fluid communication with the respective inlet port (i), vent port (v), and outlet port (o) (e.g., using a TC clamp 6012 such as a Q - clamp). A cutter set 6020, such as a SERIESLOCKTM cutter, can be connected to each branch of the Y - connector 6000, whereby the filtration device can be removed from the system in a non - dripping manner (after removing the strap, if any, that holds the devices together). FIGS. 40D and 40E show similar setups for the vent port and outlet port, respectively. FIG. 40F shows a plurality of Y - tube connectors 6000 fluidly connected to an outlet port that can be connected to an external manifold 6030 (only one is shown). Similar manifolds can be connected to, or made connectable to, the Y - tube connectors 6000 fluidly connected to the inlet ports and vent ports.

[0092] According to some embodiments, the bags, bioreactors, or disposable containers described herein are designed to receive and maintain fluids such as body fluids. In some embodiments, the bags, bioreactors, or disposable containers include a single-layer or multi-layer flexible wall formed of, for example, the following polymer compositions: polyethylene (including ultra-high molecular weight polyethylene (UHMWPE), ultra-low density polyethylene (ULDPE), linear low density polyethylene (LLDPE), low density polyethylene (LDPE), medium density polyethylene (MDPE)); polypropylene (PP); ethylene vinyl alcohol (EVOH); polyvinyl chloride (PVC); polyvinyl acetate (PVA); ethylene vinyl acetate copolymer (EVA copolymer); thermoplastic elastomer (TPE) and / or blends or alloys of any of the foregoing materials, as well as various other thermoplastic materials and additives known to those skilled in the art. In some embodiments, the bags, bioreactors, or disposable containers include a substrate such as a woven fabric, non-woven fabric, and / or knitted substrate to provide additional strength. Such bags are available, for example, from EMD Millipore of Billerica, Massachusetts, USA.

[0093] Disposable containers can be formed by a variety of processes including, but not limited to: coextrusion of similar or different thermoplastic plastics; multilayer laminates of various thermoplastic plastics; welding and / or heat treatment, heat staking, calendering, etc. Any of the foregoing processes can further include layers such as adhesives, tie layers, primers, surface treatments, etc. to promote adhesion between adjacent layers. "Different" means not only different polymer types, such as a polyethylene layer with one or more EVOH layers, but also polymers of the same polymer type but with different properties such as molecular weight, linear or branched polymers, fillers, etc. are considered herein. Generally, medical grade plastics, and in some embodiments, plastics that do not contain animals are used in the manufacture of the containers. Medical grade plastics can be sterilized, for example, by steam, ethylene oxide, or radiation including beta and / or gamma or X-rays. Also, most medical grade plastics are specified to have excellent tensile strength and low gas permeability. In some embodiments, the medical grade plastic includes a transparent or translucent polymer material that allows visual monitoring of the contents and is typically weldable and unsupported. In some embodiments, the container can be a bioreactor that can support a biologically active environment, such as one that can grow cells in the context of cell culture. In some embodiments, the bag, bioreactor, or container can be a two-dimensional (2D) or "pillow" bag, or alternatively, the container can be a three-dimensional (3D) bag. The specific geometric shape of the container or bioreactor is not limited in any of the embodiments disclosed herein. In some embodiments, the container can include a rigid base that provides access points such as ports or vents.Any container described herein can include one or more inlets, one or more outlets, and optionally, a sterile gas vent, a sparger, and ports for detecting a liquid within the container for detecting parameters such as conductivity, pH, temperature, dissolved gases such as oxygen and carbon dioxide, and other things known to those skilled in the art. The container can be sized to hold fluids such as cells and culture medium to be mixed, ranging from pilot scale (e.g., 50 L) to small or large production volume containers (e.g., 500 L to 3000 L, or larger bioreactors).

[0094] In some embodiments, the bag, bioreactor, or container can be a disposable, deformable, foldable bag that defines a closed volume, can be sterilized for disposal, can hold contents such as a liquid state biopharmaceutical solution, and can partially or fully contain a mixing device within the closed volume of the container, e.g., the working volume. In some embodiments, the closed volume can be opened by appropriate valve operation, etc., to introduce fluid into and discharge fluid from the volume, such as after mixing is complete.

[0095] In some embodiments, each container includes an impeller assembly for mixing, dispersing, homogenizing, and / or circulating one or more liquids, gases, and / or solids contained within the container, either partially or fully within it.

[0096] All ranges of formulations described in this specification include the ranges between them and can include endpoints, either including or excluding the endpoints. Optionally included ranges are at the enumerated digits or one digit smaller and are from the integer values between them (or including one of the original endpoints). For example, if the lower range value is 0.2, optionally included endpoints can be 0.3, 0.4, … 1.1, 1.2, etc., as well as 1, 2, 3, etc.; if the upper range is 8, optionally included endpoints can be 7, 6, etc., as well as 7.9, 7.8, etc. Similarly, one-sided boundaries such as 3 or more include consistent boundaries (or ranges) starting with the enumerated digits or an integer value one digit smaller. For example, 3 or more includes 4, or 3.1 or more.

[0097] Throughout this specification, references to "one embodiment", "a particular embodiment", "one or more embodiments", "some embodiments", or "an embodiment" mean that the features, structures, materials, or characteristics described in connection with the embodiment are included in at least one embodiment of the present disclosure. Thus, expressions such as "in one or more embodiments", "in a particular embodiment", "in an embodiment", "in some embodiments", or "in an embodiment" throughout this specification do not necessarily refer to the same embodiment.

[0098] Although some embodiments have been described above, other implementations and applications are also included in the following claims. In this specification, although some embodiments are described with reference to them, it should be understood that these embodiments merely exemplify the principles and applications of the technologies described within the present disclosure. Therefore, it should be further understood that many modifications can be made to the exemplary embodiments without departing from the spirit and scope of the embodiments according to the present disclosure, and other arrangements and patterns can be devised. Furthermore, specific features, structures, materials, or characteristics can be combined in any suitable manner in any one or more embodiments.

[0099] Publications of patents, patent applications, and other non-patent literature cited in this specification are hereby incorporated by reference in their entirety as if each individual publication or reference were specifically and individually indicated to be incorporated by reference herein as if fully set forth. Any patent application for which this application claims priority is also incorporated by reference herein in the manner described above for publications and references.

Claims

1. 1. An apparatus for treating a body fluid, comprising: a plurality of filtration devices, each of which includes a filtration medium, at least one inlet, and at least one outlet; and a first insert plate and a second insert plate opposite the first insert plate; Including, The plurality of filtration devices are disposed between the first and second insert plates.

2. The apparatus of claim 1 , wherein each of the plurality of filtration devices further comprises at least one vent port.

3. 10. The device for treating a bodily fluid according to claim 1, wherein said at least one inlet further comprises a sterile-to-sterile connector.

4. 10. The device for treating a bodily fluid according to claim 1, wherein the at least one outlet further comprises a sterile-to-sterile connector.

5. The device of claim 2 , wherein the at least one vent port terminates in a vent filter.

6. 10. The method of claim 1, wherein at least one inlet from each of the plurality of devices is connected in fluid communication via a manifold.

7. The apparatus of claim 1 , wherein at least one outlet from each of the plurality of devices is connected in fluid communication via a manifold.

8. 3. The method of claim 2, wherein the at least one vent port from each of the plurality of devices is connected in fluid communication via a manifold.

9. The apparatus of claim 6 , wherein the manifold comprises a sterile-to-sterile connector.

10. 10. The device of claim 1, wherein the filtration media comprises a media effective for viral filtration, depth filtration or adsorptive filtration.

11. The device of claim 10 , wherein the filtration medium comprises a chromatographic membrane.

12. 2. The apparatus of claim 1, wherein the plurality of filtration devices are combined and loaded onto a cart having holder hardware including a side A and a side B.

13. The apparatus of claim 12 , wherein the holder hardware includes a pressure gauge, a hydraulic pump, a clamp rod, a frame, and two platens.

14. 1. A device for sealing a sterile filtration device, comprising: A container comprising two rigid bases and a plastic film, between which are disposed a plurality of filtration devices. Including, one of said rigid bases having a protruding hose barb fitting connected to a tubing and a sterile-to-sterile connector, and said plastic film enclosing said plurality of filtration devices between said rigid bases.

15. 15. The device of claim 14, wherein the plastic film is heat welded, glued, or otherwise joined to at least a portion of the periphery of the rigid base.

16. 16. The device of claim 15, comprising two plastic films, said plastic films overhanging a periphery of said rigid base.

17. 15. The apparatus of claim 14, further comprising at least one alignment key on the at least one rigid base.

18. 15. The apparatus of claim 14, wherein each end plate has at least one groove for retaining a strap band.

19. 15. The apparatus of claim 14, further comprising at least one hose barb adapter or at least one blind end cap, each hose barb adapter or blind end cap adapter further comprising a gasket and a snap fit connection.

20. 1. An assembly including a filtration module, the assembly including a filtration medium and one or more fluid ports; and an insert plate having a thickness and configured to be attached to a face of the filtration module, the insert plate having at least one recess configured and arranged to receive a connection component fluidly connectable to one of the fluid ports, such that the connection component is contained within the thickness of the insert plate when the insert plate is attached to the face of the filtration module.

21. 1. An assembly including a filtration module, the filtration module including a filtration medium and one or more fluid ports, the filtration module having an end face, the end face having at least one recess configured and arranged to receive a connection component fluidly connectable to one of the fluid ports, whereby the connection component is received within the recess.

22. 23. The assembly of claim 21 or 22, wherein the filtration module is surrounded by a sterile barrier.

23. 24. The assembly of claim 23, wherein the sterility barrier comprises a polybag.

24. 11. A method of deploying a seal in a filtration device including a filtration medium, an inlet and an outlet, the method comprising the steps of inserting an applicator into each of the inlet and outlet, and introducing a seal material through each of the applicators.

25. 25. The method of claim 24, wherein the sealing material comprises a material selected from the group consisting of cotton, rayon, foam, polyurethane, polyether, polyester, and cellulose.

26. 1. An apparatus for treating a body fluid, comprising: A plurality of filtration devices, each of which includes a filtration medium, at least one inlet, and at least one outlet. Including, The apparatus, wherein two inlets of the plurality of filtration devices are fluidly connected by a first Y-connector.

27. 27. The apparatus of claim 26, wherein the outlets of two of the plurality of filtration devices are fluidly connected by a second Y-connector.

28. 27. The apparatus of claim 26, wherein each of the plurality of filtration devices further comprises at least one vent.

29. 30. The apparatus of claim 28, wherein the vents of two of the plurality of filtration devices are fluidly connected by a third Y-connector.

30. 27. The apparatus of claim 26, wherein the Y-connector is fluidly connectable to a manifold.

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