Patent application title: BIOPHARMACEUTICAL PRODUCT STORAGE SYSTEM
Eugene M. Calhau (American Canyon, CA, US)
BAYER HEALTHCARE LLC
IPC8 Class: AB65D8138FI
Class name: Receptacle having means to facilitate maintaining contents above or below ambient temperature (e.g., compartment for holding a heat exchange medium) thermally insulated receptacle multiple insulation layers
Publication date: 2013-03-07
Patent application number: 20130056480
A biopharmaceutical product storage system is disclosed. In one
embodiment, the system includes a polymeric product container for storage
of a biopharmaceutical product, a protective envelope for housing the
container, and a cushioning layer disposed between the container and the
envelope. The protective envelope and the cushioning layer include
mineral fibers that protect and insulate the polymeric product container
during handling, transport, and storage. Thus, the combination of the
polymeric product container, the protective envelope, and the cushioning
layer, the system substantially prevents leakage of the biopharmaceutical
product during product handling, transport, and storage. In addition,
where the biopharmaceutical product is frozen, the system substantially
prevents leakage of product during freeze-storage-thaw cycles, during
which temperatures range from -100° C. to 8° C.
1. A protective envelope for a biopharmaceutical product subjected to a
freeze-storage-thaw cycle, comprising: a product container filled with
the biopharmaceutical product; and at least one insulation section,
comprising: a first layer, a second layer, and a protective and
insulative layer having mineral fibers that insulate the product and
protect the filled product container.
2. The protective envelope of claim 1, wherein the mineral fibers have a density ranging from about 2.7 g/cm3 to about 2.9 g/cm.sup.3.
3. The protective envelope of claim 1, wherein the mineral fibers comprise basalt rock.
4. The protective envelope of claim 1, where the mineral fibers comprise plagioclase.
5. The protective envelope of claim 1, wherein the mineral fibers comprise pyroxene.
6. The protective envelope of claim 1, wherein the mineral fibers comprise olivine.
7. The protective envelope of claim 1, wherein the mineral fibers comprise slag.
8. The protective envelope of claim 1, wherein the mineral fibers comprise basalt rock and slag.
9. The protective envelope of claim 1, wherein the first layer comprises a polymeric material.
10. The protective envelope of claim 1, wherein the second layer comprises a polymeric material.
11. The protective envelope of claim 1, wherein the first layer comprises biaxially-oriented polyethylene terphthalate.
12. The protective envelope of claim 1, wherein the second layer comprises biaxially-oriented polyethylene terphthalate.
13. The protective envelope of claim 1, wherein the first layer has shear strength from about 18 kpsi to about 22 kpsi.
14. The biopharmaceutical product storage system of claim 1, wherein the second layer has shear strength from about 18 kpsi to about 22 kpsi.
15. A method of protecting a biopharmaceutical product subjected to a freeze-storage-thaw cycle comprising: (a) inserting the biopharmaceutical product into a polymeric product container, wherein the polymeric product container is configured to house the biopharmaceutical product at a temperature ranging from -100.degree. C. to 8.degree. C.; (b) subjecting the biopharmaceutical product and the polymeric product container to a temperature that freezes the biopharmaceutical product; and (c) inserting the polymeric product container, having the frozen biopharmaceutical product, into a protective envelope, the protective envelope comprising at least one insulation section including a first layer, a second layer, and an protective and insulative layer disposed between the first layer and the second layer, wherein the first layer and the second layer are sealed to contain the protective and insulative layer, and wherein the protective envelope and the polymeric product container form a system that substantially prevents leakage of the biopharmaceutical product during the freeze-storage-thaw cycle.
16. A kit comprising: a polymeric product container configured to house a biopharmaceutical product at a temperature ranging from -100.degree. C. to 8.degree. C.; and a protective envelope comprising at least one insulation section including a first layer, a second layer, and a protective and insulative layer disposed between the first layer and the second layer, wherein the protective and insulative layer comprises mineral fibers and first layer and the second layer are sealed to contain the protective and insulative layer.
 Because of the numerous benefits offered by disposable or "single use" technology, it has become an integral part of biopharmaceutical manufacturing. Single use technology eliminates the need for cleaning, validation, and maintenance of multi-use storage systems. By using this technology, biopharmaceutical manufacturers can lower cost, save processing time, and utilize processing flexibility. In addition, single-use technology often provides for efficient and space-saving storage of biopharmaceutical products. For example, multi-use stainless steel cryo vessels require much more space to store than flexible plastic bags.
 Production of biopharmaceuticals is expensive. To optimize use of production facilities, bulk biopharmaceutical solutions produced in manufacturing campaigns are often stored at frozen temperatures for extended periods of time until market demand is such that the bulk product is thawed, further purified and formulated into the final product for commercial sale. Because single use technology has several advantages, many biopharmaceutical manufacturers prefer to freeze liquid biopharmaceutical products in single use containers. In some cases, these products are stored and transported at temperatures as low as -100° C. Unfortunately, single-use containers are often plastic materials which become particularly fragile at lower temperatures. In addition, the freezing and thawing techniques used by manufacturers can also adversely affect these types of container materials.
 Damage to single-use containers can also occur during handling, particularly during transport and warehousing. In one study, single-use containers, in the form of plastic bioprocess bags, were subject to extensive manipulation to assess container resiliency under simulated processing conditions. Only bags that did not leak product after testing were considered to survive the test. The study determined that even the most resilient bags only survived 50% of the time during testing. Kilburn et al., "Evaluating Single-Use Frozen Storage Systems," Am. Pharmaceutical Review, Apr. 12, 2010, pp. 12-18.
 Unfortunately, damage to these types of single-use containers is often not discovered until the product is thawed. As a result, manufacturers often have difficulty with, among other things, production scheduling and planning, and with unnecessary costs associated with storage of unusable product. Damage to the single-use container also likely means compromise of the sterility of the biopharmaceutical product and therefore loss of valuable product. Although some manufacturers have implemented process improvements and procedural controls to improve handling techniques, damage to single-use containers still occurs.
 In view of the potential for damage to plastic single-use containers and the potential for monetary loss due to product leakage, a need exists for a biopharmaceutical product storage system using single-use technology that can withstand worst-case product handling without damage to the biopharmaceutical product. Such systems will benefit biopharmaceutical manufacturers by limiting loss of expensive biopharmaceutical product due to leakage of products from the single-use container resulting from container damage during handling, transport, and storage, and particularly damage incurred during freeze-storage-thaw cycles.
 The present embodiments are directed toward a biopharmaceutical product storage system. In one embodiment, the system includes a polymeric product container for storage of a biopharmaceutical product, a protective envelope for housing the filled product container, and optionally a cushioning layer disposed within the envelope adjacent to the container. The protective envelope and the cushioning layer comprise materials such as mineral fibers manufactured from rock and/or slag that insulate and protect the product container during storage, transport, and handling.
 By combining the polymeric product container, the protective envelope, and optionally the cushioning layer, the system also substantially prevents leakage of biopharmaceutical product during product handling, transport, and storage. In addition, where the biopharmaceutical product is frozen, the system substantially prevents leakage of product during freeze-storage-thaw cycles. Typically, product temperatures during theses cycles range from -100° C. to 8° C.
 Accordingly, a biopharmaceutical product storage system is disclosed. Advantages of the system will appear from the drawings and detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
 FIG. 1 shows an exploded view of a biopharmaceutical product storage system;
 FIG. 2A is a front elevational view of a polymeric product container used in the system of FIG. 1;
 FIG. 2B is a cross-sectional view of the polymeric product container shown in FIG. 2A;
 FIG. 3 is a front elevational view of an insulation section or cushioning layer used in the system of FIG. 1;
 FIG. 4 is a cross-sectional view of the insulation section or cushioning layer shown in FIG. 3 taken along line 4-4;
 FIG. 5 is a top view of a pre-assembled protective envelope;
 FIG. 6 is a front elevational view of an assembled protective envelope used in the system of FIG. 1; and
 FIG. 7 is a side view of the assembled protective envelope shown in FIG. 6.
 Turning in detail to the drawings, FIG. 1 shows an exploded view of a biopharmaceutical product storage system 10. In this configuration, the system 10 includes a polymeric product container 12 for storage of biopharmaceutical product 8, a protective envelope 14 for housing the filled product container and, optionally, at least one cushioning layer 16, which upon assembly is placed between the product container 12 and the protective envelope 14. The protective envelope 14 and the cushioning layer 16 comprise materials such as mineral fibers 28 that insulate and protect the product container during storage, transport, and handling.
 As used herein, a biopharmaceutical product 8 refers to any biopharmaceutical product or product intermediary which changes, at some point during processing, from a liquid to a frozen state. The temperature of the biopharmaceutical product 8 while in the liquid state typically is maintained from 2° C. to 8° C. The temperature of the biopharmaceutical product 8 while in the frozen state typically ranges from -100° C. to 0° C. Specifically, the biopharmaceutical product may be handled, stored, and transported at temperatures at or slightly below 0, -10, -20, -30, -40, -50, -60, -70, -80, -90 or -100° C. or at a temperature falling within any combination of these temperatures as an upper and lower limit, such as at 0 to -10° C. inclusive of the endpoints. Temperatures of the biopharmaceutical product while in either the liquid or frozen state may also be lower or higher than those stated, depending on the properties and processing specifications of the biopharmaceutical product.
 The biopharmaceutical product 8 may comprise a liquid solution of recombinant proteins, antibodies (monoclonal or otherwise), vaccines, blood/plasma-derived products, nonrecombinant culture-derived proteins, and cultured cells. The liquid solution of recombinant protein may comprise a solution of any recombinant protein obtained from recombinant cell culture and isolated at least partially from the cell culture medium using affinity chromatography, ion-exchange chromatography, or the like. As used herein, "solution" includes suspensions, dispersions and the like of the biopharmaceutical product in a liquid vehicle.
 The solution may comprise a bulk solution, which is a solution which has been partially purified. As used herein, a "bulk" solution comprises a partially but not fully purified liquid solution of biopharmaceutical product such as a recombinant protein. Bulk solutions are further characterized by their very low product concentration. In some embodiments, the solution may be of a biopharmaceutical product such as a recombinant protein at about 0.0001 micromolar, 0.001 micromolar, 0.01 micromolar, or a range between 0.0001 to 0.001 micromolar or 0.001 to 0.01 micromolar. In some embodiments of the invention, the concentration of biopharmaceutical product such as a recombinant protein can be as high as about 10 micromolar, 1.0 micromolar, or 0.1 micromolar, or a range between 10 to 1.0 micromolar or 1.0 to 0.1 micromolar or 0.1 to 0.01 micromolar or 10 to 0.01 micromolar or 10 to 0.0001 micromolar or 10 to 0.001 micromolar or 10 to 0.1 micromolar or any other concentration falling between any combination of these upper and lower limits of protein concentration.
 Often during production of recombinant proteins, an elution buffer of high salt content is used to elute the desired protein from a first-pass purification treatment. In the case of elution from a column, a high salt concentration is needed to release the protein from the column. Accordingly, the bulk solution recovered from first pass purification treatment can comprise a solution having a high concentration of monovalent salts, normally sodium chloride but potentially potassium chloride or other salts. The concentration of sodium chloride or potassium chloride in some embodiments is at least 100 millimolar, at least 200 millimolar, at least 300 millimolar, at least 400 millimolar, at least 500 millimolar, at least 600 millimolar, at least 700 millimolar, or at least 800 millimolar. The bulk solution may also contain varying amounts of other salts, such as divalent salts, including calcium chloride. By "partially but not fully purified" is meant the liquid solution has been subjected to at least one purification step, but the liquid solution still contains sufficient residual impurities that at least one further purification step is required prior to final product formulation. For example, a "bulk" solution of recombinant Factor VIII must be further purified prior to final formulation, which in the case of Factor VIII and other proteins may include lyophilization.
 Recombinant proteins include, for example and without limitation, coagulation factors, virus antigens, bacterial antigens, fungal antigens, protozoal antigens, peptide hormones, chemokines, cytokines, growth factors, enzymes, blood proteins such as hemoglobin, α-1-antitrypsin, fibrinogen, human serum albumin, prothrombin/thrombin, antibodies, blood coagulation and/or clotting factors, and biologically active fragments thereof, such as Factor V, Factor VI, Factor VII, Factor VIII and derivatives thereof such as B-domain deleted FVIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII, Fletcher Factor, Fitzgerald Factor, and von Willebrand Factor; milk proteins such as casein, lactoferrin, lysozyme, α-1-antitrypsin, protein factors, immune proteins, and biologically active fragments thereof; and antibodies, including monoclonal antibodies, single chain antibodies, antibody fragments, chimeric antibodies, humanized antibodies, and other antibody variant molecules which can be produced in recombinant cell culture.
 The biopharmaceutical product may be derived from cell culture. The cell culture may comprise any type of cell including a plant, insect, mammalian, yeast or bacterial cell. In one embodiment, the biopharmaceutical product is an ultrafiltered/diafiltered (UF/DF) solution obtained from cell culture. In another embodiment the biopharmaceutical product is an ultrafiltered/tissue culture concentrated filtered (UF/TCF) solution obtained from cell culture.
 In one embodiment, the biopharmaceutical product is recombinant Factor VIII. Factor VIII as used herein includes engineered variants of Factor VIII, such as B-domain deleted variants of Factor VIII and site-specific mutation variants of Factor VIII or of B-domain deleted Factor VIII. The biopharmaceutical product may be a derivative of Factor VIII having Factor VIII procoagulant activity.
 During processing, the biopharmaceutical product 8 is inserted into a polymeric product container 12. Depending upon the product used and its processing specifications, after this insertion step, the product and the product container may be frozen. Moreover, depending upon the freezing technique used by a biopharmaceutical manufacturer, both the product and the product container may be subject to significant stress, as the product changes from a liquid to a frozen state. Freezing techniques can, therefore, result in osmotic stresses and other types of stresses due to ice interface formation, pH changes, and phase separation.
 Many manufacturers agree that it is generally better to blast freeze or supercool biopharmaceutical products using liquid nitrogen and water or dry ice and/or ethanol baths. In one type of blast freezing process, filled polymeric product containers are blast frozen in a freezer having a temperature of about -56° C. Unfortunately, this type of technique may damage polymeric product containers due to their fragility at lower temperatures.
 Once a product is frozen, some products, like proteins, must maintain temperature stability for long periods. Biopharmaceutical products may be maintained at temperatures as low as -10, -20, -30, -40, -50 or -100° C. After freezing, the product is often transported to another location for long-term storage. During the handling, transporting, and storage, the temperature of the product and the polymeric product container must remain relatively stable, often at a temperature of -30° C. or less. Storage at this temperature may be maintained for a long term, such as for a time period of at least 30, 60, 90, or 180 days. Often freezing occurs at one site in the manufacturing facility and the long term storage is at a second site some distance away. Therefore, safe transport conditions which protect fragile frozen product and product containers are needed.
 When product is ready for further purification and formulation, it must be thawed. Many thawing techniques agitate products to speed up the thawing process. Agitation, however, further subjects polymeric product containers to additional stress, which may result in areas where product leakage can occur.
 In one configuration, the polymeric product container 12 comprises a bioprocess bag having a generally rectangular shape, as shown in FIGS. 1 and 2A. Containers of other shapes, however, are suitable. In one embodiment, the container 12 is manufactured from a natural or synthetic polymeric material. This material has a thickness, as specified by the product manufacturer, and acceptable flexibility and compatibility with the biopharmaceutical product 8. Further, the material is not to be reactive, additive, or absorptive such that the purity, strength, or identity of the product is compromised. Some compatibility tests used by biopharmaceutical product manufacturers include those performed according to U.S. Pharmacopeia Reference Standards.
 Materials typically used for product container such as bioprocess bags include thermoplastic materials, such as copolymers of ethylene and vinyl acetate (EVA) and polyvinylidene fluoride (PVDF) and polyolefin homopolymers, such as polyethylene and polypropylene, polytetrafluoroethylene, and silicone. Various other polymer blends, however, may be suitable. Bioprocess bags may include those manufactured by Arkema, Inc., DuPont, Dow Chemical Company, Sartorius-Stedim Biotech S.A. and Charter Medical, Ltd., among other manufacturers.
 In addition to compatibility requirements, the polymeric product container should meet additional product specific validation and biocompatibility requirements. Typically, these validation requirements are specified by the biopharmaceutical product manufacturer and relate to sterility of the polymeric product container, product stability, product adsorption, etc. Other validation requirements may be set by other authorities. These requirements include, but are not limited to, acceptable limits for leachables, extractables, gas permeability, and container integrity. Some manufacturers perform validation and/or qualification testing by inserting biopharmaceutical products into product containers and then measuring affects of the container on the product over a specified duration.
 As shown in FIG. 2B, the product container 12 may have two or more layers, such as a contact layer 13a and one or more backing layers 13b. These materials are coupled using any method sanctioned by the biopharmaceutical product manufacturer. These methods may include the use of tie layer adhesives, for example.
 The contact layer 13a comes in contact with the biopharmaceutical product 8 and should thus be compatible with the biopharmaceutical product. The biopharmaceutical product 8 should also not unacceptably degrade, react, or absorb when in contact with the contact layer 13a. The contact layer must, therefore, have a thickness that prevents unacceptable effects on the product over long periods. In some embodiments, the contact layer 13a has a thickness of about 360 μm.
 The contact layer 13a may also be specified to meet validation requirements, as specified by the biopharmaceutical product manufacturer. These requirements may include specified parameters for gas permeability, sterilization, chemical compatibility, leachables, and extractables. Suitable materials for the contact layer include, but are not limited to, ethylene vinyl acetate (EVA), ethyl vinyl alcohol (EVOH), polyethylene, polyvinylidene fluoride, polytetrafluoroethylene, and polypropylene (low density and high density).
 In some product containers, one or more backing layers 13b are configured to provide dimensional stability and structural support. The backing layer 13b may be manufactured from various types of polymeric materials. These materials may include EVA, polyolefins, nylon, and polyesters.
 In assessing the validation requirements for the contact layer 13a, certain material properties may be specified. For example, in some embodiments the contact layer 13a may have a density of about 0.94 g/cm3. Additional material properties of the contact layer 13a may include tensile strength at 100% elongation of about 6 MPa (870 psi) and an elastic modulus of about 50 MPa (7.25 kpsi). These properties may be measured, using accepted industry standards, including but not limited to ISO 527-2.
 As shown in FIG. 2A, the product container 12 has at least one opening 18 for receiving and transferring the biopharmaceutical product 8. The opening 18 has any suitable reclosable sealing element 19 that allows for insertion and later removal of the biopharmaceutical product 8.
 After the product container 12 is filled and frozen, it is placed into a protective envelope 14 that protects the product container 12 and allows the biopharmaceutical product to maintain its temperature during transport and handling. The product container 12 comprises mineral fibers 28 (FIG. 4) that protect and insulate the container 12 and the product 8, as further described below. The use of the protective envelope 14, therefore, shields the product 8 and the product container 12 from physical damage during handling, transport, and storage, such as physical damage from jostling during transport to storage areas and from accidental dropping of the product container during such transport or storage. As such, the biopharmaceutical product storage system protects the product from leakage as it undergoes the conditions of freeze-storage-thaw cycles. Generally, these cycles have a broad temperature range of -100° C. to 8° C., inclusive. In other cases, the freeze-storage-thaw cycle ranges from -30° C. to 2° C., inclusive.
 In one embodiment, the protective envelope 14 comprises one or more insulation sections 20, as shown particularly in FIG. 4. An insulation section 20 comprises at least three layers: a first layer 22, at least one protective and insulative layer 24, and at least one second layer 26. The first layer 22 and the second layer 26 may be made from a resilient material that is resistant to tears, cracks, and punctures. Depending on the overall thickness of the material, its shear strength ranges from about 124 MPa (18 kpsi) to about 150 MPa (22 kpsi). The material typically maintains dimensional stability over a wide temperature range from about -70° C. to about 150° C. and, under certain conditions, is suitable for use at temperatures from about -250° C. to about 200° C.
 In one embodiment, the first layer 22 should also be compatible with the product container, while the second layer 26 should be suitable for direct contact during handling by manufacturing personnel. The first and second layers 22, 26 are made from the same material. In one configuration, these layers are made from a polyester based material such as biaxially-oriented polyethylene terphthalate ("BoPet"). One commercially available type of BoPet is Mylar®, manufactured by DuPont Teijin Films. Biodegradable plastics are also suitable materials.
 As shown in FIG. 4, disposed between the first and second layers 22, 26 is a protective and insulative layer 24. The layer 24, therefore, provides insulation to maintain the temperature of a frozen or chilled biopharmaceutical product, as specified by the product manufacturer. The layer 24 also is protective in that it surrounds the protective envelope 14 and the product container 12 during handling, thereby providing impact resistance. Impact resistance, as used herein, is the ability of materials to withstand applied forces without damage, where damage is punctures, tears, or other disruptions in the product container that causes leakage of the biopharmaceutical product 8.
 This protective and insulative layer 24 may also be eco-friendly, biodegradable, and generally semi-rigid. In one embodiment, the layer 24 comprises one or more mineral fibers 28 made from rock and/or slag. In some embodiments, the rock material is basalt rock. Basalt rock is a volcanic rock generally comprising plagioclase, pyroxene, and olivine. Before formation into a mineral fiber, basalt rock is hard and dense with a glassy appearance. After the rock is formed into a fiber, its density ranges from about 2.7 g/cm3 to about 2.9 g/cm3. Slag materials are byproducts of various types of metallurgical operations. These materials are generally non-metallic and comprise oxides of silica, lime, alumina and magnesia. After the slag is cooled and solidified, it may be spun to form mineral fibers. Where the fibers are manufactured from a combination or basalt rock and recycled slag, the rock and slag are heated to approximately 1540° C. (2000° F.), until in a molten state. After the molt is cooled and solidified, it is spun to form mineral fibers 28. The fibers 28 are used to form the protective and insulative layer 24.
 The first layer 22 and the second layer 26 are each cut into a similar shape. The shape of these layers is shown as substantially rectangular; however, any shape may be used to form the insulating section 20. As shown in FIGS. 4-5, the protective and insulative layer 24 is placed in between the first layer 22 and the second layer 26 in one or more insulating areas 32 such that there are layer sealing areas 34 around the peripheries of the first and second layers 22, 26. Optionally, either or both of the first and second layers may extend beyond the area of the protective and insulative layer 24 to form a flap 30. In another optional configuration, the mineral fiber is placed on two or more separate insulating areas (not shown) between the first and second layer.
 In one embodiment, the layers 22, 26 are sealed with an adhesive such that the mineral fiber is encompassed within the layers. The adhesive used should be suitable for temperatures as low as -100° C. such that the seal is maintained. After sealing of the protective and protective and insulative layer 24, an insulation section 20 is formed. One example of an insulation section 20 is CONTROL TEMP PACKAGING® material, manufactured by R.N.C. Industries Inc., Norcross, Ga. The overall thickness of the insulation section 20 depends on the temperature specifications set by the product manufacturer. In one configuration, the insulation section 20 has an approximate overall thickness of about 1 inch. One or more insulation sections 20 may be used to form the protective envelope 14.
 As shown in FIG. 5, a pre-assembled protective envelope 14' has a width that is about one-half of the approximate length. In another configuration, the envelope 14' has a width of about 21 inches and a length of about 59 inches and contains a 5-liter product container. These dimensions, however, are not to be construed as limiting, but should be determined, in part, by the size of the product container 12 housed within the envelope. Located on the pre-assembled protective envelope 14 are envelope sealing sections 44, which are used with an adhesive or a mechanical sealing method, e.g. VELCRO® hook and loop fasteners, to form the envelope. Where an adhesive is used, it is suitable for temperatures as low as -100° C. such that a seal is maintained. Before the protective envelope is formed, it can be folded to form a fold line 46.
 FIGS. 6 and 7 show the protective envelope 14 after assembly. When assembled or formed, the protective envelope 14 is adapted to have a front wall 60, a back wall 62, a base 64, and a top 66. In one configuration, the front wall 60, back wall 62, and base 64 are made from three insulation sections 20. The top 66 is made from a plastic material and attached to a back edge 68 of the envelope using an adhesive. Other methods of attachment may, however, be suitable. Optionally, the top 66 is made using the flap 30. Alternatively, the flap is made from another material and separately attached to the back edge 68 of the back wall 62. The flap 30 is adapted to extend from the top 66 and positioned to extend from the back edge 68 to an area on the front wall 60.
 Optionally, the protective envelope 14 may have a pouch 48 for insertion of a label 56. The pouch 48 is made from a transparent plastic material and adhesively or mechanically attached to the flap 30. The label 56 is inserted into the pouch 48 to allow for product identification, using bar code labeling or other acceptable methods of identification. In one configuration, the pouch is a 6 in.×4 in. piece of transparent plastic adhesively attached to an area on the outside of the flap. The pouch may, however, be any desired size and placed on any other area on the envelope for identification purposes.
 Additionally, the protective envelope 14 may include an envelope closure element 50. This element provides for secure closure of the envelope during handling, transport, and storage. The envelope closure element 50 is reclosable and made using VELCRO® hook and loop fasteners strips. These strips are then attached to a closure area 52 located on the outside of the protective envelope and an inside edge 54 of the flap.
 Optionally, the system 10 can also include at least one cushioning layer 16 disposed between the product container 12 and the protective envelope 14. This cushioning layer 16 allows for additional insulation and product protection. As shown in FIGS. 4 and 5, the cushioning layer 16 is made from the same materials and has the same general configuration as the insulation section 20. In one embodiment, the cushioning layer comprises at least one first layer 72, at least one protective and insulative layer 74, and at least one second layer 76, where the layer 74 includes mineral fibers 78. Other types of cushioning materials may be suitable, depending upon the application and the expected level of product handling. Another suitable material for the cushioning layer 16 is one or more layers of expanded polystyrene foam.
 By combining the product container 12, the protective envelope 14, and optionally the cushioning layer 16, the system substantially prevents damage to the product container 12 that would result in exposure of the biopharmaceutical product 8 during product handling, storage, and transport, and substantially prevents liquid leakage of the product when a frozen biopharmaceutical product is subsequently thawed for further processing. The biopharmaceutical product storage systems 10, therefore, protect and insulate the product 8 during the conditions of the freeze-storage-thaw cycle and substantially prevent leakage upon thawing, which may result if the product container has been damaged during the cycle. This substantial leakage prevention can be measured when, for example, at least 100 product containers are subjected to a freeze-storage-thaw cycle and fewer than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% of the product containers leak during the cycle or upon thawing. This measurement may be made under any standard conditions of freeze-storage-thaw cycles known to one of skill in the art for the biopharmaceutical product, and may be, for example, freezing temperatures of -30° C. and storage of at least 30, 60, 90, or 180 days and thawing to a temperature of between 2° C. and 8° C.
 The biopharmaceutical product storage system for use with a biopharmaceutical product subjected to a freeze-storage-thaw cycle can comprise:
 a polymeric product container configured to house the biopharmaceutical product at a temperature ranging from -100° C. to 8° C.; and
 a protective envelope configured to house the polymeric product container, the protective envelope comprising at least one insulation section including a first layer, a second layer, and a protective and insulative layer disposed between the first layer and the second layer, wherein the first layer and the second layer are sealed to contain the protective and insulative layer, wherein the system substantially prevents leakage of the biopharmaceutical product subjected to the freeze-storage-thaw cycle. The polymeric product container can comprises a bioprocess bag, where the bioprocess bag comprises ethylene vinyl acetate or polypropylene. Further, the polymeric product container can comprise a contact layer and at least one backing layer, where the contact layer and/or the backing layer comprise ethylene vinyl acetate. Moreover, the biopharmaceutical product storage system may further comprise a flap adapted to extend from a back edge of the protective envelope to a front wall of the protective envelope, a pouch positioned on the protective envelope, and a cushioning layer disposed within the protective envelope that is comprised of mineral fibers.
 While various embodiments have been shown and described, it will be apparent to those skilled in the art that many more modifications are possible without departing from the inventive concepts herein.
Patent applications by BAYER HEALTHCARE LLC
Patent applications in class Multiple insulation layers
Patent applications in all subclasses Multiple insulation layers