SEMI-RIGID BIOCONTAINER AND METHODS OF MANUFACTURING THE SAME

A biocontainer including a rigid frame and a flexible membrane. The frame includes a lattice core. The membrane may flex to adjust to a volume of biomaterial sealed within the interior of the biocontainer as a temperature of the biomaterial changes.

BACKGROUND

1. Technical Field

The present disclosure relates to storage of biopharmaceutical compositions and, more specifically, to semi-rigid biocontainers and methods of manufacturing the same.

2. Discussion of Related Art

Frozen storage is a key step in production of biopharmaceutical compositions including monoclonal antibodies, vaccines, cell banks, virus banks, and cell therapy products. By immobilizing the macromolecules, cells, or virus particles in a solid matrix, stability of the biopharmaceutical compositions can be extended enabling more efficient manufacturing operations, global transport, and long-term availability.

The use of polymeric single-use containers (bags, bottles, tubing, and components such as connectors) at temperatures in the range −20° C. to −196° C. is a significant challenge requiring careful attention to material selection and packaging. For example, as biopharmaceutical compositions (hereinafter “biomaterial”) are frozen, 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 forming the biocontainer may change. Some materials that form the biocontainers may become less flexible and/or become brittle.

In some applications, materials forming a biocontainer may create a challenge for rapid freezing or thawing of a biomaterial within the biocontainer. Specifically, the heat transfer into or out of a biocontainer may be limited by a type of material and/or an amount of material forming the biocontainer. While the type of material or the amount of material may be selected to prevent damage to the biocontainer during filling, freezing, storage, thawing, and transport, the type of material or the amount of material forming the biocontainer may prevent or inhibit rapid freezing or thawing of a biomaterial disposed within the biocontainer.

In some applications, biocontainers are handled by hand, equipment, or machines before, during, or after freezing. The handling of the biocontainers can damage the biocontainers if the material forming the biocontainer is brittle. In addition, when handling by machines, there is a need for a uniform shape and size to allow for the machine to move the biocontainer without damaging the biocontainer.

In some applications, a flexible bag is used as a biocontainer. Such flexible bags allow for rapid heat transfer into or out of a biomaterial within the bag. However, as noted above, these flexible bags may become brittle when frozen. Additionally, these flexible bags may change shape as biomaterial disposed therein is frozen making the flexible bags difficult to handle. Additionally, these flexible bags may be difficult to stack or store due to an irregular shape of the flexible bags when the biomaterial is frozen therein.

There is therefore a need for biocontainers that can be cryogenically frozen without damage. There may be a need for biocontainers that can be handled by machines or equipment without being damaged. There may be a need for biocontainers that have a uniform shape when frozen to allow for condensed and/or simplified storage.

SUMMARY

This disclosure relates generally to a semi-rigid biocontainer for storing biopharmaceutical compositions. The biocontainers disclosed herein may have a uniform shape that allow for the biocontainers to be manipulated by machines or equipment without being damaged. In some embodiments, the biocontainers may remain sealed at cryogenic temperatures.

In an embodiment of the present disclosure, a biocontainer includes a rigid frame and a flexible membrane. The rigid frame includes a latticed core. The flexible membrane is attached to the frame and forms a sealed interior of the biocontainer.

In embodiments, the biocontainer includes a first tube that extends through the frame and is in fluid communication with the interior of the biocontainer. The biocontainer may include a second tube that extends through the frame and in fluid communication with the interior of the biocontainer. The first tube may be formed of a thermoset 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 over-molded to the frame.

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 within the interior of the frame.

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

In particular embodiments, the frame may be encapsulated within a sheath. The membranes may be attached to the sheath. The sheath forms a portion of an interior of the biocontainer.

In another embodiment of the present disclosure, a method of manufacturing 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.

In embodiments, forming the frame includes over-molding the lattice core. Forming the frame may include forming the frame via additive manufacturing techniques.

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.

In certain embodiments, 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. Securing the first tube and the second tube may include over molding the first tube and the second tube. Securing the first tube and the second tube may include the first tube being a thermoset tube, e.g., a silicone tube, and the second tube being a thermoplastic tube.

In particular 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.

In another embodiment of the present disclosure, a method of storing a biopharmaceutical composition includes loading a biocontainer with biopharmaceutical composition and cryogenically freezing the biocontainer containing the biopharmaceutical composition.

Further, to the extent consistent, any of the embodiments or aspects described herein may be used in conjunction with any or all of the other embodiments or aspects described herein.

DETAILED DESCRIPTION

The present disclosure will now be described more fully hereinafter with reference to example embodiments thereof with reference to the drawings in which like reference numerals designate identical or corresponding elements in each of the several views. These example embodiments are described so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. Features from one embodiment or aspect can be combined with features from any other embodiment or aspect in any appropriate combination. For example, any individual or collective features of method aspects or embodiments can be applied to apparatus, product, or component aspects or embodiments and vice versa. The disclosure may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification and the appended claims, the singular forms “a,” “an,” “the,” and the like include plural referents unless the context clearly dictates otherwise. In addition, while reference may be made herein to quantitative measures, values, geometric relationships or the like, unless otherwise stated, any one or more if not all of these may be absolute or approximate to account for acceptable variations that may occur, such as those due to manufacturing or engineering tolerances or the like. As used in the specification and the appended claims, the term “cryogenic” refers to temperatures at or below −20° C. and refers to temperatures generally in a range of −20° C. to −196° C. Further, as used herein the term “biopharmaceutical compositions” refers to a product coming from biotechnology, culture environments, cell cultures, buffer solutions, artificial nutrition liquids, blood products and derivatives of blood products, a pharmaceutical product, or more generally a product intended to be used in the medical field including, without any limitation, monoclonal antibodies (mAbs), therapeutic proteins, viruses including lipid nanoparticles vaccines and virus banks, exosomes, cell banks, and cell therapy products.

Referring now toFIGS.1-3, a semi-rigid biocontainer10is provided in accordance with an embodiment of the present disclosure. The biocontainer10has a defined shape and includes tubing connections12,14,16that allow for the flow of material into an interior18of the biocontainer10. The junctions or connections of the tubes may be over-molded, adhesively attached, or mechanically fastened to sealingly attach thermoset tubing, e.g., silicone tubing, and/or thermoplastic tubing, e.g., PVC, polyolefin, TPE, to the biocontainer10. In some embodiments, a single biocontainer10may include both thermoset and thermoplastic tubing. The biocontainer10may be relatively thin with a length and a width significantly greater than a thickness similar to a traditional fluid bag. The dimensions of the biocontainer10may allow for uniform and rapid heat transfer into and out of the biocontainer10. The dimensions of the biocontainer10may allow for long term storage of biomaterial within the biocontainer10.

The defined shape of the biocontainer10may allow for simplified handling of the biocontainer10by equipment, machines, or by hand. The simplified handling of the biocontainer10may allow for increased automation of filling, freezing, storing, thawing, and/or emptying of the biocontainer10. The defined shape of the biocontainer10may allow for simplified storage and/or stacking of multiple biocontainers10. For example, when a flexible bag is used to store biomaterial, it may be difficult to stack multiple flexible bags as the shape of each of the respective flexible bags may differ from adjacent bags. In contrast, the defined shape of the biocontainer10may allow for stacking multiple biocontainers10. The defined shape of the biocontainer10may provide a defined or known volume of the biocontainer10. The defined or known volume of the biocontainer may ease determination of volume of biomaterial within the biocontainer10.

The biocontainer10includes a rigid frame20and flexible membranes40. The rigid frame20defines the dimensions of the biocontainer10and supports the membranes40. The rigid frame20defines the shape of the biocontainer10. The frame20includes a core22that may be formed of a rigid lattice structure that defines the shape of the frame20, and thus, the shape of the biocontainer10. The rigid lattice structure may minimize an amount of material forming the frame20while providing a rigid structure. In some embodiments, the core22is encapsulated within a sheath24. The sheath24may partially form a seal for the interior18of the biocontainer10. In some embodiments, portions of the sheath24may be configured to contact biomaterial disposed within the biocontainer10. The sheath24may prevent the core22or portions thereof from being contacted by biomaterial within the biocontainer10. In certain embodiments, the sheath24may be compatible with the membranes40such that the membranes40or the sheath24may be locally melted to bond the membranes40to the frame20.

The entire frame20or portions thereof may be disposed within the interior18of the biocontainer. In some embodiments, the entire frame20or portions thereof may be outside of the interior18. Portions of the frame20disposed outside of the interior18may be considered an exoskeleton of the biocontainer10. Portions of the frame20disposed within the interior18may be considered an inner frame of the biocontainer10.

When the frame20includes an inner frame, the inner frame may form a lattice structure. The lattice structure of the inner frame may have a void volume of greater than 75% to maximize a storage volume of the biocontainer10. In some embodiments, a thickness of the lattice structure is minimized to maximize a storage volume of the biocontainer10. In certain embodiments, the inner frame is formed of the core22of the frame20. In particular embodiments, portions of the core22may be configured to contact biomaterial within the biocontainer10.

Portions of the frame20, including the core22or the sheath24, may include a variety of materials including thermosets or thermoplastics. In some embodiments, portions of the frame10are formed of resin based thermosets such as Carbon including CE221 or MPU100. In certain embodiments, portions of the frame10are formed by selective laser sintering (SLS) of nylon, polyether ether ketone (PEEK), polyolefin, polytetrafluoroethylene (PTFE) or other thermoplastics. In some embodiments, portions of the frame20may be metalized. Metalizing portions of the frame20may increase heat transfer into or out of the biomaterial stored within the biocontainer10. In some embodiments, metalizing portions of the frame20may allow for induction heating of a biomaterial within the biocontainer10. In certain embodiments, metalizing portions of the frame20may increase stiffness of the frame20. In particular embodiments, metalizing the frame20may increase an inertness of the frame20and/or a purity of a biomaterial disposed within the biocontainer10.

In embodiments, portions of the frame20may be formed of additive manufacturing techniques. Forming the frame20by additive manufacturing techniques may allow for increased adhesion or bonding of the membranes to the frame20as detailed below. In certain embodiments, the core22is formed of additive manufacturing techniques in a manner to increase adhesion or bonding of the sheath24and/or the membranes40to the core22. In embodiments, the core22or the sheath24of the frame20may be molded.

The membranes40may be adhered or bonded to the rigid frame20to form the interior18of the biocontainer10. In some embodiments, the interior18of the biocontainer10is defined between the membranes40. In some embodiments, portions of the interior18are defined by the frame20disposed between the membranes40.

The membranes40may be formed of a flexible material that conforms to volume changes of biomaterial disposed within the interior18of the biocontainer10. The membranes40may be formed of or include a thermoset material or a thermoplastic material. For example, the membranes40may include silicone and/or thermoplastic. In some embodiments, the membrane40includes a microporous material for lyophilization or improved oxygen or carbon dioxide transport into or out of the biocontainer10. Improved oxygen or carbon dioxide transport may improve cell growth within the biocontainer10.

In some embodiments, the membranes40may be composite membranes with a first side formed of a first material and a second side formed of a second material. In certain embodiments, a composite membrane40may include a thermally conductive silicone as an exterior surface laminated to a pure silicone membrane that forms the inner surface. In some embodiments, a composite membrane40includes an electrically conductive silicone laminated to a pure silicone membrane for induction heating of biomaterial within the biocontainer10.

The membranes40may be uniform on both sides of the biocontainer10or may be different on each side of the biocontainer10. In certain embodiments, each membrane40may be of uniform construction. In particular embodiments, portions of the membrane40may have a different construction from other portions of the membrane40. For example, one or more portions of a membrane40may include a thermally conductive silicone, an electrically conductive silicone, or a microporous material. In embodiments, the membrane40may include a silicone rubber having a thickness in a range of 0.01 mm to 3 mm, e.g. 1 mm. The membrane40may be formed of a silicone having any hardness. In some embodiments, the membranes40may be formed of a silicone having a Shore A hardness in a range of 30-80. As noted above, the membrane40may be a silicone rubber calendared into multilayer films including a thermally conductive layer on the exterior side and a silicone with a Shore A hardness in a range of 30-80 on the biomaterial contact side, e.g., the inside surface. The membrane40may be a multilayer film with an electrically conductive film on the exterior surface for induction or RF heating of a biomaterial within the container and a film with a Shore A hardness in a range of 30-80 on an inside surface. The membrane40may be rubber cast onto an expanded polytetrafluoroethylene (ePTFE) film or microporous membrane, e.g. polyethersulfone (PES), polypropylene (PP), etc. In some embodiments, the membrane40may be silicone rubber cast onto a non-woven film. The membranes40may be perfluoropolyether (PFPE) rubber calendared into sheet form. The membranes may be a TPE membrane that may be attached with EPE adhesive, e.g., Santoprene™ 8291 TB. The membranes40may be a nylon, a PE material, a cyclo olefin polymer such as Zeonex, metalized plastic films, glass coated plastic films, PEEK, PES, a polyetherimide (PEI) such as Ulterm, a polyimide (PI) material such as Kapton. The membranes40may be functionalized film to improve crystal structure of frozen product or to interact with the biomaterial stored within the biocontainer10.

The membranes40may be attached, bonded, or adhered to the frame20. In some embodiments, the membranes40may be adhered with a LIM™ 8040 available from Momentive Performance Materials or another platinum catalyzed silicone adhesive. In some embodiments, the frame20and the membranes40are compatible with one another such that the frame20and the membranes40may be bonded by locally melting the frame40and/or the membranes40together. In some embodiments, the frame20may be molded about the membranes40such that the frame20is bonded to the membranes40. In certain embodiments the frame20is compatible with an outer surface of the membranes40and incompatible with an inner surface of the membranes40and in other embodiments, the frame20is compatible with the inner surface of the membranes40and incompatible with an outer surface of the membranes40.

The biocontainer10may include one or more embedded sensors50. The sensors50may monitor a temperature of biomaterial disposed within the biocontainer10. In certain embodiments, the biocontainer10includes a thermowell for temperature monitoring. The thermowell may be positioned to be a leading indicator of a temperature change of a biomaterial or may be positioned to be a trailing indicator of a temperature change of a biomaterial.

Referring now toFIGS.4-6, a method of manufacturing a biocontainer is disclosed in accordance with an embodiment of the present disclosure and is referred to generally as method100. While the method100may be used to form a variety of biocontainers, the method100is described herein with reference of the biocontainer10ofFIGS.1-3. The method100may include forming the frame20(Step110). Forming the frame20may include molding the core22of the frame20or producing the core22via additive manufacturing techniques. The core22may include a latticed structure. The latticed core22may reduce an amount of material forming the frame20. With the core22formed, the core22is positioned in a mold210as shown inFIGS.4and5(Step120).

The method100may include positioning tubing12,14,16in mold210(Step130). The tubing12,14,16may be silicone tubing and/or TPE tubing. In certain embodiments, at least one of the tubes12,14,16is a silicone tube and at least one of the tubes12,14,16is a TPE tube. Each tube of the tubing12,14,16may pass through an opening in the core22. With the tubing12,14,16positioned in the mold210, the mold210is closed and material is poured into or injected into the mold210to encapsulate the core22of the frame20within the sheath24(Step140). The material poured or injected into the mold210to form the sheath24may be silicone. After the material is poured into the mold210, the material is allowed to cure or cool within the mold to form the frame20and/or to bond the tubing12,14,16to the frame20(Step150). As the material is poured into the mold210, the material forming the frame20, may bond to the tubing12,14,16. For example, the tubing12,14,16may be over-molded to secure and seal the tubing12,14,16to the frame20. By over-molding the tubing12,14,16, multiple types of tubing may be used with the method100to form the biocontainer10. When the material encapsulating the core22forming the sheath24is cooled, the mold210is opened and the completed frame20including the tubing12,14,16is removed from the mold210(Step160).

When the frame20is completed, the membranes40are attached to the frame20to form and seal the interior18of the biocontainer10(step170). The membranes40may be adhered or bonded to the frame20. In some embodiments, the membranes40include a silicone layer that is adhesively adhered to a silicone of the frame20. The membranes40and the frame20may form an all silicone contact surface for the interior18of biocontainer10. In certain embodiments, the membranes40may be formed by casting silicone onto a carrier film. The carrier film may be a PET Film, a PES film, or a polycarbonate film. In some embodiments, the membranes40may be bonded to the frame20. In certain embodiments, the membranes40and/or the portions of the frame20are locally melted to bond the membranes40to the frame20. The membranes40may be joined to an inside of the frame20with the frame20forming an exoskeleton for the membranes40or the membranes40may be joined to an outside of the frame20such that portions of the frame20are disposed in the interior18.

The method100is one example of a method for forming a biocontainer, e.g., biocontainer10. In some embodiments, portions of the frame20may be formed by additive manufacturing techniques, e.g., three-dimensional printing, or molding. In certain embodiments, portions of the frame20may be formed separate from the membranes40. In such embodiments, the membranes40may be adhered to the frame20by use of one or more adhesives.

Referring now toFIGS.7and8, another biocontainer310is disclosed in accordance with an embodiment of the present disclosure. The biocontainer310includes a frame320and membranes340. Elements of the biocontainer310may be similar to elements of the biocontainer10detailed above with respect toFIGS.1-3and are represented with similar labels with a preceding3. As such, aspects of the biocontainer310will not be described in detail except for the differences with the biocontainer10.

The frame320of the biocontainer310may include a core322having edge portions321and a central portion323. The edge portions321are rigid to define at least two dimensions of the biocontainer310, e.g., the width and the length. In some embodiments, the edge portions321define the width, the length, and the thickness of the biocontainer310. As shown, the edge portions321may be substantially solid. In some embodiments, the edge portions321may include a lattice to reduce an amount of material forming the edge portions321. The frame320may be formed via molding or additive manufacturing techniques. In some embodiments, the frame320is molded such that tubing (not explicitly shown) is over-molded to secure the tubing to the frame320.

The central portion323may form a lattice that extends between opposite edges of edge portions321of the frame320. The lattice of the central portion323may be rigid such that the central portion323maintains its dimensions or may be flexible such that the central portion323may flex when a force is applied. In certain embodiments, the central portion323may flex inward to decrease a thickness of the biocontainer310or may flex outward to increase a thickness of the biocontainer310. The flexing of the central portion323may be in response to an increase or decrease in a volume of a biomaterial stored within the biocontainer310. In certain embodiments, the central portion323may include a stacking or reinforcement feature326. In particular embodiments, a central portion323on a first side of the biocontainer310may have a stacking feature326having a first dimension and a central portion323on the second opposite side of the biocontainer310may have a stacking feature326having a second dimension that is sized to complement the stacking feature326on the first side of the biocontainer310. For example, when the biocontainer310is stacked with other biocontainers310, the stacking features326may aid in stacking biocontainers310to allow for an increased number of biocontainers310to be stacked together.

As shown, the membranes340of the biocontainer310are adhered or bonded to an internal surface of the frame320such that the frame320acts as an exoskeleton. In some embodiments, the membranes340may be adhered to or bonded to an outside surface of the frame320with the frame320disposed inside the membranes340. The membranes340may be adhered to the frame320such that the membranes340may flex into or away from the frame320. The flexing of the membranes340may allow for the membranes340to adjust to a volume of a biomaterial contained within the biocontainer310.