Specification
METHODS FOR MAKING A HOUSINGLESS HOLLOW FIBER FILTRATION
APPARATUS
BACKGROUND
[0001] Hollow fiber filters are used extensively in pharmaceutical, health care, water filtration,
5 gas filtration, and fluid sterilization applications. Typically, a hollow fiber filter is made using
a maximum number of hollow fiber strands that will fit tightly and uniformly within a rigid
cylindrical housing. The cylindrical housing is used to protect the hollow fibers themselves,
which may be delicate and susceptible to damage.
[0002] In most hollow fiber filtration processes, the desired product is the permeate, which
10 refers to material that passes through the membrane wall. For example, in the pharmaceutical
industry, target proteins are removed from the cell culture through hollow fiber filtration; where
the small proteins pass through the filter pores while the much larger cells are excluded. As
such, hollow fiber filters are typically designed to allow for maximized recovery of the
permeate, through washing or rinsing, as well as ease of scale-up to larger, commercial systems.
15 [0003] Currently, there is little difference in filter design between a large filter intended for
thousands of hours of service in a pharmaceutical manufacturing plant and a small lab-scale
filter intended for a short service lifetime.
[0004] Thus there is a need for design simplification and cost control that will expand the use of
the filter in applications where cost or design complexities are concerns.
20
BRIEF DESCRIPTION
[0005] In general, the invention provides methods of manufacturing a housingless filtration
apparatus. Methods include batch, continuous, and semi-continuous processes.
[0006] In one embodiment, a method of manufacturing a housingless hollow fiber filtration
25 apparatus is provided comprising the steps of preparing a hollow fiber bundle and inserting the
ends of the bundle into potting cups that contain a curable potting material, curing the potting
material and cutting to expose the hollow fibers and retaining a portion of the potting cup,
inserting end caps, arranging the end caps between two thermoplastic layers, and melt sealing
the layers to form a container around the hollow fibers.
[0007] In one embodiment, a method of manufacturing a housingless hollow fiber filtration
apparatus is provided comprising the steps of forming a continuous bundle of hollow fibers
aligned longitudinally along a winding apparatus, applying a potting materials to the fibers to
form a potting sleeve, cutting the bundle to expose the hollow fibers, attaching end caps,
5 arranging the end caps between two thermoplastic layers, and melt sealing the layers to form a
container around the hollow fibers.
[0008] In another embodiment, a method of manufacturing a housingless hollow fiber filtration
apparatus is provided comprising the steps of forming a continuous bundle of hollow fibers
aligned longitudinally along a winding apparatus, attaching end cap housings to the bundle of
10 hollow fibers at a set position along the winding apparatus wherein the end cap housing
comprises an exterior fill port, injecting a potting material into the exterior fill port and curing
the material to form a potting sleeve around the fiber bundle, cutting the bundle to expose the
hollow fibers, arranging the end caps between two thermoplastic layers, and melt sealing the
layers to form a container around the hollow fibers.
15 [0009] Methods to increase rigidity of the using rigid films or additional perimeter
compartments are also provided.
DRAWINGS
[0010] These and other features, aspects, and advantages of the present invention will become
20 better understood when the following detailed description is read with reference to the
accompanying drawings in which like characters represent like parts throughout the drawings,
wherein:
[0011] FIG. 1 is a schematic drawing of an embodiment of the system of the invention where
hollow fibers are directly laminated into a permeate bag part of a Cell Sample Processor (CSP)
25 system.
[0012] FIG. 2 is a schematic drawing of the housingless filter in a vertical configuration
[0013] FIG. 3 is a schematic drawing of rigid thermoplastic parts used to form a three
dimensional container around the hollow fibers.
[0014] FIG. 4 is a schematic drawing showing the use of three dimensional compartments for
30 added rigidity.
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PCT Ted.dcc 2
[0015] FIG. 5 is a schematic drawing of one embodiment showing a batch process used to
construct the hollow fiber unit.
[0016] FIG. 6 is a schematic drawing of one embodiment showing a semi-continuous
manufacturing process.
5 [0017] FIG. 7 is a schematic drawing showing a potting material being applied to the fiber
bundle using an intermittent inkjet type spray nozzle in a continuous manufacturing process.
[0018] FIG. 8 is a schematic drawing showing potting material being applied using a hot resin
fill with a retractable mold.
[0019] FIG. 9 is a schematic drawing showing a combination curable compound and hot melt
10 seal process.
[0020] FIG. 10 is a process configuration for continuous sealing of hollow fibers within a
flexible bag.
[0021] FIG. 11 is an illustration of various bag-sealing concepts.
[0022] FIG. 12 is a schematic drawing of an assembly scheme for a U-shape filter.
15 I00231 FIG. 13 is a schematic drawing of an assembly scheme for a straight through filter
[0024] FIG. 14 is a schematic drawing of an end cap filter design.
[0025] FIG. 15 is a schematic drawing of a process for attaching an end cap and insertion into a
flexible bag.
DETAILED DESCRIPTION
20 [0026] In general, the invention described herein involves hollow fiber filtration apparatus
designed to reduce component and manufacturing cost. Instead of a hollow fiber unit wherein
the fibers are sealed in a separate cylindrical housing for support or protection, the hollow
fibers are sealed directly into a flexible bag or rigid container that is an integral part of a
filtration system. The flexible bag or rigid container may be used as a receptacle for a starting
25 material, permeate, waste filtrate, or target retentate. Target retentate refers to one or more of
submaterials that is intended to be separated from the starting material and collected separately.
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FCT Textdoc 7
100451 The bag may be constructed over the hollow fiber unit. As shown, the hollow fiber unit
may be positioned between two flexible sheet films and the peripheral edges of the two planar
flexible films are sealed together to form the flexible bag. In certain embodiments, the
positioning of the hollow fiber unit is aided by providing two film layers where the film layers
5 have matching apertures along the edges of the films to form inlet and outlet ports when sealed.
The hollow fiber unit may be positioned between the two flexible sheet films such that the end
cap housings are inserted into the apertures. The peripheral edges of the two planar flexible
films may be sealed to form a flexible bag. In an alternative embodiment, rigid threedimensional
parts may be used in place of the flexible films to provide a rigid container for the
10 hollow fibers.
[0046] In other embodiments, the hollow fiber unit may be disposed separately within a preformed
container and the end caps may then be inserted into the inlet and outlet ports of the
container. The hollow fiber unit may be disposed within the container prior to sealing. In other
embodiments, the hollow fiber unit may be inserted through the inlet or outlet port into' the
15 container. In each embodiment the container may be a flexible bag or a rigid container and
results in a closed filtration apparatus.
100471 FIG. 7 shown an embodiment using a continuous manufacturing process whereby a
potting material is applied to a bundle of hollow fibers at a set position along the winding
apparatus. As shown in FIG.7, a UV curable potting material 11 is applied using an intermittent
20 inkjet type spray nozzle. Alternative methods of applying the potting material directly to the
fiber bundle may also be used including, but not limited to spray coating, roll coating, and blade
coating. The potting material is cured on line to form a potting sleeve 12. The hollow fibers
may then be cut along the potting sleeve to expose open hollow fibers while retaining a portion
of the potting sleeves. End cap housings may be attached to the end portions of the potting
25 sleeve to form the hollow fiber unit. In other embodiments, the potting sleeve may act as an end
cap housing and be inserted directly into the inlet and outlet ports of the bag.
[0048] As shown fbrther in FIG. 7, in certain embodiments a nozzle 13 may be positioned
within the hollow fiber bundle infusing a sealant coating on to an interior section. The sealant
coating may provide adhesion between the fibers. The sealant may be the same as or a different
30 material than the potting material. In certain embodiments the potting material may be used
however processing aids or solvents may be added to alter the viscosity or other properties to aid
in dispersion.
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FCT Tzxt.doc 8
[0049] In certain embodiments fibers may be added at various times during the inline winding
process to increase the size of the fiber bundle while maintaining bundle integrity or strength.
The sealant coating may also be added at different times during the manufacturing process,
upstream or downstream of the potting material.
5 [0050] FIG. 8 is a schematic drawing of an embodiment showing potting material being applied
as a hot thermoplastic resin fill with a retractable mold 14. An advantage of this process is that
the mold will provide a good cylindrical shape for mating with the end cap. An injectable resin
may be selected as the potting material that has a mold-filling rate sufficient to seal the fibers,
without causing the fibers to collapse or melt. The material should also have good mold release
10 properties The injectable resins may include, but is not limited to, high flow polypropylene or
ethylene vinyl acetate.
[0051] Other embodiments may combine both spray coating and in-line molding to form the
hollow fiber unit. This is shown in FIG. 9 where a UV cure resin on the interior and exterior of
the fiber bundle 15 is used followed by an injection over molding of hot thermoplastic resin 16.
15 The over molding may be used to insure dimensional specification related to shape and outer
diameter of the potting sleeve and allow adequate mating with an end cap while the initial UV
spray coating may give sufficient rigidity to maintain the integrity of the hollow fiber lumens
during the molding step.
[0052] In certain embodiments, the hollow fiber unit may be disposed within a preformed
20 flexible bag and the end caps attached to the inlet and outlet port of the flexible bag. The
attachment of the end cap to the bag may use a variety of methods including, but not limited to a
solvent bond, threaded seal, melt seal, or a combination thereof.
[0053] Figure 10 shows one embodiment of the process by which a hollow fiber unit 1 is sealed
in the bag 2. The process may use a clamshell type press wherein rapidly cooled platens may be
25 used to seal the fibers in bag.
[0054] Alternative bag sealing concepts are shown in Figure 1 1 and depict various sealing
techniques of the hollow fiber bundles. As shown, the bundles may be adhered using an end cap
melt seal 19, a seal directly to the end caps, a housing melt seal 20, or a combined melt seal 21
method which may be used in certain embodiments. An end cap melt seal may be used to
30 maintain sterility if there is a rupture in the filter unit. The end cap melt seal would insure the
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PCT Text.doc 9
material is contained in the bag, allowing for hll sterile recovery and testing in a different filter
set. A combined hybrid melt seal would also maintain sterility as well as eliminating the need
for a solvent weld or threaded connection. In each embodiment, a rigid thermoplastic part may
be used in place of the bag.
5 EXPERIMENTAL
(00551 A housingless filter was constructed using the batch process illustrated in FIG. As
shown, a hollow fiber bundle 3 is blocked, inserted into potting cups 4 containing potting
material and a potting sleeve 5 is formed around the bundle. End caps 6 are attached and
inserted into inlet and outlet ports 7 of the filter bag. The filter was tested in a paired test with a
10 standard housing type filter. Results are shown in Table 1.
Tablel. Results of paired test of standard and housingless U-shape filters
[0056] As shown in Table 1, the cell recoveries with a housingless filter apparatus are
essentially the same as the control; small difference may be attributed unrelated process
variables. TNC refers to total nucleated cells; MNC refers to mono nucleated cells. During
filtration, no significant operational issues were observed with the housingless filter. A slightly
20 elevated feed pressure for the housingless filter was noted along with a slightly lower filtration
time. Both of these effects are most likely due to having a slightly larger fiber length in the
housingless filter as compared with the control.
TNU MNC
recovery
Final
hema tocrit
Final volume
100571 A second bag filter was constructed according to the process shown in Fig. 13. A thermal
block of fibers was used. The bag filter was also made in a "straight-through" configuration to
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PST Text.doc 10
Standard filter
75.8% * 1.8%
65.7% * 3.6%
10.7% * 0.1%
21.7 m~
Filter in a bag
76.1% * 1.8%
67.2% * 2.4%
7.9% * 0.1%
24.1 m~
help with fiber wetting. The fluid flow path during the filtration step was from the top down.
Table 2 shows the result of the flow through filter compared to a control.
Table 2: Results of paired test of standard and housingless filters straight configuration
5
[0058] A typical end cap design for manual potting operations and testing is shown in FIG 14.
The unit 22 is a combined breakable potting cup 23 with a bonded end cap 24 to allows for a
manual potting step that does not require operator adjustment of potting cup height. The design
10 of the potting cup is nonsymmetrical having a closed cylindrical lower portion and an open
funnel shaped upper portion to allow for a single fiber insertion step of the fiber bundle, without
potting material overflowing or running up too high on the fibers. The ends cap housing has a
tapered design such that the inner diameter of the end cap housing, on the side opposite the
hollow fiber bundle, is reduced. The end cap design may reduce stagnation volume of material
15 in this area of the filtration. The design may allow for air purge to more completely displace
material present in the endcap.
TNClMNC
recovery
TNC viability
Final hematocrit
Hemolysis
Final volume
[0059] A process for attaching the end caps is shown in FIG. 15. A total number of twenty-one
fibers, were drawn into a bundle using a reducing device 25, in this case a funnel. At the desired
20 length, the fiber bundle is crimped with a cylindrical metal bar 26 and tightly bundled using a
thin piece of scotch tape. A hot knife 27 (Therrno-Schneider 20 ZTS, knife temp at
approximately 400' F) was used to cut the bundle. The cut can be made so that the fibers are
melt sealed on both sides of the cut. The fiber bundle is then potted in the customized potting
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PCT 7ext.rJoc 11
Standard filter
89.3% 54.0%
88.6% 53.0%
98.3% 50. 1 %
32% 50.1%
0.8% ~0.01%
21.2mL
Filter in bag
90.8% 54.1 %
91.5% ~ 3 . 2 %
98.6% 50.3%
31.4% 20.1%
0.6% 50.01 %
22.2mL
cup 28; the tight bundle provided by the scotch tape allows the fibers to be inserted easily into
the cup.
[0060] Because the end of the fiber bundle is tightly held together from the melt seal, the
standard potting epoxy of two parts EPON@ Resin 828 (Shell Chemical Company) and one part
5 ~~i-cur3e 1@40 (Shell Chemical Company) is too viscous to fully penetrate the inter-fiber area
before curing. We have found that mixing the standard epoxy, heating the mixture at 40' C for
15 min, pouring into the potting cup, and inserting the fibers, and holding at 40' C fully
penetrates the inter-fiber area within the bundle and gives a good seal after 24 hr. After curing,
the ends of the cup are broken off (a tab on the cup facilitates this step), and the end caps 29 are
10 inserted. The end caps were sealed with a small amount of polysulfone glue (polysulfone chips
dissolved in methylene chloride). The fiber assembly is inserted into a bag 30 by pushing the
end caps through the bag ports and melt sealing the bag. In an alternative production laminating
two EVA sheets around the end caps may be used to form a flexible bag.
[0061] While only certain features of the invention have been illustrated and described herein,
15 many modifications and changes will occur to those skilled in the art. It is, therefore, to be
understood that the appended claims are intended to cover all such modifications and changes as
fall within the true spirit of the invention.
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Claims:
1. A method of manufacturing a housingless hollow fiber filtration apparatus comprising
the steps of:
compressing, cutting, and heat-sealing the ends of a bundle of hollow fibers;
5 inserting both ends of the cut hollow fiber bundle into separate potting cups that are
filled with curable potting material;
curing the potting material;
cutting the potting cups and bundle of hollow fibers to expose open hollow fibers while
retaining a portion of the potting cups;
10 attaching end cap housings to the retained portion of the potting cups; providing two
thermoplastic parts wherein said thermoplastic parts have matching apertures along the edges of
the thermoplastic parts to form inlet and outlet ports when sealed;
positioning the hollow fiber unit between two thermoplastic parts such that the end cap
housings are inserted into the apertures; and
15 sealing the peripheral edges of the two thermoplastic parts together to form a closed
filtration apparatus.
2. The method of claim 1 wherein the thermoplastic parts comprise planar flexible films.
20 3. The method of claim 2 further comprising the steps of:
forming additional melt seals longitudinally along opposing sides of the flexible films to
form a flexible bag having two additional compartments along the peripheral edges of said
flexible bag; and
filling said compartments with at least one of air, liquid, or foam.
4. The method of claim 3 wherein the inlet and outlet ports are in juxtaposition along one
edge of the flexible bag and the two planar flexible films are melt sealed along the opposing side
of the inlet and outlet ports to form a compartment along the lower edge of the flexible bag and
wherein said compartment if filled with at least one of air, liquid, or foam.
30
5. The method of claim 1 wherein the thermoplastic parts comprise rigid three dimensional
parts.
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6. The method of claim 1 wherein the potting material comprises a UV cured adhesive,
visible light cured adhesive, heat cured adhesive, thermoplastic resin, thermoset resin, or
combination thereof.
5 7 The method of claim 1 wherein the ends cap housing has a tapered design such that the
inner diameter of said end cap housing, on the side opposite the hollow fiber bundle, is reduced.
8. The method of claim1 wherein the potting cup is designed so the closed portion
is cylindrical and the open portion has a funnel shape.
10
9. The method of claiml wherein the end cap housing is independently attached to the
potting sleeves, inlet port, and outlet port by an adhesive, solvent bond, threaded seal, retaining
clip, melt seal, compression seal, pressure fit, or a combination thereof.
10. A method of manufacturing a housingless hollow fiber filtration apparatus comprising
15 the steps of:
forming a continuous bundle of hollow fibers aligned longitudinally along a winding
apparatus;
applying a potting material to the bundle of hollow fibers at a set position along the
winding apparatus;
curing the potting material to form a potting sleeve;
cutting the potting sleeves and bundle of hollow fibers to expose open hollow fibers
while retaining a portion of the potting sleeves;
attaching end cap housings to the retained portion of the potting sleeves; providing two
thermoplastic parts wherein said thermoplastic parts have matching apertures along the edges of
25 the films to form inlet and outlet ports when sealed;
positioning the hollow fiber unit between two thermoplastic parts such that the end cap
housings are inserted into the apertures; and
sealing the peripheral edges of the two thermoplastic parts together to form a closed
filtration apparatus.
30
1 1. The method of claim 10 wherein the thermoplastic parts comprise planar flexible films.
12. The method of claim 1 1 further comprising the steps of:
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FCT Text.doc 14
forming additional melt seals longitudinally along opposing sides of the planar flexible
films to form a flexible bag having two additional compartments along the peripheral edges of
said flexible bag; and
filling said compartments with at least one of air, liquid, or foam.
5
13. The method of claim 12 wherein the inlet and outlet ports are in juxtaposition along one
edge of the flexible bag and the planar flexible films are melt sealed along the opposing side of
the inlet and outlet ports to form a compartment along the lower edge of the flexible bag and
wherein said compartment if filled with at least one of air, liquid, or foam.
10
14. The method of claim 10 wherein the thermoplastic parts comprise rigid threedimensional
parts.
15. The method of claim 10 wherein the potting material comprises a UV cured adhesive,
15 visible light cured adhesive, heat cured adhesive, thermoplastic resin, thermoset resin, or
combination thereof.
16. The method of claim 10 wherein the ends cap housing has a tapered design such that the
inner diameter of said end cap housing, on the side opposite the hollow fiber bundle, is reduced.
20
17. The method of claim 10 wherein the end cap housing is independently attached to the
potting sleeves, inlet port, and outlet port by an adhesive, solvent bond, threaded seal, retaining
clip, melt seal, compression seal, pressure fit, or a combination thereof.
25 18. The method of claim 10 further comprising the step of applying a sealant coating to the
bundle of hollow fibers to provide adhesion between fibers.
19. A method of manufacturing a housingless hollow fiber filtration apparatus comprising
the steps of:
3 0 forming a continuous bundle of hollow fibers aligned longitudinally along a winding
apparatus;
attaching end cap housings to the bundle of hollow fibers at a set position along the
winding apparatus wherein the end cap housing comprises an exterior fill port;
injecting a potting material into the exterior fill port such that potting material contacts
the bundle of hollow fibers;
curing the potting material to form a potting sleeve;
cutting the end cap housings to expose open hollow fibers while retaining a portion of
5 the end cap housings;
providing two thermoplastic parts wherein said thermoplastic parts have matching
apertures along the edges of the thermoplastic parts to form inlet and outlet ports when sealed;
positioning the hollow fiber unit between the two thermoplastic parts such that the end
cap housings are inserted into the apertures; and
10 melt sealing the peripheral edges of the two thermoplastic parts together to form a closed
filtration apparatus.
20. The method of claim 19 wherein the end cap housings are attached using a two part
locking connection, overmolding, or a combination thereof.
15
2 1. The method of claim 19 wherein the potting material comprises a UV cured adhesive,
visible light cured adhesive, heat cured adhesive, thermoplastic resin, thermoset resin, or
combination thereof.
20 22. The method of claim 19 further comprising the step of applying a sealant coating to the
bundle of hollow fibers to provide adhesion between fibers.
23. The method of claim 19 wherein the thermoplastic parts comprise planar flexible films.
25 24. The method of claim 23 further comprising the steps of:
forming additional melt seals longitudinally along opposing sides of the planar flexible
films to form a flexible bag having two additional compartments along the peripheral edges of
said flexible bag; and
filling said compartments with at least one of air, liquid, or foam.
25. The method of claim 24 wherein the inlet and outlet ports are in juxtaposition along one
edge of the flexible bag and the planar flexible films are melt sealed along the opposing side of
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FCT Text.doc 16
the inlet and outlet ports to form a compartment along the lower edge of the flexible bag and
wherein said compartment if filled with at least one of air, liquid, or foam.
26. The method of claim 19 wherein the thermoplastic parts comprise rigid three-
5 dimensional parts.
27. The method of claim 19 wherein the end cap housing is attached to the inlet port and
outlet port by an adhesive, solvent bond, threaded seal, retaining clip, melt seal, compression
seal, pressure fit, or a combination thereof.
10
28. The method of claim 19 further comprising the step of applying a sealant coating to the
bundle of hollow fibers to provide adhesion between fibers.
Dated this 6/6/20 12
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PCT Text.doc