阅读说明：本技术 封闭生物加工装置 (Closed biological processing device ) 是由 M·J·苏西恩卡 J·佩罗 J·格林格 B·希利尔 J·穆尔杜恩 J·P·阿马拉 于 2019-08-12 设计创作，主要内容包括：提供了过滤模块,所述模块包括至少一个过滤包,所述过滤包包含过滤介质或一个或多个薄膜,诸如一堆薄膜,所述至少一个过滤包具有一个或多个流体端口,所述一个或多个流体端口被主要密封件和与主要密封件间隔开的次要密封件围绕。次要密封件被设计成在运输、搬运和/或安装期间维持组件的无菌性。可移除膜可以覆盖一个或多个流体端口以在使用前维持无菌性。(A filtration module is provided that includes at least one filtration packet containing filtration media or one or more membranes, such as a stack of membranes, having one or more fluid ports surrounded by a primary seal and a secondary seal spaced from the primary seal. The secondary seal is designed to maintain the sterility of the assembly during shipping, handling, and/or installation. A removable membrane may cover one or more fluid ports to maintain sterility prior to use.)

1. A filtration module comprising at least one filtration pack containing filtration media or one or more membranes, the at least one filtration pack having one or more fluid ports surrounded by a primary seal and a secondary seal spaced apart from the primary seal.

2. The filtration module of claim 1, further comprising first and second end caps sandwiching the at least one filtration cartridge therebetween, the first and second end caps including at least one fluid channel in fluid communication with the one or more fluid ports.

3. The filtration module of claim 2, wherein the at least one fluid port is configured to direct fluid flow through the one or more filter cartridges in a first direction, the at least one fluid channel redirecting the fluid flow into a second direction different from the first direction.

4. A filtration module according to claim 3, wherein the second direction is orthogonal to the first direction.

5. The filtration module of claim 1, further comprising a membrane covering the one or more fluid ports.

6. A filtration module according to claim 5, wherein the membrane is folded over itself so as to create first and second membrane layers covering the one or more fluid ports.

7. A plurality of filtration modules, each of the filtration modules comprising one or more filtration packets containing filtration media or one or more membranes, wherein a first filtration module of the plurality of filtration modules comprises a first fluid port surrounded by a first primary seal and a first secondary seal spaced apart from the first primary seal; a second filtration module of the plurality of filtration modules comprising a second fluid port surrounded by a second primary seal and a second secondary seal spaced from the second primary seal; wherein when first and second filtration modules are engaged under pressure such that the first fluid port is aligned with the second fluid port, and the first secondary seal contacts the second secondary seal to prevent contaminants from entering the first and second fluid ports.

8. The plurality of filtration modules of claim 7, wherein each of the packets and the modules are sterile.

9. The plurality of filtration modules of claim 7, wherein each first filtration module comprises a membrane covering the first fluid port prior to joining the first filtration module and the second filtration module under pressure.

10. A plurality of filtration modules according to claim 9, wherein the membrane is folded over itself so as to create a first membrane layer and a second membrane layer covering the first fluid port.

11. A plurality of filtration modules according to claim 9, wherein a handle is attached to the membrane.

12. The plurality of filtration modules of claim 7, further comprising first and second end caps sandwiching the plurality of filtration modules therebetween, the first and second end caps comprising at least one fluid channel in fluid communication with the first and second fluid ports.

13. The plurality of filtration modules of claim 12, wherein the first fluid port is configured to direct fluid flow through the one or more filtration cartridges in a first direction, the at least one fluid channel redirecting the fluid flow into a second direction different from the first direction.

14. The filtration module of claim 13 wherein the second direction is orthogonal to the first direction.

15. An assembly comprising a plurality of pre-assembled pre-sterilized filtration modules, each of the filtration modules comprising at least one filtration packet containing filtration media or one or more membranes, the at least one filtration packet having one or more fluid ports surrounded by a primary seal and a secondary seal spaced from the primary seal.

16. A plurality of filtration modules, each of the filtration modules comprising one or more filtration packets containing filtration media or one or more membranes, wherein a first filtration module of the plurality of filtration modules comprises a first fluid port; and a spacer plate free of filter media and having a second fluid port configured and positioned to align with the first fluid port of a first filtration module when in an assembled condition; the second fluid port of the spacer plate has a gasket positioned concentric with the second fluid port; wherein the center gasket prevents contaminants from entering the first fluid port when the plurality of filtration modules and the spacer plate are engaged under pressure such that the first fluid port is aligned with the second fluid port.

The plurality of filtration modules of claim 16, wherein the spacer plate has first and second opposing surfaces, and wherein the spacer plate includes first and second radially projecting members, each extending from a respective one of the first and second opposing surfaces, each having an annular seal.

Background

Bioprocessing operations in which the material being manufactured is exposed to the indoor environment must be controlled and sterilized at all times to avoid contamination of the product. Therefore, such bioprocessing operations must be performed in a controlled, classified space (i.e., a "clean room") to minimize the risk of contamination of the product feed stream. The construction, operation and maintenance of the classified spaces is very expensive. Despite precautions taken to avoid contamination, contamination events can still occur. Contamination can lead to downtime, cleaning, and revalidation, each of which is expensive and time consuming. Thus, bioprocessing equipment and materials need to be sterilized prior to use in order to minimize the risk of contamination.

In view of the expense and time investments required to build, operate, and maintain a controlled environment, biopharmaceutical manufacturers desire to move bioprocessing operations into controlled, non-classified spaces (i.e., "gray spaces") to allow manufacturing flexibility and potential cost savings. While existing bioprocess filters (particularly depth filtration, tangential flow filtration, and viral filtration devices) can be sterilized prior to use, the use of these devices in gray spaces results in immediate destruction of their sterility after removal from their bags or other packaging containers due to the presence of one or more open fluid ports on the device. These fluid ports are necessary to allow for modularity, i.e., the ability to vary the total filter area, media grade, or other characteristics depending on batch size, product properties, etc., and thus eliminating these fluid ports is not an effective option.

Accordingly, there is a need for a completely enclosed sterile filtration device that is capable of maintaining the sterility of their interior prior to assembly and during bioprocessing operations. These closed filtration devices may also require sterile connections to other bioprocessing operations. "sterile" is defined herein as being free of contamination by harmful bacteria, viruses, or other microorganisms, e.g., having a sterility level of less than about 1 CFU/ml.

Conventional filters are sold as individual modules, wherein the end user loads them into a holder that compresses the assembly to engage the seal and constrain the system so as to be able to operate under pressure (e.g., -60 psi working internal pressure). However, such systems may not maintain sterility due to the module connection port being open to the ambient environment, for example, during loading into the holder.

It is therefore an object of embodiments disclosed herein to provide a suitable and effective seal for the one or more fluid ports present in a filter cassette or end cap (which allows multiple modules to be interconnected to form a filter assembly).

It is another object of embodiments disclosed herein to provide a pre-sterilization module that includes a plurality of filter cartridges or end caps having seals in their fluid ports to maintain sterility, such as during shipping.

It is a further object of embodiments disclosed herein to provide a plurality of pre-sterilization modules that can be assembled to form a filtration device suitable for filtration in bioprocessing operations.

Disclosure of Invention

Embodiments disclosed herein relate to a device that enables closed bioprocessing, such as so-called "downstream processing," e.g., processing to remove or reduce contaminants from material that has been harvested in a bioreactor (e.g., depth filtration). In certain embodiments, the device enables sterile fluid transfer. In some embodiments, the device is pre-sterilized and is a disposable device suitable for single use. In particular embodiments, the device is a pre-assembled series of individual filter cartridges, each of which contains filter media and/or one or more membranes. In certain embodiments, the pre-assembled series of bags are under tension, such as tie rods (tie rod) loaded to a certain force, for example 300 lbf each. The bag and end cap may be interconnected to form a module, and one or more modules together with the manifold end cap may be held together to form a modular assembly and engage the device inner seal and prevent accidental access through one or more fluid ports. The completed assembled device may be sterilized, such as by gamma radiation, autoclaving, steam, ozone, or ethylene oxide treatment, in order to make the interior of the device sterile. Subsequent aseptic connections to the process piping may be made to allow for aseptic fluid transfer, such as filtration operations without contaminating the filter media or process fluid.

In certain embodiments, one or more fluid ports of one or more filtration devices may be surrounded by two separate or independent seals. The fluid port may itself provide a fluid path to and from the filter media or to and from one or more membranes, or may provide a gas path such as for ventilation. In certain embodiments, the primary seal is disposed around the fluid port and acts as an internal seal capable of withstanding the high pressures (e.g., 30-60 psi) generated during bioprocessing operations. In certain embodiments, the secondary seal also surrounds the fluid port and acts as an external seal that is a low pressure/high compliance seal. In certain embodiments, the secondary seal is concentric with, spaced apart from, and has a larger diameter than the primary seal. In some embodiments, the secondary seal maintains sterility of the interior of the device during transport and/or handling of the device.

These features enable bioprocessing to be performed in a controlled, non-classified space in a sterile manner. Thus, the apparatus may be designed and operated such that the product is not exposed to an indoor environment.

Accordingly, in some embodiments, a filtration module is provided, the module comprising at least one filtration packet containing filtration media or one or more membranes, such as a stack of membranes, the at least one filtration packet having one or more fluid ports surrounded by a primary seal and a secondary seal spaced apart from the primary seal. One fluid port may be an inlet port. One fluid port may be an outlet port. One fluid port may be a vent port.

More specifically, in some embodiments, a plurality of filtration modules are provided, each of the filtration modules comprising one or more filtration packets containing filtration media or one or more membranes, wherein a first filtration module of the plurality of filtration modules comprises a first fluid port surrounded by a first primary seal and a first secondary seal spaced apart from the first primary seal. A second filtration module of the plurality of filtration modules includes a second fluid port surrounded by a second primary seal and a second secondary seal spaced from the second primary seal. When the first and second filtration modules are engaged under pressure such that the first fluid port is aligned with the second fluid port, the first secondary seal contacts the second secondary seal and prevents contaminants from entering the first and second fluid ports.

In some embodiments, the at least one fluid port is configured to direct fluid flow in a first direction through the one or more filter cartridges, and the end cap that sandwiches the plurality of filter cartridges in the module includes at least one fluid channel that redirects fluid flow in a second direction different from the first direction. In some embodiments, the second direction is orthogonal to the first direction.

In some embodiments, a membrane covers one or more of the fluid ports, and the membrane may be removed when the module is partially engaged and/or partially compressed.

In certain embodiments, a pre-assembled sterile modular device is provided that includes a plurality of filtration modules, each filtration module including one or more filtration cartridges. One or more modules can be interconnected and can be stored and/or transported in a rack.

In some embodiments, a spacer plate without filter media (i.e., without media and membranes) may be positioned between two filtration modules. The spacer plate may have one or more fluid ports, each fluid port being configured and positioned to align with a respective one of the fluid ports when in an assembled condition. In certain embodiments, each of the fluid ports of the spacer plate has primary and secondary seals. In particular embodiments, the spacer plate may have one or more co-radial annular seals extending radially outward from opposing front and rear surfaces of the spacer plate. Each co-radial seal may include a radially projecting member having an annular seal, such as a gasket.

Additional features and advantages of the embodiments disclosed herein will be set forth in the detailed description and in the appended claims. It will be apparent to those skilled in the art that many modifications and variations can be made without departing from the spirit and scope thereof. It is to be understood that both the foregoing general description and the following detailed description, claims, and drawings are exemplary and explanatory only and are intended to provide an explanation of various embodiments of the present teachings.

Drawings

FIG. 1A is a perspective view of a filtration module having inner and outer fluid port seals according to certain embodiments;

FIG. 1B is a cross-sectional view of a fluid port having inner and outer fluid port seals, according to a particular embodiment;

FIG. 2A is a cross-sectional view of two aligned filtration modules, according to a particular embodiment;

FIG. 2B is a cross-sectional view of two aligned filtration modules with an acceptable gap therebetween, in accordance with certain embodiments;

FIG. 3 is a perspective view of a filter assembly loaded into a holder, according to certain embodiments;

FIG. 4 is an exploded view of a plurality of modules and manifold end caps in a partially assembled condition in accordance with certain embodiments;

FIG. 5 is a cross-sectional view of a plurality of modules and a manifold end cap in an assembled condition, in accordance with certain embodiments;

FIG. 6 is an exploded view of a manifold end cap according to certain embodiments;

fig. 7A is a perspective view of a filtration module showing fluid flow paths, in accordance with certain embodiments;

fig. 7B is another perspective view of a filtration module showing fluid flow paths, in accordance with certain embodiments;

FIG. 8 is a perspective view of a filtration module having a membrane providing a temporary and removable seal for a fluid port, according to a particular embodiment;

9A, 9B, and 9C are schematic diagrams illustrating removal of the temporary seal shown in FIG. 8, according to certain embodiments;

FIG. 10A is a perspective view of a spacer plate according to certain embodiments;

FIG. 10B is a cross-sectional view of the spacer plate of FIG. 10A;

FIG. 11A is a perspective view of an alternative embodiment of a spacer plate according to certain embodiments;

FIG. 11B is a top view of a portion of the spacer plate of FIG. 11A;

FIG. 11C is a top view of the spacer plate of FIG. 11A shown between two filtration modules in accordance with certain embodiments;

FIG. 11D is a cross-sectional view of the spacer plate of FIG. 11A positioned in a device according to certain embodiments;

FIG. 12A is a perspective view of a spacer plate with an attachment clip according to certain embodiments;

FIG. 12B is a perspective view of a module including the spacer plate of FIG. 12A;

FIG. 12C is a cross-sectional view of the spacer plate of FIG. 12A;

FIG. 13 is a cross-sectional view of an improved end cap with a TC-type adapter in accordance with certain embodiments;

FIG. 14A is a perspective view of an integrated dual purpose seal according to certain embodiments;

FIG. 14B is a perspective view of a portion of the dual seal of FIG. 14A, cut away for internal visibility;

FIG. 14C is a cross-sectional view of the dual-purpose seal of FIG. 14A;

FIG. 15 is a perspective view of an enclosed cabin (pod) with a piping manifold, according to certain embodiments;

FIG. 16A is a perspective view of a plurality of enclosures having piping manifolds, in accordance with certain embodiments;

FIG. 16B is a first cross-sectional view of the embodiment of FIG. 16A;

FIG. 16C is a second cross-sectional view of the embodiment of FIG. 16A;

FIG. 17 is a perspective view of a filter unit constructed of different media grades, according to certain embodiments; and

fig. 18A and 18B are perspective views of a bracket for holding a filter device according to certain embodiments.

Detailed Description

A more complete understanding of the components, processes, and devices disclosed herein can be obtained by reference to the accompanying drawings. The drawings are merely schematic representations based on convenience and the ease of demonstrating the present disclosure, and are, therefore, not intended to indicate relative size and dimensions of the devices or components thereof and/or to define or limit the scope of the various exemplary embodiments.

Although specific terms are used in the following description for the sake of clarity, these terms are intended to refer only to the particular structure of the embodiments selected for illustration in the drawings, and are not intended to define or limit the scope of the disclosure. In the drawings and the following description that follows, it is to be understood that like reference numerals refer to components having like functions.

The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

As used in the specification, various devices and portions may be described as "comprising" other components. As used herein, the terms "comprising," "including," "having," "capable of," "containing," and variations thereof are intended to be open-ended transition phrases, terms, or words, that do not exclude the possibility of additional components.

Turning now to fig. 1A and 1B, a filter module 100 is shown, in accordance with certain embodiments. The filter module 100 may be an assembly of a plurality of rigid filter packets 10, each of the filter packets 10 including one or more fluid ports 12, the fluid ports 12 providing fluid communication to one or more fluid channels formed in each packet 10. In the illustrated embodiment, there are ten such packets 10, although fewer or more packets may be used to form the module 100. The filter module 100 also includes two opposing rigid end caps 10', which end caps 10' sandwich the bag 10 between them. The pack 10 and module 100 may be disposable single-use devices and may be made of a suitable material that is sterilizable, such as plastic, polycarbonate, or a polyolefin, such as polypropylene.

In certain embodiments, a plurality of individual packets 10 may be arranged in series and form a module 100, and may be interconnected to provide fluid communication therebetween through their respective fluid ports 12. The modular device can be assembled using a plurality of packets 10 and a plurality of modules 100, which can be interconnected to form a filtration device. The device may be stored and/or transported in a rack or the like. In particular embodiments, one of the fluid ports 12 may be an inlet port for introducing a liquid sample into the assembly, one or more may be an outlet port for removing a liquid sample from the assembly, and one or more may be a vent port for venting gas, such as air, from the assembly.

One or more of the filter cartridges 10 may contain media, such as media suitable for depth filtration, tangential flow filtration, cross-flow filtration, and the like. Exemplary depth filtration media include diatomaceous earth, cellulose, activated carbon, polyacrylic fibers, and silica, such as by millipore sigma in Clarisolve^®And Millistatk +^®Those sold under the name of (a). One or more of the filter packs 10 may include one or more membranes, such as a stack of membranes. A typical fluid flow path through the filter module 100 is shown in fig. 7A and 7B, as known to those skilled in the art. In the illustrated embodiment, fluid enters the inlet fluid port 12 and flows into the channel 15 formed through the packet body and then down through the small slits 17 formed in the channel 15 to the upstream side of the media or film 25. The fluid then flows through the media or membrane 25 and enters a similar slit in the channel at the upstream side of the media or membrane 25 and out the outlet fluid port 12, as seen in fig. 7B.

In certain embodiments, one or more of the fluid ports 12 of the module 100 are surrounded or encompassed by two seals. Preferably, each of the fluid ports 12 is surrounded by two seals, and preferably the seals surround the inlet (or outlet) opening of the fluid port 12 and are thus positioned on the end cap 10'. In a particular embodiment, there is an inner primary seal 20 and an outer secondary seal 30. In some embodiments, the primary seal 20 is closer to the inlet (or outlet) opening of the fluid port 12, i.e., it is disposed radially inward of the secondary seal 30 relative to the axial bore of the fluid port 12 (the bore extending between the opposing end caps 10'). In some embodiments, each of the primary seal 20 and the secondary seal 30 is a gasket. The primary seal 20 should be able to withstand the high pressures (e.g., 30-60 psi) generated during bioprocessing operations (e.g., filtration). In certain embodiments, the secondary seal 30 is an external seal that is a low pressure/high compliance seal. The secondary seal 30 need not be able to withstand the high pressures generated during bioprocessing operations; its primary purpose is to mitigate or prevent contamination of the fluid port 12 during transport and/or handling of the device. In certain embodiments, the secondary seal is concentric with, spaced apart from, and of a larger diameter than the primary seal 20, and extends outwardly from the end cap 10' a greater distance than the primary seal 20 (see fig. 1B). In some embodiments, the secondary seal maintains sterility of the interior of the device during transport and/or handling of the device. Suitable primary seals may be made of thermoplastic vulcanizate (TPV) and may have a durometer value (shore a) in the range of about 35-45, more preferably about 38-42, and most preferably about 42. Suitable secondary seals may have a hardness value less than the hardness of the primary seal, such as in the range of about 25-35 (shore a), preferably about 28-32. In certain embodiments, each seal is secured in a corresponding groove 201, 301 (FIG. 1B) formed in the end cap 10' by friction fit and/or using an adhesive.

When multiple modules 100-100N are placed in series (as shown in fig. 2A and 2B), one or more fluid ports 12 from a first end cap 10' of a first module 100 are aligned with corresponding second fluid ports 12' of a second end cap 10' of a second module 100A. The second fluid port 12' of the second module 100A also includes an inner primary seal 20 ' and an outer secondary seal 30 '. When the first module 100 is aligned with the second module 100A, the outer secondary seal 30 from the first module 100 is aligned with and contacts the outer secondary seal 30' from the second module 100A, as shown in cross-section in fig. 2A. Thus, the outer secondary seals 30 and 30' together form a barrier into the fluid port 12, even at pressures significantly below the operating pressure. As shown in fig. 2B, the size, location and configuration of the outer secondary seals 30 and 30 'are sufficient to create such an access barrier even though there is a small gap between the first and second modules 100, 100A, while the primary inner seals 20, 20' need not contact each other during transport and/or handling. That is, because outer secondary seals 30 and 30 ' extend outwardly from their respective end caps 10' a greater distance than the respective primary seals 20 and 20 ', outer secondary seals 30 and 30 ' contact each other before primary seals 20 and 20 ' contact each other as the modules are aligned.

As shown in fig. 3 and 4, in particular embodiments, individual modules 100, 100A, 100B, etc. may be assembled and interconnected at each end along with a manifold end cap 150 so as to create a continuous, sealed fluid flow path. Such a closed continuous fluid flow path may be sterilized, for example, before being shipped to an end user. The outer seals 30 and 30' are used to maintain sterility. The end user may then load the pre-assembled pre-sterilized assembly into the appropriate holder 200 and aseptically connect it to the mating flow path, such as using a sterile-to-aseptic connector, a sterile tube welder, or the like.

In certain embodiments, as best seen in fig. 4 and 5, tie rods 40 or the like may be used to attach, restrain and tension components of the individual filter modules 100, 100A, 100B, etc. The tie rod may be made of any suitable material to perform these functions, such as thermoplastic resin, and may be threaded. In some embodiments, tie rod 40 is positioned through appropriate apertures in the plurality of filter modules 100 and secured by bolts, fasteners, or the like to compress modules 100 and cause opposing outer secondary seals 30, 30' to contact each other and provide the necessary sterility barrier for their respective filter ports 12. The tie rods 40 can be preloaded using a predetermined tension/pressure, such as using a hydraulic pump, to maintain compression of the module and thus integrity of the module during transport, handling, storage, and/or installation. Preferably, sufficient tension is created to ensure that each of the secondary seals 30 remain engaged and intact throughout the transportation and handling process. A suitable force is, for example, about 300 lbf. A strap or clip may be used in place of the tie rod 40 to accomplish the same function.

In particular embodiments, as shown in fig. 6, one or more of the manifold end caps 150 may be configured to divert or redirect the fluid flow paths in a common direction, such as from a normal direction (parallel to the components of the series arrangement) to an orthogonal direction (perpendicular to the components of the series arrangement). This allows the entire assembly (including tubing, fittings, connectors, etc.) to be fitted on a standard pallet for useTransport and sterilization, and facilitate connection to ancillary equipment. In certain embodiments, one or more of the end caps 150 can be constructed of two molded pieces and welded together, such as the plate 151 and the body 152. Inside the body 152 are channels 160 and 161, each of which is angled to redirect flow from the X direction to the Y direction as shown. The flow path may terminate in a hose barb fitting 70 as shown, or other suitable fitting or the like, such as a clover (TC) or sanitary fitting. Preferably the flow path fitting provides a means of making an aseptic connection between the filtration device and process tubing or the like without risk of contamination of the filtration media or process fluid, and can include a fitting, such as LYNX, commercially available from Millipore Sigma^®S2S and a CDR connector. Additionally, the filter inlet, vent and outlet ports (as shown in fig. 3, 4, 6, 17) may be standard hose barbs 70, sanitary flange connectors (TC connectors), or any commercially available sterile-to-sterile connector known in the art, such as AseOptiquik^®G (cooler Products Corp), ReadyMate Disposable sterile connector (GE Healthcare), or Kleenpak^®Presto sterile connectors (Pall Corp.).

In certain embodiments, a pre-assembled sterile module assembly can be loaded into a holder 200 (fig. 3), such as a stainless steel holder, and hydraulic pressure can be applied to bring the assembly to the appropriate operating/working pressure required for the bioprocessing operation. Such pressure provides sufficient compression between the inner primary gasket seal 20 to enable a fluid tight connection between each of the filter arrangement modules in the assembly.

Turning now to fig. 8, an embodiment is shown in which a membrane 300 is used to protect one or more fluid ports 12 in a filter module. The membrane may be constructed of a vapor permeable material or a vapor impermeable material. One suitable material is under the name TYVEK from Dupont^®Flash spun high density polyethylene fibers are sold. The membrane 300 may be affixed or sealed to the device housing (e.g., end cap 10') using an adhesive, thermal bonding, or other suitable technique.The membrane 300 should be sized to completely cover its associated fluid port 12 (in fig. 8, the seals 20, 30 can be seen through the membrane 300; for clarity, depicted in this manner to show the location of the seals 20 and 30, it should be understood that the membrane 300 is intended to cover the fluid port 12 and the seals 20 and 30 (if present)).

In certain embodiments, the membrane 300 is folded over itself in order to reduce or minimize the pulling force required to remove them, and to minimize the possibility of microbial ingress into the fluid port 12 by ensuring that the potentially contaminated face of the membrane is never exposed to the interior of the device. Fig. 9A, 9B, and 9C illustrate one embodiment of a suitable folded film. Thus, as seen in fig. 9A, the membrane 300 is attached to the end cap body over the fluid port. In the illustrated embodiment, there are both primary and secondary seals 20, 30, although those skilled in the art will appreciate that the use of a secondary seal 30 is not required. The membrane is folded at the bottom attachment area at 301 and then extends over itself, forming a second membrane layer over the fluid port 12. This helps to ensure sterility and also reduces the pulling force required to remove the film. Preferably, the outer overlaminate extends over the bag body as shown, and can include a handle 305 to facilitate manual grasping and pulling of the film to remove the film from the bag at the appropriate time and to provide for more ergonomic handling of the module. Fig. 9B depicts the membrane 300 on two modules that have been brought together to allow fluid communication between their respective fluid ports 12. Handle 305 is pulled in the direction of arrow 400 to remove the film. As shown in fig. 9C, the folded films from each module slide together as they are pulled simultaneously. Once the primary seal 20 is exposed, they radially expand to their normal (uncompressed) dimensions and engage each other, thereby maintaining the integrity of the seal. The removal membrane 300 serves to open the flow path between the filter modules in a sterile manner. The handle 305 may have clips and/or alignment pins or the like to assist in alignment and attachment.

In a particular embodiment, the individual filter modules 100 with the membranes 300 in place will be loaded into a holder, such as the stainless steel holder 200 shown in fig. 3, such that the fluid ports 12 on each device are aligned accordingly. The hydraulic pressure of the retainer 200 can be increased to an intermediate state (e.g., 100-.

In particular embodiments, one or more spacer plates 350 (fig. 10A and 10B) may be positioned between two or more individual end caps 10' of adjacent modules 100 in a filtration unit. In certain embodiments, each spacer plate 350 is free of filter elements (i.e., free of media and free of membranes). The spacer plate 350 may have one or more fluid ports 12', and preferably the same number of fluid ports 12' as the end cap 10 '. Each of the fluid ports 12 'is configured and positioned to align with a respective one of the fluid ports 12 in the end cap 10' when in an assembled condition. In a particular embodiment, each of the fluid ports 12' of the spacer plate 350 has a minor concentric large diameter gasket 30 ', preferably made of a highly compliant elastomeric material, positioned around each fluid port 12' and extending radially outward from opposite front and rear surfaces of the spacer plate 350, as best seen in fig. 10B. These gaskets may be made of the same material as the gasket 30 and may be force fit into the grooves and/or secured using an adhesive. The spacer plate 350 thus incorporates the required secondary seal into a separate fixture.

Fig. 11A, 11B, 11C and 11D illustrate a modified spacer plate 350'. Similar to the spacer plates 350, each spacer plate 350' is free of filter elements (i.e., free of media and free of membranes). In such an embodiment, the spacer plate 350 'has one or more co-radial annular seals 360 extending radially outward from opposing front and rear surfaces of the spacer plate 350', as best seen in fig. 11B. Each co-radial seal includes a radially projecting member 361 having an annular gasket 362. Preferably the spacer plate 350 'has the same number of co-radial annular seals 360 as the number of fluid ports 12 that the end cap 10' has. Each of the co-radial annular seals 360 may be configured and positioned to align with a respective one of the fluid ports 12 in the end cap 10' when in an assembled condition. The spacer plate 350' may be configured to be inserted into the device inlet, outlet and vent ports, thereby providing the required hermetic/closed/sterile environmental seal with the radial annular seal for shipping, handling and set up. In the embodiment of fig. 11D, the spacer plate 350 'also includes a primary seal 20', which may be made of the same material as the gasket 361.

In some embodiments, as shown in fig. 12A, 12B, and 12C, the spacer plate 350' (or 350) may include one or more clips 370 or the like to facilitate connection to an adjacent device (as opposed to or in addition to using tie rods or the like). In the illustrated embodiment, there are a total of four clips: two on the top surface and two on the bottom surface, although those skilled in the art will appreciate that fewer or more may be used. In the illustrated embodiment, the clip 370 is generally L-shaped and may engage an existing groove/channel present on the bag, or may be fitted into a specially designed receiving slot/groove/channel designed into the retrofit device.

FIG. 13 illustrates an alternative embodiment of an end cap 10', which end cap 10' includes a TC-type (clover) adapter 275 to which tubing may be connected. The tubing may terminate in a suitable sterile connector, such as a Lynx S2S connector. By integrating/pre-attaching the adapters 275 directly to one or more of the fluid ports of the end cap, preferably all of the fluid ports of the end cap, and attaching tubing leads or tubing that terminate in appropriate sterile connectors, the devices are functionally closed while maintaining the inter-device fluid paths as they are conventionally configured.

Fig. 14A, 14B and 14C illustrate an alternative embodiment in which the primary and secondary seals are integrated into a single seal 500. In certain embodiments, integrated seal 500 is configured to occupy the same footprint as primary seal 20, and includes a dual function design that allows the device to remain airtight, closed, and/or sterile at low clamping forces (e.g., during shipping, handling, and set up), and to achieve liquid-tightness at high clamping forces (e.g., during higher pressure operation). According to particular embodiments, a portion of the seal 500 provides the high compliance required to maintain a closed system and sterility, and another portion of the seal 500 provides the low compliance required to withstand high liquid pressure operations. In a particular embodiment, the integrated seal 500 includes a hollow portion 501 that provides high compliance and maintains closure/sterility and a solid portion 502 that provides low compliance and withstands operating pressures. In a particular embodiment, the integrated seal 500 extends radially outward from a surface of the fluid port a distance sufficient to contact an opposing integrated seal on an adjacent device to form an integral environmental/sterile seal. Other embodiments include dual function seals where the two seals are not integral but are seated radially on each other. In particular embodiments, integrated seal 500 is made of thermoplastic vulcanizate (TPV) and may have a durometer value (Shore A) in the range of about 35-45, more preferably 38-42, and most preferably 42.

In certain embodiments, pre-assembled depth filtration units (containing, for example, 1, 2, 3, or 6 pods) may be formed, each unit utilizing a single endplate manifold with integrated hose barbs. One skilled in the art will appreciate that the hose barb may be terminated with a suitable sterile to aseptic connection fitting. The following table contains exemplary calculations for the total filter area, calculation units for each holder, and estimated batch for each example:

TABLE 1

Media grade	X0SP*	D0SP**	D0SP**	D0SP**
					Number of compartments	1	2	3 (half support)	6 (Whole support)
Total filtration area (m2)	1.1	1.54	2.31	4.62
					Approximate batch size (L)	165	231	346	693
Units of supports per 1 high processing scale	6	3	2	1

X0SP is a two-layer depth filter media combination, typically used for secondary purification.

D0SP is a four layer depth filter media combination that includes an upstream nonwoven layer and is typically used for primary cleaning.

These particular devices may be constructed using a modified end cap (such as those shown in fig. 1 and 2) containing two concentric gaskets/seals, or by using a spacer plate such as that shown in fig. 10A, 11A or 12A, or a dual gasket such as that shown in fig. 14A. These devices may be held together using internal tie rods (e.g., fig. 4 and 5) or external metal straps/bands or plastic clips (as shown in fig. 12A).

In certain embodiments, the pre-assembled filtration unit may be formed from multiple media grades contained in a single unit, as illustrated in fig. 17. In the illustrated embodiment, the left/rear portion of the unit 100 "has two devices, each housing a media grade relative to the open pore structure, while the right/front portion of the unit 100" has a device containing a relatively denser media grade. The assembly allows multiple media grades to be loaded into a single holder. These embodiments may use a modified end cap (as shown in fig. 1 and 2) configuration that contains two concentric gaskets/seals or by using a spacer plate as shown in fig. 10A, 11A and 12A and a dual gasket configuration as shown in fig. 14A. The device may be held together using internal tie rods as shown in fig. 4 and 5 or using external metal strips or bands or plastic clips (as shown in fig. 12A).

The illustration of one embodiment of the invention includes an improved pod device 100' having an improved end cap 10 "with rearranged inlet/outlet/vents and terminating in hose barbs 70 or other suitable fittings, as shown in fig. 15, 16A, 16B and 16C. Fig. 15 shows a device end cap 10 "which device end cap 10" provides a closed inlet/outlet/vent port. One skilled in the art will appreciate that tubing 95 (as shown in fig. 13) with a suitable sterile connector 96 may be attached to the hose barb 70 or other suitable fitting. The vent ports on the device may be kept sterile using Aerovent @ -50 (available from Millipore Sigma, for example) filters. Such an embodiment requires neither a spacer plate nor a different radial annular seal. By modifying the two end caps 10 "(one shown) so that there are no more open ports in the normal flow direction, the ports themselves can be closed/shielded. In addition, the end cap 10 "is modified so that all three flow paths are redirected to be vertical (orthogonal to the normal direction) and terminate in a connector (such as the hose barb 70 shown in fig. 15 or other suitable connector). The inlet, outlet and vent ports are in fluid communication with vertically oriented inlet, outlet and vent hose barbs 70. Suitable fluid flow paths are shown in fig. 16B and 16C.

One advantage of this design is that all of the pod-to-pod "connection" fluid paths are redirected into the external piping manifold, thereby avoiding the problem of having open ports in the normal orientation (which must remain closed and sterile prior to use). The modular nature of the pod form is also maintained, where any number, size or type of pods can be linked together in series (fig. 16) as long as they fit within the holder/cradle.

Fig. 18A and 18B illustrate the process scale rack 600 before (fig. 18A) and after (fig. 18B) the pre-assembled unit is loaded on the pallet. Those skilled in the art will appreciate that different configurations of pre-assembled units may be used, including configurations having one manifold end plate, or configurations having two manifold end plates as shown in fig. 18A and 18B.