Patent Publication Number: US-2023144783-A1

Title: Pharmaceutical containers including sealing assembly with filler material

Description:
TECHNICAL FIELD 
     This application claims the benefit of priority under 35 U.S.C. § 119 of U.S. Provisional Application Ser. No. 63/277,492 filed on Nov. 9, 2021, the content of which is relied upon and incorporated herein by reference in its entirety. 
     The present specification generally relates to containers for storing pharmaceutical compositions and, more particularly, containers including a sealing assembly formed from a material having a high coefficient of thermal expansion and a filler member having a low coefficient of thermal expansion to improve sealing when subjected to relatively low temperatures. 
    
    
     BACKGROUND 
     Pharmaceutical containers, such as vials and syringes, are typically sealed via a stopper or other closure to preserve the integrity of the contained material. Closures are typically made of synthetic rubbers and other elastomers. Such materials beneficially have high permeation resistance and elasticity to facilitate insertion into the container to seal the container&#39;s interior. The elasticity of typically-used closure materials, however, may reduce at low temperatures. For example, synthetic rubbers currently in use as material closures may comprise transition temperatures that are greater than or equal to −70° C. and less than or equal to −10° C. Below the transition temperature, closures constructed of such synthetic rubbers may behave as a solid and be unable to expand elastically to compensate for the relatively large difference between coefficients of thermal expansion of the glass and a crimping cap used to secure the closure to the container. Given this, existing sealing assemblies for pharmaceutical containers may fail at temperatures less than or equal to −10° C. 
     Some biological materials (e.g., blood, serum, proteins, stem cells, and other perishable biological fluids) require storage at temperatures below the glass transition temperatures of conventional elastomers to remain useful. For example, certain RNA-based vaccines may require storage at dry-ice temperatures (e.g., approximately −80° C.) or liquid nitrogen temperatures (e.g., approximately −180° C.) to remain active. Such low temperatures may result in dimensional changes in the closure components (e.g., the glass or plastic container, the stopper, an aluminium cap), leading to issues in the integrity of the seal, and potential contamination of the material stored therein. 
     SUMMARY 
     In one embodiment, a sealed pharmaceutical container includes: a shoulder; a neck extending from the shoulder; a flange extending from the neck, the flange including: an underside surface extending from the neck; an outer surface extending from the underside surface, the outer surface defining an outer diameter of the flange; and an upper sealing surface extending between the outer surface and an inner surface defining an opening in the sealed pharmaceutical container, and a sealing assembly including: a stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and an insertion portion extending into the opening and in contact with the inner surface of the flange, the stopper having a first CTE; and a filler member encased within the stopper and having a second CTE, the second CTE being lower than the first CTE. 
     In another embodiment, a sealed pharmaceutical container includes: a syringe including: a tubular barrel having an open end and closed end opposite the open end; a needle extending from the closed end and in fluid communication with an interior of the tubular barrel defined by an inner wall of the tubular barrel; and a sealing assembly movably positioned within the interior of the tubular barrel, the sealing assembly including: a stopper having an inner wall and an outer wall opposite the inner wall at least partially in contact with the inner wall of the tubular barrel the stopper having a first CTE; a filler member at least partially encased within the stopper and having a second CTE, the second CTE being lower than the first CTE; and a plunger coupled to the stopper and extending through the open end of the tubular barrel. 
     In yet another embodiment, a method of sealing a pharmaceutical container includes: providing a pharmaceutical container including a shoulder, a neck extending from the shoulder and a flange extending from the neck, the flange including: an underside surface extending from the neck; an outer surface extending from the underside surface, the outer surface defining an outer diameter of the flange; and an upper sealing surface extending between the outer surface to an inner surface of the pharmaceutical container that defines an opening; inserting a pharmaceutical composition into the pharmaceutical container; and providing a stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and an insertion portion extending into the opening and in contact with the inner surface of the flange, the stopper having a first CTE, a filler member encased within the stopper and having a second CTE, the second CTE being lower than the first CTE. 
     These and additional features provided by the embodiments described herein will be more fully understood in view of the following detailed description, in conjunction with the drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The embodiments set forth in the drawings are illustrative and exemplary in nature and not intended to limit the subject matter defined by the claims. The following detailed description of the illustrative embodiments can be understood when read in conjunction with the following drawings, where like structure is indicated with like reference numerals and in which: 
         FIG.  1    schematically depicts a cross-sectional view of an embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein; 
         FIG.  2    schematically depicts a partial cross-sectional view of another embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein; 
         FIG.  3    schematically depicts a partial cross-sectional view of another embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein; 
         FIG.  4    schematically depicts a cross-sectional view of another embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein; 
         FIG.  5    schematically depicts a cross-sectional view of another embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein; 
         FIG.  6    schematically depicts a cross-sectional view of another embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein; and 
         FIG.  7    schematically depicts a cross-sectional view of another embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein. 
     
    
    
     DETAILED DESCRIPTION 
     Reference will now be made in detail to embodiments of sealed pharmaceutical containers including sealing assemblies that maintain container closure integrity at relatively low storage temperatures (e.g., less than or equal to −30° C., less than or equal to −40° C., less than or equal to −50° C., less than or equal to −60° C., less than or equal to −70° C., less than or equal to −80° C., less than or equal to −100° C., less than or equal to −125° C., less than or equal to −150° C., less than or equal to −175° C., less than or equal to −180° C.). In embodiments, the structure of the pharmaceutical containers described herein may vary from that of existing pharmaceutical containers in one or more respects to facilitate the maintenance of a seal at an interface between the pharmaceutical containers and a sealing assembly inserted therein. For example, embodiments of the pharmaceutical containers described herein may be vials (though other container shapes are within the scope of the present disclosure) including a shoulder, a neck, and a flange including an upper sealing surface against which a stopper of a sealing assembly is pressed by a cap. Various characteristics of the upper sealing surface may be adapted to facilitate the maintenance of a seal when the sealed pharmaceutical containers are cooled to such low storage temperatures. For example, in embodiments, the upper sealing surface may include an inclined sealing surface that descends with increasing radial distance from a central axis of the pharmaceutical container. The inclined sealing surface may descend at an angle of greater than 0 degrees (e.g., greater than 0 degrees and less than or equal to 45 degrees) relative to a plane extending over an end of the pharmaceutical container so as to increase an initial force against the stopper applied during a crimping process and increase tolerance for stopper shrinkage when cooled to lower temperatures. In embodiments, the upper sealing surface extends perpendicular to the central axis of the pharmaceutical container (e.g., extends at an angle of greater than or equal 90 degrees and less than or equal to 89.5 degrees) to maximize a contact area between the upper sealing surface and the stopper. In embodiments, various other characteristics of the upper sealing surface (e.g., surface roughness, flatness, and the like) may be tailored to increase the sealing integrity. 
     In embodiments, the sealing assembly of the pharmaceutical containers described herein may be formed of various combinations of materials to facilitate seal maintenance at low storage temperatures. Sealing assemblies of the present specification may include a stopper, a filler member encased within the stopper, and a metal-containing cap formed from compositions tailored to prevent excessive deformation of the stopper relative to the metal-containing cap at low storage temperatures to maintain sufficient sealing force applied to the stopper via the metal-containing cap. For example, in embodiments, the metal-containing cap may be constructed of a material that increases the CTE thereof over existing, aluminum crimping caps. In embodiments, the metal-containing cap may be constructed of at least one of Zn or Mg instead of Al to provide a higher CTE. In embodiments, the metal-containing cap is constructed of an aluminum-containing polymer composite material. In embodiments, the metal-containing cap is constructed of a metallic alloy comprising at least one of Zn, Al, Mg, Cu. The stopper has a first CTE and the filler member has a second CTE lower than the first CTE. As such, the filler member reduces the amount of shrinkage of the stopper when subjected to relatively low temperatures. 
     As used herein, the term “container closure integrity” refers to maintenance of a seal at an interface between a pharmaceutical container and a sealing assembly (e.g., between an upper sealing surface of a pharmaceutical container and a stopper) that is free of gaps above a threshold size to maintain a probability of contaminant ingress or reduce the possibility of gas permeability below a predetermined threshold based on the material stored in a pharmaceutical container. For example, in embodiments, a container closure integrity is maintained if a helium leakage rate during a helium leak test described in USP &lt;1207&gt; (2016) is maintained at less than or equal to 1.4×10 −6  cm 3 /s. 
     In the embodiments of the pharmaceutical containers described herein, the concentration of constituent components (e.g., SiO 2 , Al 2 O 3 , B 2 O 3  and the like) of the glass composition from which the pharmaceutical containers are formed are specified in mole percent (mol. %) on an oxide basis, unless otherwise specified. 
     The term “substantially free,” when used to describe the concentration and/or absence of a particular constituent component in a glass composition, means that the constituent component is not intentionally added to the glass composition. However, the glass composition may contain traces of the constituent component as a contaminant or tramp in amounts of less than 0.05 mol. %. 
     The term “CTE,” as used herein, refers to the coefficient of thermal expansion over a temperature range from about −200° C. to about 300° C., unless stated otherwise. 
     As used herein, the term “about” means that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. When the term “about” is used in describing a value or an end-point of a range, the specific value or end-point referred to is included. Whether or not a numerical value or end-point of a range in the specification recites “about,” two embodiments are described: one modified by “about,” and one not modified by “about.” It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. 
     Directional terms as used herein—for example up, down, right, left, front, back, top, bottom—are made only with reference to the figures as drawn and are not intended to imply ab solute orientation. 
     As used herein, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a” component includes aspects having two or more such components, unless the context clearly indicates otherwise. 
     Referring now to  FIG.  1   , one embodiment of a pharmaceutical container  100  for storing a pharmaceutical formulation is schematically depicted in cross section. The pharmaceutical container  100  includes a glass container  102  and a sealing assembly  104  coupled to the glass container  102  at an opening  105  of the glass container  102 . Although referred to herein as a glass container  102 , it should be appreciated that, in embodiments, the glass container  102  may be formed from a plastic or any other suitable material. The sealing assembly  104  includes a stopper  106 , a filler member  107 , and a metal-containing cap  108 . In the embodiment depicted in  FIG.  1   , the stopper  106  comprises an insertion portion  117  and a sealing portion  119 . It should be appreciated that, in embodiments, the insertion portion  117  may not be provided. As such, the stopper  106  may not extend into the opening  105  of the glass container  102 . 
     The filler member  107  is encased within the stopper  106 , particularly the sealing portion  119  of the stopper  106 . The filler member  107  includes a filler body  121  having an upper surface  121   a , a lower surface  121   b  opposite the upper surface  121   a , and an outer edge  121   c . Although not shown, it should be appreciated that the filler body  121  may have a circular or elliptical geometry, as defined by the outer edge  121   c , when viewed from a plan view corresponding to a geometry of an outer edge of the sealing portion  119  of the stopper  106 . As such, a distance between the outer edge of the sealing portion  119  and the outer edge  121   c  of the filler body  121  remains substantially constant along the entire outer edge  121   c  of the filler body  121 . As shown in  FIG.  1   , the filler member  107  is positioned within the stopper  106  such that the filler body  121  overlaps the insertion portion  117  of the stopper  106 , which is shown inserted through the opening  105  formed in the glass container  102 . As such, the filler body  121  has a body diameter D 1  that is greater than an opening diameter D 2  of the opening  105  of the glass container  102 . In embodiments, a body channel  121   d  is formed in the filler body  121  and extends through the upper surface  121   a  and the lower surface  121   b  of the filler body  121  to permit a needle, such as that of a syringe, to extend into the glass container  102  through the filler member  107 . In embodiments, the body channel  121   d  has a length greater than the opening diameter D 2 . 
     In embodiments, the filler member  107  is formed from a first material such as, for example, glass, a crystalline material, a polymer, a metal, and the like, or any combination thereof. In embodiments, the first material may include, for example, oxide, halide, nitride, chalcogen, or a combination thereof. In embodiments, the first material forming the filler member  107  is coated with a second material. The second material may be, for example, butyl rubber, nitrile rubber, fluoro rubber, butyl silicone rubber, polyacrylate elastomer, and the like, or any combination thereof. Accordingly, the stopper  106  has a first CTE and the filler member has a second CTE less than the first CTE. In embodiments, the second material has a glass transition temperature (T g ) between −200° C. to 300° C. In embodiments, the stopper  106  also has a T g  between −200° C. to 300° C. 
     The insertion portion  117  is inserted into the opening  105  of the glass container  102  until the sealing portion  119  contacts an upper sealing surface  110  of the glass container  102 . The sealing portion  119  is then pressed against the upper sealing surface  110  via crimping of the metal-containing cap  108  to form a seal at the upper sealing surface  110 . Various aspects of the glass container  102  and the sealing assembly  104  are designed to ensure maintenance of container closure integrity of the glass container  102  at low storage temperatures, as described herein. 
     The glass container  102  generally comprises a body  112 . The body  112  has a wall thickness T W  which extends between an inner surface  114  and an outer surface  116  of the glass container  102 , includes a central axis A, and generally encloses an interior volume  118 . In the embodiment of the glass container  102  shown in  FIG.  1   , the body  112  generally includes a wall portion  120  and a floor portion  122 . The wall portion  120  transitions into the floor portion  122  through a heel portion  124 . In the depicted embodiment, the wall portion  120  of the glass container  102  defines a flange  126 , a neck  128  extending from the flange  126 , a barrel  115 , and a shoulder  130  extending between the neck  128  and the barrel  115 . The floor portion  122  is coupled to the barrel  115  via the heel portion  124 . In embodiments, the glass container  102  is symmetrical about the central axis A, with each of the barrel  115 , the neck  128 , and the flange  126  being substantially cylindrical-shaped. 
     In embodiments, the glass container  102  may be formed from Type I, Type II, or Type III glass as defined in USP &lt;660&gt;, including borosilicate glass compositions such as Type 1B borosilicate glass compositions under USP &lt;660&gt;. Alternatively, the glass container  102  may be formed from alkali aluminosilicate glass compositions such as those disclosed in U.S. Pat. No. 8,551,898, hereby incorporated by reference in its entirety, or alkaline earth aluminosilicate glasses such as those described in U.S. Pat. No. 9,145,329, hereby incorporated by reference in its entirety. In embodiments, the glass container  102  may be constructed from a soda lime glass composition. In embodiments, the glass container  102  is constructed of a composition having a coefficient of thermal expansion that is greater than or equal to 0×10 −7 /K and less than or equal to 100×10 −7 /K (e.g., greater than or equal to 30×10 −7 /K and less than or equal to 70×10 −7 /K). 
     While the glass container  102  is depicted in  FIG.  1    as having a specific form-factor (i.e., a vial), it should be understood that, as discussed in more detail herein, the glass container  102  may have other form factors, including, without limitation, Vacutainers®, cartridges, syringes, ampoules, bottles, flasks, phials, tubes, beakers, or the like. Further, it should be understood that the glass containers described herein may be used for a variety of applications including, without limitation, as pharmaceutical packages, beverage containers, or the like. 
     Although referred to herein as a glass container  102 , it should be appreciated that the glass container  102  may be formed of a material other than glass such as, for example, a polymer, metal, ceramic, and the like. Further, the coefficient of thermal expansion of these materials can be greater than or equal to 0×10 −7 /K and less than or equal to 8,000×10 −7 /K. 
     The wall thickness T W  of the glass container  102  may vary depending on the implementation. In embodiments, the wall thickness T W  of the glass container  102  may be from less than or equal to 6 millimeters (mm), such as less than or equal to 4 mm, less than or equal to 2 mm, less than or equal to 1.5 mm, or less than or equal to 1 mm. In some embodiments, the wall thickness T w  may be greater than or equal to 0.1 mm and less than or equal to 6 mm, greater than or equal to 0.3 mm and less than or equal to 4 mm, greater than or equal to 0.5 mm and less than or equal to 4 mm, greater than or equal to 0.5 mm and less than or equal to 2 mm, or greater than or equal to 0.5 mm and less than or equal to 1.5 mm. In embodiments, the wall thickness T W  may be greater than or equal to 0.9 mm and less than or equal to 1.8 mm. The wall thickness T W  may vary depending on the axial location within the glass container  102 . 
     As depicted in  FIG.  1   , the flange  126  comprises an underside surface  132 , an outer surface  136 , and the upper sealing surface  110 . The outer surface  136  may define an outer diameter of the flange  126 . In embodiments, the metal-containing cap  108  of the sealing assembly  104  is crimped around the flange  126  via any suitable crimping method (e.g., a pneumatic crimping apparatus or the like). During the sealing process, the stopper  106  is inserted into the opening  105 , and a compression force is applied to the metal-containing cap  108  during crimping. For example, as depicted in  FIG.  1   , the metal-containing cap  108  includes an underlying portion  109  that contacts the underside surface  132  of the flange  126  to force the stopper  106  to remain in a compressed state and form a seal after the crimping process. Compression of the stopper  106  generates a residual sealing force within the flange  126  that maintains compression on the stopper  106  after the metal-containing cap  108  is crimped into place. In embodiments, the length of the underlying portion  109  of the metal-containing cap  108  that directly contacts the underside surface  132  of the flange  126  possesses a length  111  (e.g., in the X-direction depicted in  FIG.  1   ) that is greater than or equal to 1 mm to facilitate maintenance of residual sealing force within the stopper  106  at storage temperatures of less than or equal to −80° C. 
     When the glass container  102  is cooled to or relatively low storage temperatures of less than or equal to −80° C. (e.g., less than or equal to −80° C., less than or equal to −100° C., less than or equal to −125° C., less than or equal to −150° C., less than or equal to −175° C., −180° C.), each of the constituent components of the glass container  102  may undergo a volumetric shrinkage that is dependent on the thermal properties of that component. As depicted in  FIG.  1   , the volume of material disposed between the underlying portion  109  and an upper portion  113  of the metal-containing cap  108  circumscribes the sealing portion  119  of the stopper  106  and the flange  126  of the glass container  102 . If the combination of the stopper  106  and the flange  126  shrinks in an amount that is greater than the amount of shrinkage of the metal-containing cap  108 , the compression on the stopper  106  provided by the metal-containing cap  108  may diminish, increasing the probability of the seal at the upper sealing surface  110  being broken. However, the filler member  107  having a CTE lower than the CTE of the stopper reduces the amount of shrinkage that the stopper  106  would otherwise exhibit. As such, the sealing assembly  104  including the filler member  107  encased within the stopper  106  reduces the overall CTE of the sealing assembly  104 , thereby reducing the likelihood of the seal at the upper sealing surface  110  being broken. 
     For example, as depicted in  FIG.  1   , the combined height  138  (e.g., in the Z-direction depicted in  FIG.  1   ) of the flange  126  and the stopper  106  is approximately equal to the distance between the upper portion  113  and the underlying portion  109  of the metal-containing cap  108 . In such a state, the metal-containing cap  108  may compress the stopper  106  against the upper sealing surface  110  to form a seal. If the combined height  138  shrinks to a greater extent than the metal-containing cap  108 , however, the compression of the stopper  106  may diminish, reducing the residual seal force. To maintain a compression of the stopper  106 , shrinkage ΔL of the metal-containing cap  108 , the stopper  106 , and the glass container  102  may satisfy the following relation: 
       Δ L   cap   =ΔL   vial   +ΔL   stopper   (1)
 
     where the shrinkage of ΔL of each component may be approximated by 
       Δ L=L   i ×( e   ∫α(T) −1),  (2)
 
     where L i  is an initial dimension of the component and α(T) is the temperature-dependent CTE of the material out of which each of the metal-containing cap  108 , the stopper  106 , and the glass container  102  are constructed. 
     In embodiments, the stopper  106  is constructed of a polymer-based material (e.g., butyl or other synthetic rubbers). Such materials may comprise a T g  that is greater than or equal to −70° C. and less than or equal to −10° C. Below the T g , the stopper  106  may behave as a solid (e.g., lose its elasticity), resulting in a diminished sealing force at the upper sealing surface  110 . For example, if the stopper  106  is cooled to beneath its T g , the stopper  106  may not fill the entirety of the gap between the upper sealing surface  110  and the upper portion  113  of the metal-containing cap  108 , increasing the probability of the seal breaking. That is, the stopper  106  effectively behaves as two different materials as it is cooled below its glass transition temperature: an elastic material above the transition temperature, and a solid glass below the transition temperature. According to equation 2 herein, the shrinkage of the stopper  106  disposed between the flange  126  and the upper portion  113  of the metal-containing cap  108  when cooled from an initial temperature T i  to a final temperature T F  may be approximated as: 
     
       
         
           
             
               
                 
                   
                     
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     where α glass  refers to the CTE of the glass-like material that the rubber of the stopper  106  transforms into below its glass transition temperature T g . In embodiments, to maintain the seal, the metal-containing cap  108  and stopper  106  may be constructed such that the shrinkage of the metal-containing cap  108  is greater than or equal to the combined shrinkage of the glass container  102  and the stopper  106 . To facilitate meeting such a relationship, the shrinkage of the metal-containing cap  108  may be increased, the shrinkage of the stopper  106  and flange  126  may be decreased, or any combination thereof. Alternatively or additionally, the structure of the glass container  102  may be designed to increase an initial capping compression imparted on the stopper  106 , thereby providing a greater tolerance for shrinkage of the stopper  106 . 
     Additionally, to maintain a compression of the stopper  106 , the CTE and a thickness of the filler member  107  extending between the upper surface  121   a  and the lower surface  121   b  of the filler body  121  should satisfy the following condition: 
     
       
         
           
             
               
                 
                   
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     where h rubber  refers to the thickness of the rubber coating in the stopper  106 , α cap  refers to the CTE of the metal-containing cap  108 , α cartridge  refers to the CTE of the glass container  102 , α stopper  refers to the CTE of the stopper  106 , α filler  refers to the CTE of the filler member  107 , and h flange  refers to a thickness or distance  156  of the flange  126 , and h rubber  refers to the thickness of the stopper  106 , which includes the rubber coating and the filler member  107  in a vertical direction. 
     In embodiments, the metal-containing cap  108  is constructed of aluminium, which may have a CTE of approximately 240×10′/K. Typical rubbers out of which the stopper  106  is constructed (e.g., Butyl 325, Butyl 035, etc.) may have CTEs of greater than or equal to 1,400×10 7 /K. That is, purely in terms of CTE differential, the metal-containing cap  108  has a tendency to shrink less than the stopper  106 , resulting in a diminished sealing force at lower storage temperature. In addition to the above-described CTE mismatch, as depicted in  FIG.  1   , the stopper  106  may make up a larger volumetric percentage of the sealing assembly  104  than the metal-containing cap  108 , further compounding the tendency of the stopper  106  to undergo a larger thermal shrinkage. 
     In the embodiment depicted in  FIG.  1   , to counteract such tendencies of the stopper shrinkage to overwhelm the shrinkage of the metal-containing cap  108  at low storage temperatures, the structure of the glass container  102  has been modified to deviate from existing glass containers to provide greater compression of the stopper  106  during the process of crimping the metal-containing cap  108 . Specifically, in embodiments, the upper sealing surface  110  includes an inclined sealing surface  140 , such as that disclosed in U.S. Patent Application Publication No. 2021/0212893, hereby incorporated by reference in its entirety. The inclined sealing surface  140  extends between the outer surface  136  of the flange  126  and the inner surface  114  of the glass container  102 . The inclined sealing surface  140  extends at an angle  150  to a plane  152  extending through an end  154  of the opening  105 . The plane  152  may be a planar surface that rests on top of the glass container  102  at the opening  105  (e.g., that rests on peaks of the inclined sealing surface  140 ). In embodiments, the plane  152  connects points extending around the upper sealing surface  110  that are most distant from a reference point (e.g., the floor portion  122 , see  FIG.  1   ) of the glass container  102 . The plane  152  may extend through the top of the glass container  102  in a direction perpendicular to the central axis A of the glass container  102  (e.g., in the X-direction depicted in  FIG.  1   ). In embodiments, the plane  152  extends perpendicular to the portion of the inner surface  114  defining the opening  105 . 
     The angle  150 , as described herein, may be referred to as a “flange angle.” Flange angles relative to the plane  152  may be measured in a variety of different ways. For example, in embodiments, to determine an extension direction for the inclined sealing surface  140 , an image may be captured of the glass container  102 , and image processing techniques may be used to determine the angle  150  of the inclined sealing surface  140  (relative to the plane  152 ). In embodiments, the extension direction of the inclined sealing surface  140  is measured via finding a plane that extends between a peak of the inclined sealing surface  140  (e.g., having the greatest distance in the Z-direction from the underside surface  132 ) and a second highest point on the inclined sealing surface  140  (e.g., the extension direction of the inclined sealing surface  140  is measured via a plane that rests on the peak of the inclined sealing surface  140  and another point of the inclined sealing surface  140  that is lower than the peak relative to the plane  152 ). In embodiments, the extension direction of the inclined sealing surface  140  is measured via connecting points on the inclined sealing surface  140  that are a predetermined distance (e.g., 0.1 mm, 0.2 mm, 0.5 mm, 1.0 mm, etc.) outward from the inner surface  114  and inward of the outer surface  136  (e.g., the points may be taken at a uniform distribution of spatial points extending between the inner surface  114  and the outer surface  136 ). In embodiments, the extension direction of the inclined sealing surface  140  is measured by curve fitting a linear plane to a plurality of different points distributed throughout the entirety of the inclined sealing surface  140 . 
     In embodiments, the angle  150  is greater than 5 degrees and less than or equal to 45 degrees (e.g., greater than 5 degrees and less than or equal to 40 degrees, greater than 5 degrees and less than or equal to 40 degrees, greater than 5 degrees and less than or equal to 30 degrees, greater than 5 degrees and less than or equal to 20 degrees, greater than 5 degrees and less than or equal to 10 degrees). In embodiments, the angle  150  is substantially uniform around a circumference of the glass container  102  (e.g., when measured at a plurality of azimuthal orientations, each of the measurements may be within 0.5 degrees of one another). In existing glass containers, the angle  150  is typically around 3 degrees. As such, in the glass container  102 , the inclination of the upper sealing surface  110  relative to the plane  152  is increased by at least 50% over existing glass containers. The greater inclination of the upper sealing surface  110  tends to increase stopper compression at low storage temperatures. The angle  150  may create a compression gradient within the stopper  106  as a result of crimping the metal-containing cap  108 . For example, in embodiments, a compression of the stopper  106  may increase with increasing radial distance from the outer surface  136  such that the compression of the stopper  106  is greater closer to the inner surface  114 . Such greater compression with proximity to the inner surface  114  may prevent gaps from forming in the seal as the stopper  106  shrinks with cooling. 
     Referring still to  FIG.  1   , as a result of the angle  150 , a distance  156  between the upper portion  113  of the metal-containing cap  108  and the upper sealing surface  110  may vary as a function of radial distance from the central axis A to a greater extent than existing glass containers. Given this, the stopper  106  is compressed to a greater extent proximate to the opening  105  than at peripheral regions of the stopper  106  disposed near the outer surface  136  of the flange  126 . Such greater compression results in a greater compression of the stopper  106  using the same crimping process, providing a higher tolerance for shrinkage of the stopper  106 . Additionally, the inclined sealing surface  140  reduces the term L i,stopper  in equation 3 above proximate to the opening  105 . This reduces the amount of shrinkage. 
     Although not illustrated herein, it should be understood that alternatives to the glass container  102  described herein with respect to  FIG.  1    may be used while still maintaining container closure integrity at storage temperatures less than or equal to −80° C. For example, the upper sealing surface  110  may extend in the plane  152  extending through the end  154  of the opening  105  in the glass container  102 . In embodiments, the upper sealing surface  110  extends substantially perpendicular (e.g., at an angle greater than or equal to 89.5 degrees and less than or equal to 90.5 degrees) to the central axis A of the glass container  102 . In embodiments, the upper sealing surface  110  extends substantially perpendicular to the inner surface  114  of the glass container  102  defining the opening  105 . Such an upper sealing surface  110  beneficially increases a contact area between the stopper  106  and the upper sealing surface  110  and may increase the probability of maintaining integrity of the seal. 
     Referring now to  FIG.  2   , a further embodiment of a pharmaceutical container  200  is illustrated including the glass container  102  and a sealing assembly  202 . The sealing assembly  202  includes the stopper  106  and a filler member  204 . Rather than the filler member  204  including the filler body  121  extending across the opening  105  formed in the glass container  102 , the filler member  204  extends at least partially within and through the opening  105 . However, it should be appreciated that the above features of the filler member  107 , such as the material of formation and CTE, are equally applicable to the filler member  204  discussed herein. 
     The filler member  204  is at least partially encased within the stopper  106 , particularly the insertion portion  117  of the stopper  106  rather than within the sealing portion  119  of the stopper  106 . With more particularity, the filler member  204  includes a filler protrusion  206  having an upper surface  206   a , a lower surface  206   b  opposite the upper surface  206   a , and an outer edge  206   c . In embodiments, the filler member  204  may not be encased within the stopper  106  at the lower surface  206   b  thereof. In other embodiments, the filler member  204  may be fully encased within the stopper  106 . In embodiments, the upper surface  206   a  of the filler protrusion  206  may be tapered radially outwardly conforming to a taper formed in the upper surface  121   a  of the sealing portion  119  of the stopper  106 , as shown in  FIG.  2   . Although not shown, it should be appreciated that the filler protrusion  206  may have a circular or elliptical geometry, as defined by the outer edge  206   c , when viewed from a plan view corresponding to a geometry of an outer edge of the insertion portion  117  of the stopper  106 . As such, a distance between the outer edge of the insertion portion  117  and the outer edge  206   c  of the filler protrusion  206  remains substantially constant along the entire outer edge  206   c  of the filler protrusion  206 . As shown in  FIG.  2   , the filler member  204  is positioned within the stopper  106  such that the filler protrusion  206  extends through the insertion portion  117  of the stopper  106 , which is shown inserted through the opening  105  formed in the glass container  102 , and parallel to the inner surface  114  of the glass container  102 . As such, the filler protrusion  206  has a protrusion diameter D 3  that is less than the opening diameter D 2  of the opening  105  of the glass container  102 . In embodiments, a protrusion channel  206   d  is formed in the filler protrusion  206  and extends through the upper surface  206   a  and the lower surface  206   b  of the filler protrusion  206  to permit a needle, such as that of a syringe, to extend into the glass container  102  through the filler member  204 . In embodiments, the protrusion channel  206   d  may be filled with a sealing material  206   e.    
     Referring now to  FIG.  3   , a further embodiment of a pharmaceutical container  300  is illustrated including the glass container  102  and a sealing assembly  302 . The sealing assembly  302  includes the stopper  106  and a filler member  304 . The filler member  304  includes a filler body  306 , similar to the filler body  121 , and a filler protrusion  308 , similar to the filler protrusion  206 , discussed herein. The filler body  306  and the filler protrusion  308  may be formed as a one-piece, monolithic structure. As such, the filler member  304  extends both across the opening  105  and within the opening  105  formed in the glass container  102  rather than only one or the other, as described in the above embodiments. It should be appreciated that the above features of the filler members  107 ,  204 , such as the material of formation and CTE, are equally applicable to the filler member  304  discussed herein. 
     The filler member  304  is at least partially encased within the stopper  106 . Particularly the filler body  306  is encased within the sealing portion  119  of the stopper  106  and the filler protrusion  308  is at least partially encased within the insertion portion  117  of the stopper  106 . With more particularity, the filler body  306  has an upper surface  306   a , a lower surface  306   b  opposite the upper surface  306   a , and an outer edge  306   c , and the filler protrusion  308  also has an upper surface  308   a , a lower surface  308   b  opposite the upper surface  308   a , and an outer edge  308   c . In embodiments, the upper surface  306   a  of the filler body  306  may be tapered radially outwardly conforming to a taper formed in the upper surface  121   a  of the sealing portion  119  of the stopper  106 , as shown in  FIG.  3   . Although not shown, it should be appreciated that the filler body  306  and the filler protrusion  308  may have a circular or elliptical geometry, as defined by the outer edge  306   c  and the outer edge  308   c , respectively, when viewed from a plan view corresponding to a geometry of the outer edge of the sealing portion  119  and the outer edge of the insertion portion  117  of the stopper  106 , respectively. As such, a distance between the outer edge of the sealing portion  119  and the outer edge  306   c  of the filler body  306  remains substantially constant along the entire outer edge  306   c  of the filler body  306 . Similarly, a distance between the outer edge of the insertion portion  117  and the outer edge  308   c  of the filler protrusion  308  remains substantially constant along the entire outer edge  308   c  of the filler protrusion  308 . In embodiments, a body channel  306   d , such as the body channel  121   d , is formed in the filler body  306  and a protrusion channel  308   d , such as the protrusion channel  206   d , is formed in the filler protrusion  308 . The body channel  306   d  and the protrusion channel  308   d  may be coaxial with one another to extend entirely though the filler member  304  and permit a needle, such as that of a syringe, to extend into the glass container  102  through the filler member  304 . In embodiments, the body channel  306   d  and the protrusion channel  308   d  may be filled with a sealing material  306   e.    
     As shown in  FIGS.  1 - 3   , it should be appreciated that a gap may be formed between outer surfaces of the sealing portion and the metal-containing cap, as well as between an outer surface of the flange and the metal-containing cap. Alternatively, as discussed herein, the outer surfaces of the sealing portion and the metal-containing cap, as well as the outer surface of the flange and the metal-containing cap, may be in contact with one another such that no gap is provided. Additionally, in embodiments, it should be noted that no sharp corners will be provided on the sealing assemblies discussed herein and, rather, any angular surfaces should be chamfered or rounded to avoid the stress concentration. 
     Referring now to  FIGS.  4 - 7   , embodiments of a pharmaceutical container are illustrated including a container depicted as a syringe, and a filler member provided within a stopper of the pharmaceutical container for sealing the syringe. With respect to  FIG.  4   , a pharmaceutical container  400  is illustrated including a container, depicted herein as a syringe  402 , and a sealing assembly  404 . It should be appreciated that the above features of the glass container  102 , such as the material of formation and CTE, are equally applicable to the syringe  402  discussed herein. However, in embodiments, the syringe  402  may be formed from a material other than glass such as, for example, plastic. The syringe  402  includes a tubular barrel  406  having an open end  408  and a closed end  410  opposite the open end  408 . In embodiments, the closed end  410  of the syringe  402  is tapered. The tubular barrel  406  has an interior  412  defined by an interior wall  414  of the tubular barrel  406 . A needle  416  is provided at the closed end  410  of the syringe  402  and in fluid communication with the interior  412  of the tubular barrel  406  to direct fluid from within the interior  412  out of the syringe  402 . 
     The sealing assembly  404  is movably positioned within the interior  412  of the tubular barrel  406  and includes a stopper  418 , a filler member  420 , and a plunger  422 . The stopper  418  has an outer wall  418   a  and an inner wall  418   b  opposite the outer wall  418   a . When the stopper  418  is positioned within the tubular barrel  406 , the outer wall  418   a  contacts the interior wall  414  of the tubular barrel  406 . The inner wall  418   b  of the stopper  418  defines a recess  418   c  which receives the filler member  420 . As such, the filler member  420  is at least partially encased within the stopper  418 . 
     The plunger  422  has a first end  422   a  and a second end  422   b  opposite the first end  422   a . The first end  422   a  of the plunger  422  may be fixed, such as by being adhered, sonic welded, or the like, to one or both of the stopper  418  and the filler member  420 . As shown, the first end  422   a  of the plunger  422  is secured to and extends from the filler member  420 . The plunger  422  may include a lip  422   c  formed at the second end  422   b  thereof opposite the stopper  418  and the filler member  420 . The lip  422   c  assists with manually positioning the plunger  422 , and more particularly the sealing assembly  404 , within the interior  412  of the syringe  402 . 
     It should be appreciated that the above features of the stopper  106  and the filler member  107 , such as the material of formation and CTE, are equally applicable to the stopper  418  and the filler member  420 , respectively, discussed herein. As such, the stopper  418  has a first CTE and the filler member  420  has a second CTE lower than the first CTE. Additionally, in embodiments, the tubular barrel  406  has a third CTE greater than the second CTE of the filler member  420 . Accordingly, the filler member  420  is formed from a first material such as, for example, glass, a crystalline material, a polymer, a metal, and the like, or any combination thereof. In embodiments, the first material forming the filler member  420  is coated with a second material. The second material may be, for example, butyl rubber, nitrile rubber, fluoro rubber, butyl silicone rubber, polyacrylate elastomer, and the like, or any combination thereof. 
     When the CTE of the stopper  418  is approximately the same or lower than the CTE of the tubular barrel  406 , the likelihood of a gap being formed between that no is significantly reduced. The CTE and thickness of the filler member  420  should satisfy the following equation: 
     
       
         
           
             
               
                 
                   
                     α 
                     filler 
                   
                   ≤ 
                   
                     
                       α 
                       
                         c 
                         ⁢ 
                         a 
                         ⁢ 
                         r 
                         ⁢ 
                         t 
                         ⁢ 
                         ridge 
                       
                     
                     - 
                     
                       
                         
                           Δ 
                           ⁢ 
                           r 
                         
                         
                           r 
                           filler 
                         
                       
                       * 
                       
                         ( 
                         
                           
                             α 
                             stopper 
                           
                           - 
                           
                             α 
                             cartridge 
                           
                         
                         ) 
                       
                     
                   
                 
               
               
                 
                   ( 
                   5 
                   ) 
                 
               
             
           
         
       
     
     where α filler , α cartridge , and α plunger  are the CTE of the filler member  420 , the tubular barrel  406 , and the stopper  418 , respectively, Δr is the thickness of the stopper  418 , and r filler  is the size or radius of the filler member  420 . 
     It should be appreciated that, the tubular barrel  406  may be formed of a material other than glass such as, for example, plastic. However, if the tubular barrel  406  is formed of glass, the CTE difference between the stopper  418  and the tubular barrel  406  may be relatively large. Since the CTE of glass is already low, then it is better to reduce the thickness of the stopper  418  so that the CTE requirement of filler member  420  can be more easily satisfied. In this case, the CTE of the filler member  420  should satisfy the following equation: 
     
       
         
           
             
               
                 
                   
                     
                       α 
                       filler 
                     
                     
                       α 
                       cartridge 
                     
                   
                   ≤ 
                   
                     1 
                     - 
                     
                       
                         
                           Δ 
                           ⁢ 
                           r 
                         
                         
                           r 
                           filler 
                         
                       
                       * 
                       
                         ( 
                         
                           
                             
                               α 
                               rubber 
                             
                             
                               α 
                               cartridge 
                             
                           
                           - 
                           1 
                         
                         ) 
                       
                     
                   
                 
               
               
                 
                   ( 
                   6 
                   ) 
                 
               
             
           
         
       
     
     Referring now to  FIG.  5   , a pharmaceutical container  500  is illustrated including the syringe  402  and a sealing assembly  504 . The pharmaceutical container  500  is substantially similar to the pharmaceutical container  400  depicted in  FIG.  4    and thus, like reference numerals are used to indicate like parts. The sealing assembly  504  includes the stopper  418 , a filler member  520 , and a plunger  522 . The filler member  520  is identical to the filler member  420 , with the exception of a cavity  520   a  being formed therein. As such, the overall mass of the filler member  520  is reduced while still providing the benefit of reducing shrinkage and deformation of the stopper  418  when the pharmaceutical container  500  is subjected to relatively low temperatures. As a result, a seal formed by contact between the outer wall  418   a  of the stopper  418  and the interior wall  414  of the tubular barrel  406  is maintained. 
     Additionally, the plunger  522  has a first end  522   a  and a second end  522   b  opposite the first end  522   a . A flange  522   c  is formed at the first end  522   a  of the plunger  522  and extends across the cavity  520   a  formed in the filler member  520 . As such, the flange  522   c  causes the cavity  520   a  to be closed off from the rest the interior  412  defined by the tubular barrel  406 . The flange  522   c  extends across at least the filler member  520  and, in embodiments, extends across the stopper  418  as well. In embodiments, the flange  522   c  has a width extending across the interior  412  of the tubular barrel  406 , and thus across both the filler member  520  and the stopper  418 , such that opposite ends of the flange  522   c  contact the interior wall  414  of the tubular barrel  406 . This ensures a fluid tight seal between the plunger  522 , the stopper  418 , and the tubular barrel  406 . The first end  522   a  of the plunger  522  may be fixed, such as by being adhered, sonic welded, or the like, to one or both of the stopper  418  and the filler member  520 . It should be appreciated that the above features of the filler member  107 , such as the material of formation and CTE, are equally applicable to the filler member  520  discussed herein. As such, the filler member  520  has a second CTE lower than the first CTE of the stopper  418 . Additionally, in embodiments, the second CTE of the filler member  520  is lower than a third CTE of the tubular barrel  406 . 
     Referring now to  FIG.  6   , a pharmaceutical container  600  is illustrated including the syringe  402  and a sealing assembly  604 . The pharmaceutical container  600  is substantially similar to the pharmaceutical containers  400 ,  500  depicted in  FIGS.  4  and  5   , respectively, and thus, like reference numerals are used to indicate like parts. The sealing assembly  604  includes the stopper  418 , a filler member  620 , and a plunger  622 . The filler member  620  is identical to the filler member  620 , with the exception of a channel  620   a  open at opposite ends thereof being formed therein rather than the cavity  520   a  closed at one end. As such, the filler member  620  is ring-shaped. Thus, the overall mass of the filler member  620  is further reduced while still providing the benefit of reducing shrinkage and deformation of the stopper  418  when the pharmaceutical container  600  is subjected to relatively low temperatures. Additionally, the channel  620   a  formed in the filler member  620  permits the plunger  622  to extend entirely through the filler member  620  and contact the stopper  418  at a first end  622   a  thereof. The first end  622   a  of the plunger  622  may be fixed, such as by being adhered, sonic welded, or the like, to the stopper  418 . It should be appreciated that the above features of the filler member  107 , such as the material of formation and CTE, are equally applicable to the filler member  620  discussed herein. As such, the filler member  620  has a second CTE lower than the first CTE of the stopper  418 . Additionally, in embodiments, the second CTE of the filler member  620  is lower than a third CTE of the tubular barrel  406 . 
     Referring now to  FIG.  7   , a pharmaceutical container  700  is illustrated including the syringe  402  and a sealing assembly  704 . The sealing assembly  704  includes a stopper  718 , a filler member  720 , and a plunger  722 . It should be appreciated that the above features of the stopper  106  and the filler member  107 , such as the material of formation and CTE, are equally applicable to the stopper  718  and the filler member  720 , respectively, discussed herein. As such, the stopper  718  has a first CTE and the filler member  720  has a second CTE lower than the first CTE. 
     As shown in  FIG.  7   , the stopper  718  has an inner wall  718   a  and an outer wall  718   b  opposite the inner wall  718   a . The inner wall  718   a  defines a cavity  718   c . The outer wall  718   b  defines one or more lobes  718   d . The lobes  718   d  extend in a radial direction to contact the interior wall  414  of the tubular barrel  406 . As shown, a pair of lobes  718   d  are illustrated defining one or more recesses  718   e  between adjacent lobes  718   d . However, it should be appreciated that more than a pair of lobes  718   d  may be provided such as, for example, three, four, or five lobes. The stopper  718  has a constant thickness defined between the inner wall  718   a  and the outer wall  718   b  thereof. In embodiments, the interior a lubricant may be provided within the interior wall  414  of the tubular barrel  406  may be coated within a lubricant, and/or provided within the recess  718   e , to facilitate sliding of the sealing assembly  704  within the interior  412  of the tubular barrel  406 . 
     The filler member  720  is provided within the cavity  718   c  defined by the inner wall  718   a  of the stopper  718 . The filler member  720  conforms to the shape of the cavity  718   c  to contact and extend along the inner wall  718   a  of the stopper  718 . As such, the filler member  720  similar defines one or more lobes  720   a . In embodiments in which the stopper  718  has a plurality of lobes  718   d  defining one or more recesses  718   e , the filler member  720  similarly has a plurality of lobes  720   a  defining one or more recesses  720   b , as shown in  FIG.  7   . The plunger  722  has a first end  722   a  which may be fixed, such as by being adhered, sonic welded, or the like, to one or both of the stopper  718  and the filler member  720 . As shown, the first end  722   a  is fixed to the filler member  720 . 
     From the above, it is to be appreciated that defined herein is a sealed pharmaceutical container including a container and a sealing assembly having a CTE lower than CTE of the container such that, when the sealed pharmaceutical container is subjected to relatively low temperatures, shrinkage of the sealing assembly relative to the container does not result in a gap in a seal formed between the container and the sealing assembly. Specifically, the sealing assembly includes a stopper including a filler member at least partially encased within the stopper. The filler member has a CTE lower than the CTE of the stopper and approximately the same or lower than the CTE of the container. 
     Further aspects of the embodiments described herein are provided by the subject matter of the following clauses: 
     Clause 1. A sealed pharmaceutical container comprising: a shoulder; a neck extending from the shoulder; a flange extending from the neck, the flange comprising: an underside surface extending from the neck; an outer surface extending from the underside surface, the outer surface defining an outer diameter of the flange; and an upper sealing surface extending between the outer surface and an inner surface defining an opening in the sealed pharmaceutical container, and a sealing assembly comprising: a stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and an insertion portion extending into the opening and in contact with the inner surface of the flange, the stopper having a first CTE; and a filler member encased within the stopper and having a second CTE, the second CTE being lower than the first CTE. 
     Clause 2. The sealed pharmaceutical container of clause 1, wherein the filler member comprises a first material, the first material including at least one of glass, a crystalline material, a polymer, and a metal. 
     Clause 3. The sealed pharmaceutical container of clause 2, wherein the first material includes at least one of oxide, halide, nitride, and chalcogen. 
     Clause 4. The sealed pharmaceutical container of clause 2, wherein the first material is coated with a second material, the second material including at least one of butyl rubber, nitrile rubber, fluoro rubber, butyl silicone rubber, and polyacrylate elastomer. 
     Clause 5. The sealed pharmaceutical container of clause 4, wherein the second material has a glass transition temperature (T g ) between −200° C. to 300° C. 
     Clause 6. The sealed pharmaceutical container of any of clauses 1-5, wherein the filler member includes a filler body having a body diameter greater than an opening diameter of the opening of the sealed pharmaceutical container. 
     Clause 7. The sealed pharmaceutical container of clause 6, wherein a body channel is formed extending through an upper surface of the filler body and a lower surface of the filler body. 
     Clause 8. The sealed pharmaceutical container of clause 7, wherein the filler member includes a filler protrusion extending at least partially through the opening of the pharmaceutical container and parallel to the inner surface of the pharmaceutical container. 
     Clause 9. The sealed pharmaceutical container of clause 8, wherein a protrusion channel is formed extending through an upper surface of the filler protrusion and a lower surface of the protrusion, the body and the protrusion form a one-piece monolithic structure, and the protrusion channel and the body channel are coaxial with one another. 
     Clause 10. The sealed pharmaceutical container of any of clauses 1-9, wherein the filler member includes a filler protrusion extending at least partially through the opening of the pharmaceutical container and parallel to the inner surface of the pharmaceutical container, the filler protrusion having a protrusion diameter less than an opening diameter of the opening of the sealed pharmaceutical container. 
     Clause 11. The sealed pharmaceutical container of any of clauses 1-10, wherein the sealing assembly maintains a helium leakage rate of the sealed pharmaceutical container at less than or equal to 1.4×10 −6  cm 3 /s as the sealed pharmaceutical container is cooled to a temperature of less than or equal to −45° C. 
     Clause 12. The sealed pharmaceutical container of any of clauses 1-11, wherein the upper sealing surface is an inclined sealing surface extending at an angle relative to a plane extending through an end of the opening such that a distance between the inclined sealing surface and the plane increases with decreasing radial distance from the outer surface. 
     Clause 13. The sealed pharmaceutical container of any of clauses 1-12, wherein the flange is constructed of a composition having a coefficient of thermal expansion that is greater than or equal to 0×10-7/K and less than or equal to 70×10-7/K. 
     Clause 14. A sealed pharmaceutical container comprising: a syringe comprising: a tubular barrel having an open end and closed end opposite the open end; a needle extending from the closed end and in fluid communication with an interior of the tubular barrel defined by an inner wall of the tubular barrel; and a sealing assembly movably positioned within the interior of the tubular barrel, the sealing assembly comprising: a stopper having an inner wall and an outer wall opposite the inner wall at least partially in contact with the inner wall of the tubular barrel the stopper having a first CTE; a filler member at least partially encased within the stopper and having a second CTE, the second CTE being lower than the first CTE; and a plunger coupled to the stopper and extending through the open end of the tubular barrel. 
     Clause 15. The sealed pharmaceutical container of clause 14, wherein the filler member comprises a first material, the first material including at least one of glass, a crystalline material, a polymer, and a metal. 
     Clause 16. The sealed pharmaceutical container of clause 15, wherein the first material includes at least one of oxide, halide, nitride, and chalcogen. 
     Clause 17. The sealed pharmaceutical container of clause 15, wherein the stopper comprises a second material, the second material including at least one of butyl rubber, nitrile rubber, fluoro rubber, butyl silicone rubber, and polyacrylate elastomer. 
     Clause 18. The sealed pharmaceutical container of clause 17, wherein the second material has a T g  between −200° C. to 300° C. 
     Clause 19. The sealed pharmaceutical container of any of clauses 14-18, wherein the plunger includes a first end provided within the interior of the tubular barrel and a second end opposite the first end that is provided outside of the interior of the tubular barrel, the first end of the plunger fixed to the filler member. 
     Clause 20. The sealed pharmaceutical container of clause 19, wherein the filler member has a cavity formed therein. 
     Clause 21. The sealed pharmaceutical container of clause 20, wherein the plunger includes a flange formed at the first end thereof extending across the cavity formed in the filler member. 
     Clause 22. The sealed pharmaceutical container of clause 20, wherein the first end of the plunger is received within the cavity formed in the filler member. 
     Clause 23. The sealed pharmaceutical container of any of clauses 19-22, wherein the stopper and the filler member each includes a pair of lobes defining one or more recesses, the pair of lobes are in contact with an interior wall of the tubular barrel and the one or more recesses are spaced apart from the interior wall of the tubular barrel. 
     Clause 24. The sealed pharmaceutical container of any of clauses 14-23, wherein the tubular barrel is constructed of a composition having a coefficient of thermal expansion that is greater than or equal to 0×10-7/K and less than or equal to 70×10-7/K. 
     Clause 25. The sealed pharmaceutical container of claim any of clauses 14-24, wherein the sealed pharmaceutical container maintains a helium leakage rate at less than or equal to 1.4×10 −6  cm 3 /s as it is cooled to the temperature at a rate of less than or equal to 5° C. per minute. 
     Clause 26. The sealed pharmaceutical container of any of clauses 14-24, wherein the sealing assembly maintains a helium leakage rate of the sealed pharmaceutical container at less than or equal to 1.4×10 −6  cm 3 /s as the sealed pharmaceutical container is cooled to a temperature of less than or equal to −20° C. 
     Clause 27. The sealed pharmaceutical container of any of clauses 14-24, wherein the sealing assembly maintains a helium leakage rate of the sealed pharmaceutical container at less than or equal to 1.4×10 −6  cm 3 /s as the sealed pharmaceutical container is cooled to a temperature of less than or equal to −120° C. 
     Clause 28. The sealed pharmaceutical container of any of clauses 14-24, wherein the sealing assembly maintains a helium leakage rate of the sealed pharmaceutical container at less than or equal to 1.4×10 −6  cm 3 /s as the sealed pharmaceutical container is cooled to a temperature of less than or equal to −180° C. 
     Clause 29. A method of sealing a pharmaceutical container, the method comprising: providing a pharmaceutical container comprising a shoulder, a neck extending from the shoulder and a flange extending from the neck, the flange comprising: an underside surface extending from the neck; an outer surface extending from the underside surface, the outer surface defining an outer diameter of the flange; and an upper sealing surface extending between the outer surface to an inner surface of the pharmaceutical container that defines an opening; inserting a pharmaceutical composition into the pharmaceutical container; and providing a stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and an insertion portion extending into the opening and in contact with the inner surface of the flange, the stopper having a first CTE, a filler member encased within the stopper and having a second CTE, the second CTE being lower than the first CTE. 
     Clause 30. The method of clause 29, further comprising cooling the pharmaceutical container to a temperature of less than or equal to −20° C., wherein, after the cooling of the pharmaceutical container, the compression is maintained on the upper sealing surface such that a helium leakage rate of the pharmaceutical container is less than or equal to 1.4×10 −6  cm 3 /s at the temperature. 
     Clause 31. The method of clause 29 or clause 30, wherein the filler member comprises a first material, the first material including at least one of glass, a crystalline material, a polymer, and a metal. 
     Clause 32. The method of clause 31, wherein the first material is coated with a second material, the second material including at least one of butyl rubber, nitrile rubber, fluoro rubber, butyl silicone rubber, and polyacrylate elastomer. 
     Clause 33. The method of clause 32, wherein the second material has a T g  between −200° C. to 300° C. 
     Clause 34. The method of any of clauses 29-33, wherein the filler member includes a filler body having a body diameter equal to or greater than an opening diameter of the opening of the pharmaceutical container. 
     Clause 35. The method of claim  34 , wherein a body channel is formed extending through an upper surface of the body and a lower surface of the body. 
     Clause 36. The method of clause 35, wherein the filler member includes a filler protrusion extending at least partially through the opening of the pharmaceutical container and parallel to the inner surface of the pharmaceutical container. 
     Clause 37. The method of clause 36, wherein a protrusion channel is formed extending through an upper surface of the protrusion and a lower surface of the filler protrusion, the filler body and the filler protrusion form a one-piece monolithic structure, and the protrusion channel and the body channel are coaxial with one another. 
     Clause 38. The method of any of clause 29, wherein the filler member includes a filler protrusion extending at least partially through the opening of the pharmaceutical container and parallel to the inner surface of the pharmaceutical container, the filler protrusion having a protrusion diameter less than an opening diameter of the opening of the pharmaceutical container. 
     It will be apparent to those skilled in the art that various modifications and variations can be made to the embodiments described herein without departing from the scope of the claimed subject matter. Thus, it is intended that the specification cover the modifications and variations of the various embodiments described herein provided such modification and variations come within the scope of the appended claims and their equivalents.