Abstract:
A container for storing a biopharmaceutical drug product is disclosed. The container includes two surface area planar walls. A plurality of smaller side walls circumscribing each of the planar walls. A method of freezing at least one biopharmaceutical product in the container is also disclosed.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention relates to a container that is used to contain biopharmaceutical material that is intended to be frozen for storage and shipping. 
       BACKGROUND OF THE INVENTION 
       [0002]    Biopharmaceutical drugs are manufactured in bulk amounts in order to lower the cost per unit of the drug. Oftentimes, the drugs are manufactured in a liquid form, with drug-containing solutes being homogeneously dissolved in a liquid solution. In order to enhance the lifetime of the drug, the drug is frozen in a container that is suitable for transport. 
         [0003]    It is well known that solutes in bulk liquid solutions are subject to a stress force induced by the advancement of the ice front during the freezing process. Depending on the ice front velocity, solutes can be either trapped in the solid phase or pushed away from the ice-liquid interface into the bulk liquid region. The migration of the solute into the liquid phase results in a heterogeneous solute distribution in the frozen material. Testing of such migration has indicated that the difference of solute percentage in the solution can be between 60% and 300% of the initial (pre-freezing) value. One solution to limit this migration is to reduce the time required to freeze the solution. 
         [0004]    The heat transfer process during freezing is well characterized by the Stefan solution equation, which correlates the thickness of the ice formed after a period of time when the temperature of the cold surface as well as the ice conductivity and heat of fusion are known. The equation indicates that the time required to freeze liquid in a container is a function of the square of the distance that heat travels from the liquid. Therefore, a reduction in the time required to freeze the liquid requires a reduction in the distance that the heat must travel to be removed from the liquid. 
         [0005]    It would be beneficial to develop a container in which a liquid drug may be stored and frozen, such that the container has a geometry that reduces the migration of solute during the freezing process. 
       SUMMARY OF THE INVENTION 
       [0006]    Briefly, the present invention provides a container for storing a biopharmaceutical drug product. The container includes two side surface walls, typically planar, and a plurality of smaller side walls, which circumscribe and connect the surface area planar walls and define the interior of the container. 
         [0007]    In one embodiment, the invention relates to a container for storing a biopharmaceutical drug product comprising two relatively large surface area planar surfaces extending opposite to one another. For example, a first and second planar surface can be intersecting, non-parallel, or parallel to each other. In addition, one embodiment also includes a plurality of relatively small surface area side walls circumscribing each of the first and second planar surfaces, wherein the plurality of side walls connect the first and second relatively large surface area surfaces, all of said surfaces collectively defining the interior of the container. 
         [0008]    In another embodiment, the first and second relatively large surface area planar surfaces are parallel surfaces. 
         [0009]    In yet another embodiment of the invention, one of the plurality of side walls extends at an oblique angle relative to an adjacent of the plurality of side walls. In another embodiment, the remaining side walls each define at least a portion of a side of a rectangle. 
         [0010]    In another embodiment, the container further comprises an opening formed within one of the plurality of side walls. In another embodiment, container further comprises a nipple formed around the opening and extending outwardly from the one of the plurality of side walls. In yet another embodiment, the container has a nipple that extends within the rectangle. 
         [0011]    In another embodiment of the invention, the container&#39;s second planar surface is spaced from the first planar surface by a distance of between about 5 to 11 centimeters. In another embodiment, the second planar surface is spaced from the first planar surface by a distance of about 8 centimeters. 
         [0012]    In a further embodiment, the container&#39;s first planar surface is spaced from the second planar surface by a distance, and wherein a maximum dimension of each of the first and second planar surface is no more than ten times that of the distance. 
         [0013]    In another embodiment of the invention, the container&#39;s first and second planar surface and the plurality of side walls all have a thickness of between about 0.1 to 0.95 centimeters. 
         [0014]    Additionally, the present invention includes a method of freezing a biopharmaceutical product. The method comprises the step of providing a container, as described above. The method further includes the steps of inserting the biopharmaceutical product into the container; subjecting the container to freezing conditions; and freezing the biopharmaceutical product within the container while maintaining a generally homogenous solution. 
         [0015]    In another embodiment of the invention, the specification discloses a method of freezing a biopharmaceutical product comprising the steps of providing a container having two relatively large surface area planar walls extending opposite to one another and a plurality of relatively small surface area side walls circumscribing each of the first and second planar surfaces, wherein the plurality of side walls connect the first and second planar surfaces, all of said surfaces collectively defining the interior of the container. The method also includes, inserting the biopharmaceutical product into the container, subjecting the container to freezing conditions, and freezing the biopharmaceutical product within the container while maintaining a generally homogenous solution. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0016]    The foregoing summary, as well as the following detailed description of desired embodiments of the invention, will be better understood when read in conjunction with the appended drawings, which are incorporated herein and constitute part of this specification. For the purposes of illustrating the invention, there are shown in the drawings an embodiment that is presently desired. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown. In the drawings, the same reference numerals are employed for designating the same elements throughout the several figures. In the drawings: 
           [0017]      FIG. 1  is a perspective view of a container according to one embodiment of the present invention; 
           [0018]      FIG. 2  is a sectional view of the container of  FIG. 1 ; and 
           [0019]      FIG. 3  is a sectional view of the container taken along lines  3 - 3  of  FIG. 2 . 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0020]    Certain terminology is used herein for convenience only and is not to be taken as a limitation on the present invention. The terminology includes the words specifically mentioned, derivatives thereof and words of similar import. The following describes a desired embodiment of the invention. However, it should be understood based on this disclosure, that the invention is not limited by the desired embodiment of the invention. 
         [0021]    Referring generally to the figures, a container  100  for receiving, freezing, and storing a biopharmaceutical product  102  is shown. 
         [0022]    Referring specifically to  FIGS. 1 and 2 , the container  100  includes a first generally planar wall  110  and a second generally planar wall  112 . In one embodiment, the first and second planar walls  110  and  112  are generally parallel to each other and are spaced apart from each other by a distance. The “distance” that separates the first and second planar walls  110  and  112  is determined by the width of the smaller side walls. In another embodiment of the invention, the dimensions of the container mentioned herein are the outside dimension/measurements of the container. For example, the distance between the first and second planar walls  110  and  112  can be 8 cm if the width of the smaller side walls  120 ,  122 ,  124 ,  126 , and  128  are all 8 cm wide. In another embodiment, the first and second side planar walls  110  and  112  may be spaced apart from each other by about 5 to about 11 centimeters in order to provide a sufficient rate of freezing of the biopharmaceutical product  102  in the container  100 , while still providing acceptable height and length dimension of the container  100  to retain a desired fluid volume. 
         [0023]    The time, t, required to fully freeze a solution in such a container is determined by the Stephan Equations (below), which calculate freezing time in a container as a function of distance. The Stephan equations are as follows: 
         [0000]                  t   =           ρ   s          λ   ′         2                     k   s          (       T   f     -     T   W       )                δ   2               Equation                 1               λ′=λ+ Cp   L ( T   i   −T   f )  Equation 2 
         [0024]    where: 
         [0025]    δ=heat transfer length (m) 
         [0026]    λ=latent heat of fusion (J/kg) 
         [0027]    ρ s =density of ice (kg/m 3 ) 
         [0028]    Cp L =heat capacity of the solution (J/kg.° K.) 
         [0029]    k s =heat conductivity of ice (W/m. ° K.) 
         [0030]    T i =initial temperature of the solution (° K.) 
         [0031]    T f =freezing temperature of the solution (° K.) 
         [0032]    T w =freezer wall temperature (° K.) 
         [0033]    t=time (s) 
         [0034]    Different solutions, which represent solutions that may be stored in the container  100 , were analyzed to determine freeze rates for different container sizes. The solutions tested were distilled water, 0.5 M NaCl solution, and formulation buffers comprising 12% and 18% sucrose. The freezing times were about the same for these solutions, with the note that the freezing temperature of the 0.5 M NaCl and the formulation buffers was −1.5+0.5 degrees Celsius, as opposed to 0 degrees Celsius for the water. 
         [0035]    Using equations 1 and 2, and the aforementioned baseline solutions, with the distance between the planar walls  110  and  112  of the container  100  being 5 cm, which corresponds to a heat transfer length of 2.5 cm since the beat is removed from both sides of the container  100 , freezing time was calculated to be about 12.6 minutes. Thus, the average ice front velocity is about 119 mm/hr. Similarly, the average ice front velocity of the container  100  with a distance  8  of 11 cm, which corresponds to a heat transfer length of 5.5 cm, is about 54 mm/hr. Freezing time was calculated to be about 61.1 minutes. 
         [0036]    In one embodiment, in order to minimize solute re-distribution in the container  100  during freezing, the freezing velocity is to be at least 50 mm/hr or faster, corresponding to a maximum surface area planar wall spacing of about 11 cm. Further, in another embodiment, a minimum planar wall spacing of the container  100  is about 5 cm. Otherwise, the container  100  to be used for large bulk material, for example about 5 to about 50 liters would necessarily have to be very thin and very tall in order to contain a sufficient volume of solution. An increase in the height of the container  100  would be required to obtain a desired internal volume, but would raise the center of gravity of the container  100 , allowing the container  100  to flip over easily. In one embodiment, a maximum dimension of each of the first and second planar walls  110  and  112  is no more than ten times that of the distance between the first and second planar walls  110  and  112 . 
         [0037]    In one embodiment, the “dimensions” of each of the first and second planar walls are the height and width of  110  and  112 . For example, if the distance between 110 and 112 is 6 cm, then the height and width of  110  and  112  should not exceed 60 cm. In another embodiment, the outside dimensions of the container are only limited in size and shape by the size and shape of the freezer used to store the containers. 
         [0038]    Generally, in one embodiment of the invention, the planar interwall spacing is about midway between the limits of 5 cm and 11 cm (about 8 cm) to cover a range of conditions of materials to be contained. In another embodiment, planar interwall spacing is about 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, or 11 cm to cover a range of conditions of materials to be contained. However, an interplanar wall distance from about 5 cm to about 11 cm should provide a desired freezing time for a wide range of materials and should keep any common solute redistribution within an acceptable limit. For different solutions with different thermodynamic properties, the rate of freezing will likely vary slightly, but it is believed by the inventor(s) that the distilled water, 0.5 M NaCl solution, and formulation buffers discussed above are representative of the thermodynamic properties of the types of solutions that may be stored within the container  100 . 
         [0039]    While the interplanar wall spacing may be from 5 to 11 cm and is generally to be about 8 cm in one embodiment, the height and width of each of the first planar wall  110  and the second planar wall  112  may be varied, depending upon the size of the freezer (not shown) into which the container  100  is intended to be placed to freeze the biopharmaceutical product  102  in the container  100 , or by the desired interior volume of the container  100 . For example, for the container  100  having a volume of 8 liters, either a length of about 300 millimeters and a height of about 500 millimeters or a length of about 400 millimeters and a height of about 400 millimeters provides the desired volume of the container  100 . 
         [0040]    A plurality of side walls circumscribe each of the first planar wall  110  and the second planar wall  112 . As can be seen in  FIG. 2 , five side walls  120 ,  122 ,  124 ,  126 ,  128  connect the first planar wall  110  and the second planar wall  112 , forming an interior volume within which the biopharmaceutical product  102  is contained. Four of the side walls  120 ,  122 ,  124 ,  126  are orthogonal to an adjacent side wall  120 ,  122 ,  124 ,  126 , while the fifth side wall  128  extends at an oblique angle relative to at least one of its adjacent side walls  120 ,  126 . The side walls  120 ,  122 ,  124 ,  126 ,  128  all fit within an area defined by an imaginary rectangle  130 , with the side walls  122 ,  124  forming the entire corresponding side walls of the rectangle  130  and side walls  120 ,  126  forming a portion of the remaining side walls of the rectangle  130 . In another embodiment, the side walls  120 ,  122 ,  124 ,  126 ,  128  all fit within an area defined by an imaginary square (not shown). 
         [0041]    The first and second planar walls  110 ,  112  and the side walls  120 ,  122 ,  124 ,  126 ,  128  also serve to enhance heat transfer between the biopharmaceutical product  102  in the container  100  and the environment external to the container  100 . In one embodiment, the first and second planar walls  110 ,  112  and the side walls  120 ,  122 ,  124 ,  126 ,  128  all have a thickness of between about 0.1 and 0.95 centimeters. In another embodiment, the first and second, planar walls  110 ,  112  and the side walls  120 ,  122 ,  124 ,  126 ,  128  all have a thickness of between about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95 cm. The walls  110 ,  112 ,  120 ,  122 ,  124 ,  126 ,  128  are of such thickness to enhance heat transfer through the walls  110 ,  112 ,  120 ,  122 ,  124 ,  126 ,  128  during freezing of the biopharmaceutical product  102  within the container  100 . 
         [0042]    The side wall  128  includes a circular opening  132  formed therein. The opening  132  allows the biopharmaceutical product  102  to be poured into and out of the container  100 . In one embodiment, the circular opening  132  is sealed with a plug (not shown) that provides adequate sealing of the opening  132  and containment of the biopharmaceutical product  102 . In another embodiment, a nipple  134  having external threads  136  is formed around the opening  132  and extends outwardly from the side wall  128 . The nipple  134  is sized such that the nipple  134  remains within the rectangle  130 . The nipple  134  remains within the rectangle  130  to accommodate the entire container  100  when the container  100  is placed into a larger container, such as a freezer, with minimal wasted space between the container  100  and the freezer. 
         [0043]    A removable cap  138  is releasably connectable to the nipple  134 . In one embodiment, the cap  138  includes internal threads (not shown) that engage with the external threads  136  of the nipple  134  for a threaded fit. In another embodiment, the cap  138  includes a seal (not shown) that is located on the underside of the cap  138  to provide adequate sealing of the cap  138  with the nipple  134 . 
         [0044]    In one embodiment, the container  100  is constructed from high density polyethylene (HDPE), because it is known that HDPE is biocompatible with the types of biopharmaceutical product  102  that is intended to be stored within the container  100 . However, those skilled in the art will recognize that other biocompatible materials may be used for the container  100  as well. For example, glass, metal, other biocompatible plastics, etc. One embodiment of the invention is that the material used to construct the container  100  should be rigid enough to maintain is structure or shape during its use and under freezing conditions. Furthermore, the material should be able to sustain the handling at a temperature ranged between +20° C. and −70° C. 
         [0045]    In use, the cap  138  is removed from the nipple  134  and the biopharmaceutical product  102  is placed, transferred, or poured into the interior of the container  100 . After the container  100  is filled with a desired amount of the biopharmaceutical product  102 , the cap  138  is replaced over the nipple  134 , sealing the container  100 . The container  100  may now be transported to a freezer for freezing of the biopharmaceutical product  102 . The container  100  is subjected to a heat transfer process by which heat contained in the container  100  and in the biopharmaceutical product  102  being stored within the container  100  is absorbed by the lower temperature of the exterior environment of the freezer surrounding the container  100 . The relatively large surface areas of the first and second planar walls  110 ,  112  allow the biopharmaceutical product  102  to freeze while maintaining a generally homogeneous concentration of solute within the frozen solution. In another embodiment, the biopharmaceutical product  102  may be a mixture of at least one biopharmaceutical product, such as monoclonal antibodies, DNA, DNA vaccines, peptides, and other protein molecules. 
         [0046]    Further, in another embodiment, the present invention is directed to a container that is used to remove heat from within the container over a reduced period of time to reduce the formation of a heterogeneous solution within the container, those skilled in the art will recognize that the container may also be used to add heat to material within the container over a reduced period of time and with reduced localized temperature differentiation, if so desired. 
         [0047]    Although the invention is illustrated and described herein with reference to specific embodiments, the invention is not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the invention.