Semi-rigid biological container and manufacturing method thereof

Abstract

The present application relates to a biological container comprising a rigid frame and a flexible membrane. The frame includes a lattice core. When the temperature of the biological material changes, the membrane may flex to accommodate the volume of the biological material sealed inside the biological container.

Description

Technical Field

[0001] The present disclosure relates to storage of biopharmaceutical compositions, and more particularly, to semi-rigid biocontainers and methods of making the same. Background Art

[0002] Cryopreservation is a critical step in the production of biopharmaceutical compositions, including monoclonal antibodies, vaccines, cell banks, virus banks, and cell therapy products. Immobilizing macromolecules, cells, or virus particles in a solid matrix can prolong the stability of biopharmaceutical compositions, allowing for more efficient production operations, global transportation, and long-term supply.

[0003] Using polymeric single-use containers (bags, bottles, tubes, and components such as connectors) in a temperature range of -20°C to -196°C is a significant challenge that requires careful selection of materials and packaging. For example, when freezing a biopharmaceutical composition (hereinafter referred to as "biomaterial"), the volume of the biomaterial may increase or decrease. The change in volume can exert forces on the biocontainer. In addition, as the biocontainer is frozen, the properties of the materials that make up the biocontainer may change. Certain materials that make up the biocontainer may become less flexible and / or more brittle.

[0004] In certain applications, the material from which the biocontainer is formed may present challenges to rapid freezing or thawing of the biomaterial within the biocontainer. Specifically, the amount of heat transferred into or out of the biocontainer may be limited by the type of material and / or the amount of material from which the biocontainer is formed. The type of material or the amount of material may be selected to prevent damage to the biocontainer during filling, freezing, storage, thawing, and shipping, and the type of material or the amount of material from which the biocontainer is formed may prevent or inhibit rapid freezing or thawing of the biomaterial within the biocontainer.

[0005] In some applications, biocontainers are handled by humans, equipment, or machines before, during, or after freezing. If the material forming the biocontainer is brittle, the biocontainer may be damaged when it is handled. In addition, when handled by machines, a uniform shape and size is required so that the machine can move the biocontainer without damaging it.

[0006] In some applications, flexible bags are used as biocontainers. Such flexible bags can quickly transfer heat into and out of the biomaterial in the bag. However, as mentioned above, these flexible bags may become brittle when frozen. In addition, these flexible bags may change shape when freezing the biomaterial therein, making the flexible bags difficult to handle. In addition, when the biomaterial is frozen in the flexible bags, the flexible bags may be difficult to stack or store due to the irregular shape of the flexible bags.

[0007] Therefore, there is a need for biocontainers that can be cryogenically frozen without damage. There may be a need for biocontainers that can be handled by machinery or equipment without damage. There may be a need for biocontainers that have a consistent shape after freezing to allow for compaction and / or simplified storage. Summary of the invention

[0008] The present disclosure generally relates to semi-rigid biocontainers for storing biopharmaceutical compositions. The biocontainers disclosed herein can have a consistent shape, allowing the biocontainers to be handled by machines or equipment without damage. In certain embodiments, the biocontainers can remain sealed under cryogenic conditions.

[0009] In one embodiment of the present disclosure, a biocontainer includes a rigid frame and a flexible membrane. The rigid frame includes a lattice core. The flexible membrane is attached to the frame, forming a sealed interior of the biocontainer.

[0010] In some embodiments, the biocontainer includes a first tube extending through the frame and in fluid communication with the interior of the biocontainer. The biocontainer may include a second tube extending through the frame and in fluid communication with the interior of the biocontainer. The first tube may be formed of a thermosetting material (e.g., silicone) and the second tube may be formed of a thermoplastic material. The first tube and the second tube may be sealingly attached to the frame. The first tube or the second tube may be overmolded onto the frame.

[0011] In some embodiments, the biocontainer remains sealed to at least -180°C or -196°C. At least a portion of the frame may be disposed within the interior of the biocontainer. The entire frame may be located within the interior of the frame.

[0012] In certain embodiments, the frame may form an exoskeleton of the biocontainer.The frame may include stacking features on a major surface of the frame.The stacking features may be configured to receive stacking features of another biocontainer.

[0013] In certain embodiments, the frame may be enclosed within a sheath. The membrane may be attached to the sheath. The sheath forms part of the interior of the biocontainer.

[0014] In another embodiment of the present disclosure, a method of making a biocontainer includes forming a rigid frame having a lattice core, and attaching a flexible membrane to the frame to seal an interior of the biocontainer.

[0015] In some embodiments, forming the frame comprises overmolding the lattice core.Forming the frame may comprise forming the frame via additive manufacturing techniques.

[0016] In some embodiments, forming the frame may include encapsulating the core with a sheath. Attaching the membrane to the frame may include bonding the membrane to the sheath.

[0017] In some embodiments, the first tube and the second tube are fixed to the frame so that the first tube and the second tube are fixed relative to the frame. Fixing the first tube and the second tube may include overmolding the first tube and the second tube. Fixing the first tube and the second tube may include the first tube being a thermoset tube, such as a silicone tube, and the second tube being a thermoplastic tube.

[0018] In certain embodiments, attaching the flexible membrane may include attaching the flexible membrane to an inner surface of the frame such that the frame forms an exoskeleton of the flexible membrane.

[0019] In another embodiment of the present disclosure, a method of storing a biopharmaceutical composition includes placing the biopharmaceutical composition into a biocontainer, and cryogenically freezing the biocontainer containing the biopharmaceutical composition.

[0020] In addition, any embodiment or aspect described herein may be used in combination with any or all other embodiments or aspects described herein, within the scope of consistency. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Various aspects of the present disclosure will be described below with reference to the accompanying drawings, which are incorporated into and constitute a part of this specification, in which:

[0022] Figure 1 is a top view of a biocontainer provided according to one embodiment of the present disclosure;

[0023] Figure 2 yes Figure 1 An enlarged top view of a biocontainer;

[0024] Figure 3 yes Figure 1 A side perspective view of a biocontainer;

[0025] Figure 4 is a top view of a mold provided according to one embodiment of the present disclosure;

[0026] Figure 5 yes Figure 4 A top view of a mold having a frame formed therein;

[0027] Figure 6 is a flow chart of a method provided according to the present disclosure;

[0028] Figure 7 is a top view of another biocontainer provided according to one embodiment of the present disclosure, with a film formed on the inner side of the frame; and

[0029] Figure 8 is a top view of the biocontainer of FIG. 9 , with a membrane formed on the outside of the frame. DETAILED DESCRIPTION

[0030] The present disclosure will be described more fully below with reference to the accompanying drawings, in which like reference numerals represent the same or corresponding elements in each of the several views. These exemplary embodiments are described so that the present disclosure will be thorough and complete and fully convey the scope of the disclosure to those skilled in the art. Features from one embodiment or aspect may be combined with features from any other embodiment or aspect in any appropriate combination. For example, any individual or common feature of the method aspect or embodiment may be applied to the device, product or component aspect or embodiment, and vice versa. The present disclosure may be embodied in many different forms and should not be construed as being limited to the embodiments described herein; on the contrary, these embodiments are provided so that the present disclosure will satisfy applicable legal requirements. In the specification and the appended claims, the singular forms "a", "the", "said", etc. include plural references unless the context clearly dictates otherwise. In addition, although quantitative measures, values, geometric relationships, or the like may be mentioned herein, unless otherwise stated, any one or more (if not all) of these may be absolute or approximate to take into account acceptable variations that may occur, such as those due to manufacturing or engineering tolerances or the like. In the specification and the appended claims, the term "low temperature" refers to a temperature of -20 ºC or below, and generally refers to a temperature range of -20 ºC to -196 ºC. In addition, the term "biopharmaceutical composition" as used herein refers to products from biotechnology, culture environments, cell cultures, buffer solutions, artificial nutrient solutions, blood products and derivatives of blood products, pharmaceutical products, or more generally refers to products used in the medical field, including but not limited to monoclonal antibodies (mAbs), therapeutic proteins, viruses (including lipid nanoparticle vaccines and virus banks), exosomes, cell banks and cell therapy products.

[0031] Reference now Figure 1-3 According to one embodiment of the present disclosure, a semi-rigid biocontainer 10 is provided. The biocontainer 10 has a defined shape and includes tubing connections 12, 14, 16 that allow material to flow into an interior 18 of the biocontainer 10. The joints or connections of the tubes may be overmolded, attached with an adhesive, or mechanically fastened to sealingly attach thermoset tubing (e.g., silicone tubing) and / or thermoplastic tubing (e.g., PVC, polyolefin, TPE) to the biocontainer 10. In certain embodiments, a single biocontainer 10 may include both thermoset and thermoplastic tubing. The biocontainer 10 may be relatively thin, with a length and width significantly greater than a thickness, similar to a conventional fluid bag. The size of the biocontainer 10 may allow heat to be transferred into and out of the biocontainer 10 evenly and quickly. The size of the biocontainer 10 may allow for long-term storage of biological materials in the biocontainer 10.

[0032] The defined shape of the biocontainer 10 can simplify handling of the biocontainer 10 by equipment, machinery, or by hand. Simplifying the handling of the biocontainer 10 can increase the degree of automation of filling, freezing, storing, thawing, and / or emptying of the biocontainer 10. The defined shape of the biocontainer 10 can simplify the storage and / or stacking of multiple biocontainers 10. For example, when flexible bags are used to store biological materials, it may be difficult to stack multiple flexible bags because each respective flexible bag may have a different shape than an adjacent flexible bag. In contrast, the defined shape of the biocontainer 10 can allow for stacking of multiple biocontainers 10. The defined shape of the biocontainer 10 can provide a defined or known volume of the biocontainer 10. The defined or known volume of the biocontainer can facilitate determining the volume of biological material within the biocontainer 10.

[0033] The biocontainer 10 includes a rigid frame 20 and a flexible membrane 40. The rigid frame 20 defines the size of the biocontainer 10 and supports the membrane 40. The rigid frame 20 defines the shape of the biocontainer 10. The frame 20 includes a core 22, which can be formed of a rigid lattice structure that defines the shape of the frame 20, and thus also defines the shape of the biocontainer 10. The rigid lattice structure can minimize the amount of material used to form the frame 20 while providing a rigid structure. In some embodiments, the core 22 is encapsulated in a sheath 24. The sheath 24 can partially form a seal for the interior 18 of the biocontainer 10. In some embodiments, portions of the sheath 24 can be configured to contact biological material disposed within the biocontainer 10. The sheath 24 can prevent the core 22 or portions thereof from contacting the biological material within the biocontainer 10. In some embodiments, the sheath 24 can be compatible with the membrane 40, such that the membrane 40 or the sheath 24 can be partially melted to bond the membrane 40 to the frame 20.

[0034] The entire frame 20 or a portion thereof may be disposed within the interior 18 of the biocontainer. In certain embodiments, the entire frame 20 or a portion thereof may be located outside the interior 18. The portion of the frame 20 disposed outside the interior 18 may be considered an exoskeleton of the biocontainer 10. The portion of the frame 20 disposed within the interior 18 may be considered an inner frame of the biocontainer 10.

[0035] When the frame 20 includes an inner frame, the inner frame can form a lattice structure. The void volume of the lattice structure of the inner frame can be greater than 75% to maximize the storage volume of the biocontainer 10. In some embodiments, the thickness of the lattice structure is minimized to maximize the storage volume of the biocontainer 10. In some embodiments, the inner frame is formed by the core 22 of the frame 20. In certain embodiments, a portion of the core 22 can be configured to contact the biological material within the biocontainer 10.

[0036] Portions of the frame 20, including the core 22 or the jacket 24, may include a variety of materials, including thermosets or thermoplastics. In some embodiments, portions of the frame 10 are formed from a resin-based thermoset material, such as a carbon-based material (Carbon) including CE221 or MPU100. In some embodiments, portions of the frame 10 are formed by selective laser sintering (SLS) of nylon, polyetheretherketone (PEEK), polyolefins, polytetrafluoroethylene (PTFE), or other thermoplastic materials. In some embodiments, portions of the frame 20 may be metallized. The metallized portions of the frame 20 may increase the transfer of heat into or out of the biomaterial stored in the biocontainer 10. In some embodiments, the metallized portions of the frame 20 may allow for inductive heating of the biomaterial in the biocontainer 10. In some embodiments, the metallized portions of the frame 20 may increase the stiffness of the frame 20. In certain embodiments, metallizing the frame 20 may increase the inertness of the frame 20 and / or the purity of the biomaterial disposed in the biocontainer 10.

[0037] In some embodiments, portions of the frame 20 may be formed using additive manufacturing techniques. As described in detail below, forming the frame 20 using additive manufacturing techniques may improve adhesion or bonding of the membrane to the frame 20. In certain embodiments, the core 22 is formed using additive manufacturing techniques in a manner that increases the attachment or bonding of the sheath 24 and / or the membrane 40 to the core 22. In some embodiments, the core 22 or the sheath 24 of the frame 20 may be molded.

[0038] The membranes 40 may be attached or bonded to the rigid frame 20 to form the interior 18 of the biocontainer 10. In certain embodiments, the interior 18 of the biocontainer 10 is defined between the membranes 40. In certain embodiments, portions of the interior 18 are defined by the frame 20 disposed between the membranes 40.

[0039] The membrane 40 can be formed of a flexible material that can accommodate changes in volume of the biomaterial disposed within the interior 18 of the biocontainer 10. The membrane 40 can be formed of or can include a thermoset material or a thermoplastic material. For example, the membrane 40 can include silicone and / or a thermoplastic. In certain embodiments, the membrane 40 includes a microporous material for dissolving or improving the transport of oxygen or carbon dioxide into and out of the biocontainer 10. Improving the transport of oxygen or carbon dioxide can improve the growth of cells within the biocontainer 10.

[0040] In some embodiments, the membrane 40 may be a composite membrane having a first side formed of a first material and a second side formed of a second material. In some embodiments, the composite membrane 40 may include a thermally conductive silicone as an outer surface laminated with a pure silicone membrane forming an inner surface. In some embodiments, the composite membrane 40 includes a conductive silicone laminated with a pure silicone membrane for inductively heating the biomaterial within the biocontainer 10.

[0041] The membrane 40 may be uniform on both sides of the biocontainer 10, or may be different on both sides of the biocontainer 10. In some embodiments, each membrane 40 may have a uniform construction. In certain embodiments, portions of the membrane 40 may have a different construction than other portions of the membrane 40. For example, one or more portions of the membrane 40 may include a thermally conductive silicone, an electrically conductive silicone, or a microporous material. In some embodiments, the membrane 40 may include a silicone rubber having a thickness in the range of 0.01 mm to 3 mm (e.g., 1 mm). The membrane 40 may be formed of silicone having any hardness. In some embodiments, the membrane 40 may be formed of silicone having a Shore A hardness in the range of 30-80. As described above, the membrane 40 may be a multi-layer film calendered from silicone rubber, including a thermally conductive layer on the outside and a silicone having a Shore A hardness in the range of 30-80 on the biomaterial contacting surface (e.g., the inner surface). The membrane 40 may be a multi-layer film, with an electrically conductive film on the outer surface for induction or radio frequency heating of the biomaterial in the container, and a film having a Shore A hardness in the range of 30-80 on the inner surface. The membrane 40 can be a rubber cast onto an expanded polytetrafluoroethylene (ePTFE) membrane or a microporous membrane, such as polyethersulfone (PES), polypropylene (PP), etc. In some embodiments, the membrane 40 can be a silicone rubber cast onto a non-woven membrane. The membrane 40 can be a perfluoropolyether (PFPE) rubber calendered into a sheet. The membrane can be a TPE membrane attached using an EPE adhesive (e.g., Santoprene™ 8291TB). The membrane 40 can be nylon, PE material, cyclic olefin polymer (e.g., Zeonex), metallized plastic film, glass-coated plastic film, PEEK, PES, polyetherimide (PEI) (e.g., Ulterm), polyimide (PI) material (e.g., Kapton). The membrane 40 can be a functionalized membrane to improve the crystal structure of the frozen product or to interact with the biological material stored in the biocontainer 10.

[0042] The membrane 40 can be attached, bonded or adhered to the frame 20. In some embodiments, the membrane 40 can be attached with LIMTM 8040 or other platinum catalyzed silicone adhesives available from Momentive Performance Materials. In some embodiments, the frame 20 and the membrane 40 are compatible with each other, so that the frame 20 and the membrane 40 can be bonded by locally melting the frame 40 and / or the membrane 40 together. In some embodiments, the frame 20 can be molded around the membrane 40 so that the frame 20 is bonded to the membrane 40. In some embodiments, the frame 20 is compatible with the outer surface of the membrane 40, but not compatible with the inner surface of the membrane 40; in other embodiments, the frame 20 is compatible with the inner surface of the membrane 40, but not compatible with the outer surface of the membrane 40.

[0043] The biocontainer 10 may include one or more embedded sensors 50. The sensors 50 may monitor the temperature of the biomaterial within the biocontainer 10. In certain embodiments, the biocontainer 10 includes a thermowell for temperature monitoring. The thermowell may be positioned as a leading indicator of a change in temperature of the biomaterial, or may also be positioned as a trailing indicator of a change in temperature of the biomaterial.

[0044] Reference now Figure 4-6 According to one embodiment of the present disclosure, a method of manufacturing a biocontainer is disclosed, generally referred to as method 100. Although the method 100 can be used to form a variety of biocontainers, this document will refer to Figure 1-3 The method 100 is described with reference to the biocontainer 10 in FIG. The method 100 may include forming the frame 20 (step 110). Forming the frame 20 may include molding a core 22 of the frame 20 or producing the core 22 via an additive manufacturing technique. The core 22 may include a lattice structure. The lattice core 22 may reduce the amount of material used to form the frame 20. When forming the core 22, the core 22 is positioned in a mold 210, such as Figure 4 and Figure 5 as shown (step 120).

[0045] The method 100 may include positioning the tubes 12, 14, 16 in the mold 210 (step 130). The tubes 12, 14, 16 may be silicone tubes and / or TPE tubes. In some embodiments, at least one of the tubes 12, 14, 16 is a silicone tube and at least one of the tubes 12, 14, 16 is a TPE tube. Each of the tubes 12, 14, 16 may pass through an opening in the core 22. With the tubes 12, 14, 16 positioned in the mold 210, the mold 210 is closed and a material is poured or injected into the mold 210 to encapsulate the core 22 of the frame 20 in the sheath 24 (step 140). The material poured or injected into the mold 210 to form the sheath 24 may be silicone. After the material is poured into the mold 210, the material is allowed to cure or cool within the mold to form the frame 20 and / or to bond the tubes 12, 14, 16 to the frame 20 (step 150). The material forming the frame 20 may be bonded to the conduits 12, 14, 16 as the material is poured into the mold 210. For example, the conduits 12, 14, 16 may be overmolded to secure and seal the conduits 12, 14, 16 to the frame 20. By overmolding the conduits 12, 14, 16, a variety of types of conduits may be used with the method 100 to form the biocontainer 10. After the material encapsulating the core 22 to form the sheath 24 cools, the mold 210 is opened and the complete frame 20 including the conduits 12, 14, 16 is removed from the mold 210 (step 160).

[0046] After the frame 20 is completed, the membrane 40 is attached to the frame 20 to form and seal the interior 18 of the biocontainer 10 (step 170). The membrane 40 can be attached or bonded to the frame 20. In some embodiments, the membrane 40 includes a silicone layer that is attached to the silicone of the frame 20 with an adhesive. The membrane 40 and the frame 20 can form an all-silicone contact surface for the interior 18 of the biocontainer 10. In some embodiments, the membrane 40 can be formed by pouring silicone onto a carrier film. The carrier film can be a PET film, a PES film, or a polycarbonate film. In some embodiments, the membrane 40 can be bonded to the frame 20. In some embodiments, portions of the membrane 40 and / or the frame 20 are locally melted to bond the membrane 40 to the frame 20. The membrane 40 can be attached to the inside of the frame 20, which forms an exoskeleton for the membrane 40, or the membrane 40 can be attached to the outside of the frame 20 so that portions of the frame 20 are disposed in the interior 18.

[0047] Method 100 is one example of a method for forming a biocontainer, such as biocontainer 10. In some embodiments, portions of frame 20 may be formed by additive manufacturing techniques, such as three-dimensional printing or molding. In some embodiments, portions of frame 20 may be formed separately from membrane 40. In such embodiments, membrane 40 may be attached to frame 20 using one or more adhesives.

[0048] Reference now Figure 7 and Figure 8 According to one embodiment of the present disclosure, another biocontainer 310 is disclosed. The biocontainer 310 includes a frame 320 and a membrane 340. The components of the biocontainer 310 may be the same as those described above. Figure 1-3 Elements of the detailed biocontainer 10 are similar and are indicated by similar reference numerals preceded by 3. Therefore, other than the differences with the biocontainer 10, aspects of the biocontainer 310 will not be described in detail.

[0049] The frame 320 of the biocontainer 310 may include a core 322 having an edge portion 321 and a center portion 323. The edge portion 321 is rigid to define at least two dimensions of the biocontainer 310, such as width and length. In some embodiments, the edge portion 321 defines the width, length, and thickness of the biocontainer 310. As shown, the edge portion 321 can be generally solid. In some embodiments, the edge portion 321 can include a lattice to reduce the amount of material forming the edge portion 321. The frame 320 can be formed by molding or additive manufacturing techniques. In some embodiments, the frame 320 is molded so that a conduit (not explicitly shown) is overmolded to secure the conduit to the frame 320.

[0050] The center portion 323 can form a lattice that extends between opposing edges of the edge portion 321 of the frame 320. The lattice of the center portion 323 can be rigid so that the center portion 323 maintains its dimensions, or can be flexible so that the center portion 323 can bend when subjected to force. In certain embodiments, the center portion 323 can bend inward to reduce the thickness of the biocontainer 310, or can bend outward to increase the thickness of the biocontainer 310. The bending of the center portion 323 can be in response to an increase or decrease in the volume of the biological material stored in the biocontainer 310. In certain embodiments, the center portion 323 can include stacking or strengthening features 326. In certain embodiments, the center portion 323 on a first side of the biocontainer 310 can include stacking features 326 having a first size, and the center portion 323 on an opposing second side of the biocontainer 310 can include stacking features 326 having a second size that is complementary to the stacking features 326 on the first side of the biocontainer 310. For example, when the biocontainer 310 is stacked with other biocontainers 310, the stacking features 326 may help stack the biocontainer 310 to allow a greater number of biocontainers 310 to be stacked together.

[0051] As shown, the membrane 340 of the biocontainer 310 is attached or bonded to the inner surface of the frame 320 so that the frame 320 acts as an exoskeleton. In certain embodiments, the membrane 340 can be attached or bonded to the outer surface of the frame 320, with the frame 320 disposed inside the membrane 340. The membrane 340 can be attached to the frame 320 so that the membrane 340 can be bent into or out of the frame 320. The bending of the membrane 340 can allow the membrane 340 to adapt to the volume of the biological material contained within the biocontainer 310.

[0052] Although several embodiments of the present invention are shown in the accompanying drawings, it is not intended to limit the present invention thereto, as the intention of the present invention is to expand the scope of the present invention to the extent permitted by technology, and the specification of the present invention is read in the same manner. Any combination of the above embodiments is also conceivable and within the scope of the appended claims. Therefore, the above description should not be understood as limiting, but merely as an illustration of a specific embodiment. Those skilled in the art will envision other modifications within the scope of the claims appended hereto.

Claims

1. A biocontainer, comprising: a rigid frame comprising a lattice core; as well as A flexible membrane is attached to the frame, the flexible membrane forming a sealed interior of the biocontainer.

2. The biocontainer of claim 1, further comprising a first tube extending through the frame and in fluid communication with an interior of the biocontainer.

3. The biocontainer of claim 2, further comprising a second tube extending through the frame and in fluid communication with the interior of the biocontainer, the first tube being formed of a thermosetting material and the second tube being formed of a thermoplastic material, the first tube and the second tube being sealingly attached to the frame. 4 . The biocontainer of claim 3 , wherein the first tube or the second tube is overmolded onto the frame.

5. The biocontainer of claim 1, wherein the biocontainer remains sealed to at least -196°C.

6. The biocontainer of claim 1, wherein at least a portion of the frame is disposed within an interior of the biocontainer.

7. The biocontainer of claim 6, wherein the entire frame is located within the interior of the biocontainer.

8. The biocontainer of claim 1, wherein the frame forms an exoskeleton of the biocontainer.

9. The biocontainer of claim 1, wherein the frame includes stacking features on a major surface of the frame configured to receive stacking features of another biocontainer.

10. The biocontainer of claim 1, wherein the lattice core of the frame is encapsulated within a sheath.

11. The biocontainer of claim 10, wherein the flexible membrane is attached to the sheath.

12. The biocontainer of claim 11, wherein the sheath forms part of the interior of the biocontainer.

13. A method for storing a biopharmaceutical composition, the method comprising: Filling the biopharmaceutical composition into the biocontainer according to claim 1; as well as The biocontainer containing the biopharmaceutical composition is cryogenically frozen.

14. A method of manufacturing a biocontainer, the method comprising: forming a rigid frame having a lattice core; as well as A flexible membrane is attached to the frame to seal the interior of the biocontainer.

15. The method of claim 14, wherein forming the frame comprises overmolding the lattice core.

16. The method of claim 14, wherein forming the frame comprises forming the frame via an additive manufacturing technique.

17. The method of claim 14, wherein forming the frame comprises encapsulating the lattice core with a sheath.

18. The method of claim 17, wherein attaching the flexible membrane to the frame comprises bonding the flexible membrane to the sheath.

19. The method of claim 14, further comprising securing a first tube and a second tube to the frame such that the first tube and the second tube are fixed relative to the frame.

20. The method of claim 19, wherein securing the first tube and the second tube comprises overmolding the first tube and the second tube.

21. The method of claim 19, wherein securing the first tube and the second tube comprises the first tube being a thermoset tube and the second tube being a thermoplastic tube.

22. The method of claim 14, wherein attaching the flexible membrane comprises attaching the flexible membrane to an inner surface of the frame such that the frame forms an exoskeleton for the flexible membrane.

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