Patent Publication Number: US-2023145946-A1

Title: Pharmaceutical containers including high cte sealing assembly encircling outer surface of container

Description:
This application claims the benefit of priority under 35 U.S.C. § 119 of U.S. Provisional Application Serial No. 63/277,488 filed on Nov. 9, 2021, the content of which is relied upon and incorporated herein by reference in its entirety. 
    
    
     TECHNICAL FIELD 
     The present specification generally relates to containers, such as glass containers for storing pharmaceutical compositions and, more particularly, glass containers including a sealing assembly formed from a material having a high 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’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 -20° 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 a rim extending at least partially along the outer surface of the flange; and a metal-containing cap securing the stopper to the flange. 
     In another embodiment, a sealed pharmaceutical container includes: a shoulder; a neck extending from the shoulder; a flange extending from the neck; an inner surface defining an opening extending through the neck and the flange, wherein the flange includes an upper sealing surface extending from the inner surface and an outer surface extending from the upper sealing surface; 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 a rim extending at least partially along the outer surface of the flange; and a metal-containing cap crimped to the flange, the metal-containing cap compressing the stopper against the upper sealing surface. 
     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; providing a stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and a rim extending at least partially along the outer surface of the flange; and crimping a metal-containing cap over the stopper and against flange to compress the stopper against the upper sealing surface. 
     In yet another embodiment, a sealed pharmaceutical container includes: a shoulder; a neck extending from the shoulder; and a flange extending from the neck, the flange includes: 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, wherein a cutout portion is formed in the outer surface of the flange extending in an inward radial direction. 
     a method of sealing a sealed pharmaceutical container includes: providing a sealed 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 sealed pharmaceutical container that defines an opening; inserting a pharmaceutical composition into the sealed pharmaceutical container; providing a stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and a rim extending at least partially along the outer surface of the flange; and crimping a metal-containing cap over the stopper and against flange to compress the stopper against the upper sealing surface. 
     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 partial 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 partial cross-sectional view of another embodiment of a pharmaceutical container, according to one or more embodiments shown and described herein; and 
         FIG.  6    schematically depicts a partial 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 -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 equal to or 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 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. In embodiments, the stopper is constructed of a material having a lower CTE than existing pure rubber stoppers. For example, in embodiments, the stopper may be constructed of a polymer composite comprising greater than 0 wt.% and less than or equal to 30 wt.% of a silicon-based filler material. The silicon-based filler material may comprise SiO2 glass particles or various silicates (e.g., cordierite, b-eucryptite, b-spodumene) or combinations thereof. The CTE of the stopper may be less than or equal to 290×10 -7 /K to reduce shrinkage thereof at low storage 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., SiO2, Al2O3, B2O3 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 absolute 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 . The sealing assembly  104  includes a stopper  106  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 . 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. As discussed in more detail herein, it should be appreciated that the CTE of the stopper is equal to or greater than a CTE of the flange, which may be formed from a glass, ceramic, polymer, metal, or the like. 
     The glass container  102  generally comprises a body  112 . The body  112  has a wall thickness TW 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 glass 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 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 TW of the glass container  102  may vary depending on the implementation. In embodiments, the wall thickness TW 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 Tw 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 TW may be greater than or equal to 0.9 mm and less than or equal to 1.8 mm. The wall thickness TW 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 pharmaceutical container  100  is cooled to relatively low storage temperatures of less than or equal to -30° C. (e.g., less than or equal to -30° 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., -180° C.), each of the constituent components of the pharmaceutical container  100  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. 
     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 
               
             
             = 
             Δ 
             
               L 
               
                 vial 
               
             
             + 
             Δ 
             
               L 
               
                 stopper 
               
             
           
         
       
     
      where the shrinkage of ΔL of each component may be approximated by 
     
       
         
           
             Δ 
             L 
             = 
             
               L 
               i 
             
             x 
             
               
                 
                   e 
                   
                     
                       
                         ∫ 
                         
                           α 
                           
                             T 
                           
                         
                       
                     
                   
                 
                 − 
                 1 
               
             
             , 
           
         
       
     
      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 glass transition temperature (T g ) that is greater than or equal to -70° C. and less than or equal to -10° C. Such materials may comprise a glass transition temperature (T g ) that is less than or equal to -20° C. Below the T g , the stopper  106  may behave as a glassy solid (e.g., lose its shape recover ability), 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: a hyperelastic 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: 
     
       
         
           
             Δ 
             
               L 
               
                 s 
                 t 
                 o 
                 p 
                 p 
                 e 
                 r 
               
             
             = 
             
               L 
               
                 i 
                 , 
                 s 
                 t 
                 o 
                 p 
                 p 
                 e 
                 r 
               
             
               
             x 
             
               
                 
                   e 
                   
                     
                       
                         ∫ 
                         
                           
                               
                             
                               
                                 T 
                                 i 
                               
                             
                             
                               
                                 T 
                                 g 
                               
                             
                           
                         
                       
                     
                     
                       a 
                       
                         r 
                         u 
                         b 
                         b 
                         e 
                         r 
                       
                     
                     
                       T 
                     
                     d 
                     t 
                     + 
                   
                 
                 
                     
                   
                     
                       
                         ∫ 
                         
                           
                               
                             
                               
                                 T 
                                 g 
                               
                             
                             
                               
                                 T 
                                 F 
                               
                             
                           
                           
                             α 
                             
                               g 
                               l 
                               a 
                               s 
                               s 
                             
                           
                           
                             T 
                           
                           d 
                           T 
                         
                       
                     
                   
                 
                 − 
                 1 
               
             
             , 
           
         
       
     
      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 . 
     In embodiments, the metal-containing cap  108  is constructed of aluminium, which may have a CTE of approximately 240×10 -7 /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 1,000×10 -   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. Pat. 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 0 degrees and less than or equal to 45 degrees (e.g., greater than 0 degrees and less than or equal to 40 degrees, greater than 0 degrees and less than or equal to 40 degrees, greater than 0 degrees and less than or equal to 30 degrees, greater than 0 degrees and less than or equal to 20 degrees, and greater than 0 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 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 a glass container  202  and a sealing assembly  204 . Although not described in detail herein, the glass container  202  and the sealing assembly  204  may include similar structure and features to the glass container  102  and the sealing assembly  104  described herein and illustrated  FIG.  1   . As shown in  FIG.  2   , the glass container  202  includes a neck  206  extending to a flange  208  defined by an upper sealing surface  210 , an underside surface  212 , and an outer surface  214 . 
     In embodiments, the sealing assembly  204  includes a stopper  216  and a metal-containing cap  218 . However, it should be appreciated that, in embodiments, the metal-containing cap  218  may not be provided. The stopper  216  includes a sealing portion  220  terminating at an outer edge  222  and a rim  224  extending from the outer edge  222  of the sealing portion  220 . In embodiments, the rim  224  may contact or not contact the metal-containing cap  218 . The sealing portion  220  has an outer diameter D1 defined by a distance between the outer edge  222  of the sealing portion  220 . The outer diameter D1 may be equal to or less than a diameter between the inner surface  230  of the metal-containing cap  218 . When the stopper  216  is positioned on the glass container  202 , the sealing portion  220  extends over the upper sealing surface  210  of the flange  208  and covers an opening  226  formed in the glass container  202 . The rim  224  extends from the outer edge  222  of the sealing portion  220  and at least partially along the outer surface  214  of the flange  208 . In embodiments, as shown in  FIG.  2   , the rim  224  has a length extending along an entire length or partial length of the outer surface  214  of the flange  208 . In embodiments, a bottom surface  228  of the rim  224  extends collinear with the underside surface  212  of the flange  208 . In embodiments in which the metal-containing cap  218  is provided, the bottom surface  228  of the rim  224  may contact the inner surface  230  of the metal-containing cap  218 , specifically, an underlying portion  232  of the metal-containing cap  218 , which extends radially inwardly along the underside surface  212  of the flange  208  and toward to the neck  206 . 
     It should be appreciated that when the pharmaceutical container  200  is subj ected to relatively low storage temperatures, as discussed above, the coefficient of thermal expansion of the stopper  216  being greater than the coefficient of thermal expansion of the glass container  202  causes the rim  224  of the stopper  216  to shrink around and toward the flange  208  of the glass container  202 , thus increasing the seal formed between the stopper  216  and the flange  208  of the glass container  202 . More particularly, the sealing portion  220  of the stopper  216  shrinks during relatively low storage temperatures such that the outer diameter D1 between the outer edge  222  of the sealing portion  220  is reduced, which results in the rim  224  becoming tighter around the outer surface  214  of the flange  208 . 
     Referring now to  FIG.  3   , a further embodiment of a pharmaceutical container  300  is illustrated including a glass container  302  and a sealing assembly  304 . Although not described in detail herein, the glass container  302  and the sealing assembly  304  may include similar structure and features to the glass container  102 ,  202  and the sealing assembly  104 ,  204  described herein and illustrated  FIGS.  1  and  2   . As shown in  FIG.  3   , the glass container  302  includes a neck  306  extending to a flange  308  defined by an upper sealing surface  310 , an underside surface  312 , and an outer surface  314 . As shown in  FIG.  3   , the outer surface  314  of the flange  308  is radially recessed inwardly defining a cutout portion  316 . The outer surface  314  of the flange  308  includes an upperside surface portion  318  opposite the underside surface  312  and extending from an outermost edge  320  of the flange  308 , and a vertical surface portion  322 . The vertical surface portion  322  extends from a joining surface portion  324  at the upperside surface portion  318  to the upper sealing surface  310 . In embodiments, the vertical surface portion  322  extends perpendicular to the upperside surface portion  318 . In embodiments, the joining surface portion  324  extending between the upperside surface portion  318  and the vertical surface portion  322  forms a chamfer. The upperside surface portion  318 , the outermost edge  320 , and the underside surface  312  of the flange  308  cooperate to define a ledge  326 . In embodiments, it should be noted that no sharp corners will be provided on the sealing assembly  304  and, rather, any angular surfaces should be chamfered or rounded to avoid the stress concentration. 
     In embodiments, the sealing assembly  304  includes a stopper  328  and a metal-containing cap  330 . However, it should be appreciated that, in embodiments, the metal-containing cap  330  may not be provided. The stopper  328  includes a sealing portion  332  terminating at an outer edge  334  and a rim  336  extending from the outer edge  334  of the sealing portion  332 . The sealing portion  332  has an outer diameter D2 defined by a distance between the outer edge  334  of the sealing portion  332 . When the stopper  328  is positioned on the glass container  302 , the sealing portion  332  extends over the upper sealing surface  310  of the flange  308  and covers an opening  338  formed in the glass container  302 . The rim  336  extends from the outer edge  334  of the sealing portion  332  and at least partially along the outer surface  314  of the flange  308 . As shown in  FIG.  3   , the rim  336  includes a bottom surface  340  that contacts the upperside surface portion  318  of the flange  308 , an inner surface  342  that contacts the vertical surface portion  322  of the flange  308 , and a joining surface portion  344  extending between the bottom surface  340  of the rim  336  and the inner surface  342  of the rim  336 . The bottom surface  340 , the inner surface  342 , and the joining surface portion  344  of the rim  336  are received within the cutout portion  316  of the flange  308 . In embodiments in which the joining surface portion  324  of the flange  308  forms a chamfer, the joining surface portion  344  of the rim  336  also forms a chamfer so as to nest with one another. In embodiments in which the metal-containing cap  330  is provided, the ledge  326  is provided between the bottom surface  340  of the rim  336  and an inner surface  346  of the metal-containing cap  330 , specifically, an underlying portion  348  of the metal-containing cap  330 , which extends radially inwardly along the underside surface  312  of the flange  308  and toward to the neck  306 . As such, the ledge  326  of the flange  308  separates the rim  336  of the stopper  328  from the underlying portion  348  of the metal-containing cap  330 . 
     It should be appreciated that when the pharmaceutical container  300  is subjected to relatively low storage temperatures, as discussed above, the coefficient of thermal expansion of the stopper  328  being greater than the coefficient of thermal expansion of the glass container  302  causes the rim  336  of the stopper  328  to shrink around and toward the flange  308  of the glass container  302 , thus increasing the seal formed between the stopper  328  and the flange  308  of the glass container  302 . More particularly, the sealing portion  332  of the stopper  328  shrinks during relatively low storage temperatures such that the outer diameter D2 between the outer edge  334  of the sealing portion  332  is reduced, which results in the rim  336  becoming tighter around the outer surface  314  of the flange  308 . 
     Referring now to  FIG.  4   , a further embodiment of a pharmaceutical container  400  is illustrated including a glass container  402  and a sealing assembly  404 . It should be appreciated that the pharmaceutical container  400  is similar to the pharmaceutical container  300  described herein and illustrated in  FIG.  3    with the exception of the joining surface portion  324  of the flange  308  and the joining surface portion  344  of the rim  336 . As described herein and illustrated in  FIG.  3   , the joining surface portion  324  of the flange  308  and the joining surface portion  344  of the rim  336  of the pharmaceutical container  300  form corresponding chamfers. However, the pharmaceutical container  400  illustrated in  FIG.  4    includes a joining surface portion  406  formed in the flange  308  and a joining surface portion  408  formed in the rim  336  that are each arcuate and correspond to one another so as to nest with one another. The arcuate joining surface portions  406 ,  408  provide a smooth mating surface between the flange  308  and the rim  336  without sharp edges that might result in a gap between the flange  308  and the rim  336 . Such a gap may result in air pockets being formed therebetween or allowing air to escape the formed seal. 
     Referring now to  FIG.  5   , a further embodiment of a pharmaceutical container  500  is illustrated including a glass container  502  and a sealing assembly  504 . Although not described in detail herein, the glass container  502  and the sealing assembly  504  may include similar structure and features to the glass containers and the sealing assemblies described herein and illustrated  FIGS.  1 - 4   . As shown in  FIG.  5   , the glass container  502  includes a neck  506  extending to a flange  508  defined by an upper sealing surface  510 , an underside surface  512 , and an outer surface  513 . 
     In embodiments, the sealing assembly  504  includes a stopper  514  and a metal-containing cap  516 . However, it should be appreciated that, in embodiments, the metal-containing cap  516  may not be provided. The stopper  514  includes a sealing portion  518  terminating at an outer edge  520  and a rim  522  extending from the outer edge  520  of the sealing portion  518 . The sealing portion  518  has an outer diameter D3 defined by a distance between the outer edge  520  of the sealing portion  518 . When the stopper  514  is positioned on the glass container  502 , the sealing portion  518  extends over the upper sealing surface  510  of the flange  508  and covers an opening  524  formed in the glass container  502 . The rim  522  extends from the outer edge  520  of the sealing portion  518  and at least partially along an outer surface  513  of the flange  508 . As shown in  FIG.  5   , the rim  522  has a length extending along at least an entire length of the outer surface  513  of the flange  508 . The stopper  514  further includes a lip  526  extending radially inwardly from an end of the rim  522  opposite the sealing portion  518  and along the underside surface  512  of the flange  508  and terminating at an inner surface  528 . In embodiments in which the metal-containing cap  516  is provided, the lip  526  extends along and contacts an inner surface  530  of the metal-containing cap  516 , specifically, an underlying portion  532  of the metal-containing cap  516 , which extends radially inwardly along the underside surface  512  of the flange  508  and toward to the neck  506 , and the lip  526  contacts and extends along the underlying portion  532  of the metal-containing cap  516  to contact the neck  506 . 
     It should be appreciated that when the pharmaceutical container  500  is subjected to relatively low storage temperatures, as discussed above, the coefficient of thermal expansion of the stopper  514  being greater than the coefficient of thermal expansion of the glass container  502  causes the rim  522  and the lip  526  of the stopper  514  to shrink around and toward the flange  508  of the glass container  502 , thus increasing the seal formed between the stopper  514  and the flange  508  of the glass container  502 . More particularly, the sealing portion  518  of the stopper  514  shrinks during relatively low storage temperatures such that the outer diameter D3 between the outer edge  520  of the sealing portion  518  is reduced, which results in the rim  522  and the lip  526  becoming tighter around the outer surface  513  of the flange  508 . 
     Referring now to  FIG.  6   , a further embodiment of a pharmaceutical container  600  is illustrated including a glass container  602  and a sealing assembly  604 . Although not described in detail herein, the glass container  602  and the sealing assembly  604  may include similar structure and features to the glass containers and the sealing assemblies described herein and illustrated  FIGS.  1 - 5   . As shown in  FIG.  6   , the glass container  602  includes a neck  606  extending to a flange  608  defined by an upper sealing surface  610 , an underside surface  612 , and an outer surface  614 . 
     In embodiments, the sealing assembly  604  includes a stopper  616  and a metal-containing cap  618 . However, it should be appreciated that, in embodiments, the metal-containing cap  618  may not be provided. The stopper  616  includes a sealing portion  620  terminating at an outer edge  622 . The sealing portion  620  has an outer diameter D4 defined by a distance between the outer edge  622  of the sealing portion  620 . When the stopper  616  is positioned on the glass container  602 , the sealing portion  620  extends over the upper sealing surface  610  of the flange  608  and covers an opening  624  formed in the glass container  602 . As shown in  FIG.  6   , a gap  626  is provided between the outer edge  622  of the sealing portion  620  and an inner surface  628  of the metal-containing cap  618 . In embodiments, a polymer ring  630  is positioned to the outer edge  622  of the sealing portion  620  to extend across the gap  626  formed between the outer edge  622  of the sealing portion  620  and the inner surface  628  of the metal-containing cap  618 . As such, the polymer ring  630  contacts the inner surface  628  of the metal-containing cap  618 . As shown, the polymer ring  630  is offset from the outer edge  622  of the sealing portion  620  such that a lower surface  632  of the polymer ring  630  is lower than a lower surface  634  of the sealing portion  620 . Thus, when the stopper  616  is positioned on the glass container  602 , the polymer ring  630  extends partially along the outer surface  614  of the flange  608  of the glass container  602 , thereby overlapping both the stopper  616  and the glass container  602 . In embodiments, the polymer ring  630  has a CTE equal to or greater than the CTE of the stopper  616 . In other embodiments, the polymer ring  630  has a CTE less than the CTE of the stopper  616 . In these embodiments, the CTE of the polymer ring  630  may be substantially equal to the CTE of the glass container  602 , such as within 10%. In embodiments, the polymer ring  630  may be adhered to the outer edge  622  of the sealing portion  620 . 
     It should be appreciated that when the pharmaceutical container  600  is subj ected to relatively low storage temperatures, as discussed above, the coefficient of thermal expansion of the stopper  616  being greater than the coefficient of thermal expansion of the glass container  602  causes the sealing portion  620  to shrink relative to the upper sealing surface  610  of the flange  608  such that the outer diameter D4 between the outer edge  622  of the sealing portion  620  is reduced. As the outer diameter D4 between the outer edge  622  of the sealing portion  620  is reduced, the polymer ring  630  is drawn radially inwardly toward the outer surface  614  of the flange  608 , thus becoming tighter around the outer surface  614  of the flange  608 . Additionally, although not illustrated in the stoppers of the pharmaceutical containers depicted in  FIGS.  2 - 6   , it should be appreciated that the stoppers may include an insertion portion extending into the opening of the respective glass container such as the insertion portion  117  illustrated in the pharmaceutical container  100  depicted in  FIG.  1   . Further, it should be appreciated that in any embodiment discussed herein in which two surfaces are shown in contact, such as an outer surface of the rim of the stopper and an inner surface of the metal-containing cap, a gap may be provided therebetween such that the two surfaces do not contact one another prior to shrinkage of the stopper. 
     From the above, it is to be appreciated that defined herein is a sealed pharmaceutical container including a glass container and a sealing assembly having a CTE higher than CTE of the glass container such that, when the sealed pharmaceutical container is subjected to relatively low temperatures, the seal formed between the glass container and the sealing assembly becomes tighter. Specifically, the sealing assembly includes a stopper including a sealing portion extending over an upper sealing surface of a flange of the glass container and covering an opening formed in the glass container. The sealing stopper further includes a rim extending at least partially along the outer surface of the flange. 
     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 a rim extending at least partially along the outer surface of the flange; and a metal-containing cap securing the stopper to the flange. 
     Clause 2. The sealed pharmaceutical container of clause 1, wherein the rim of the stopper extends along the entire outer surface of the flange. 
     Clause 3. The sealed pharmaceutical container of clause 1, wherein a cutout portion is formed in the outer surface of the flange extending in an inward radial direction, the rim of the stopper having a shape configured to nest within the cutout portion. 
     Clause 4. The sealed pharmaceutical container of clause 1, wherein the stopper includes a lip extending radially inwardly from an end of the rim opposite the sealing portion and along the underside surface of the flange. 
     Clause 5. The sealed pharmaceutical container of clause 1, wherein the rim comprises a polymer ring positioned along an outer edge of the stopper. 
     Clause 6. The sealed pharmaceutical container of any of clauses 1-5, wherein: the stopper has a glass transition temperature (T g ) that is less than or equal to -20° C.; and 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 7. The sealed pharmaceutical container of clause 6, wherein the sealing assembly maintains the helium leakage rate of the sealed pharmaceutical container of 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 -80° C. 
     Clause 8. The sealed pharmaceutical container of clause 6, wherein the sealing assembly maintains the 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 -100° C. 
     Clause 9. The sealed pharmaceutical container of any of clauses 1-8, 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 10. The sealed pharmaceutical container of clause 9, wherein the angle is greater than 5 degrees. 
     Clause 11. The sealed pharmaceutical container of clause 9, wherein the angle is less than or equal to 45 degrees. 
     Clause 12. The sealed pharmaceutical container of any of clauses 1-11, wherein the flange is constructed of a polymer. 
     Clause 13. The sealed pharmaceutical container of any of clauses 1-12, wherein a glass transition temperature of the stopper is less than or equal to -10° C. 
     Clause 14. A sealed pharmaceutical container comprising: a shoulder; a neck extending from the shoulder; a flange extending from the neck; an inner surface defining an opening extending through the neck and the flange, wherein the flange comprises an upper sealing surface extending from the inner surface and an outer surface extending from the upper sealing surface; 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 a rim extending at least partially along the outer surface of the flange; and a metal-containing cap crimped to the flange, the metal-containing cap compressing the stopper against the upper sealing surface. 
     Clause 15. The sealed pharmaceutical container of clause 14, wherein the rim of the stopper extends along the entire outer surface of the flange. 
     Clause 16. The sealed pharmaceutical container of clause 14, wherein a cutout portion is formed in the outer surface of the flange extending in an inward radial direction, the rim of the stopper having a shape configured to nest within the cutout portion. 
     Clause 17. The sealed pharmaceutical container of clause 14, wherein the stopper includes a lip extending radially inwardly from an end of the rim opposite the sealing portion and along the underside surface of the flange. 
     Clause 18. The sealed pharmaceutical container of clause 14, wherein the rim comprises a polymer ring positioned along an outer edge of the stopper. 
     Clause 19. The sealed pharmaceutical container of any of clauses 14-18, wherein the compression is maintained on the upper sealing surface as the sealed pharmaceutical container is cooled to a temperature of less than or equal to -80° C. such that a helium leakage rate of the sealed pharmaceutical container is less than or equal to 1.4×10 -6  cm 3 /s at the temperature. 
     Clause 20. The sealed pharmaceutical container of any of clauses 14-19, 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, wherein the angle is less than or equal to 45 degrees. 
     Clause 21. The sealed pharmaceutical container of any of clauses 14-20, wherein the flange is constructed of a glass 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 22. The sealed pharmaceutical container of any of clauses 14-21, wherein a difference between a coefficient of thermal expansion (“CTE”) of the metal-containing cap and a CTE of the stopper less than or equal to 50×10 -7 /K. 
     Clause 23. The sealed pharmaceutical container of clause 22, wherein the CTE of the metal-containing cap is greater than or equal to 250×10 -7 /K. 
     Clause 24. The sealed pharmaceutical container of clause 23, wherein the flange is formed from a polymer. 
     Clause 25. The sealed pharmaceutical container of clause 24, wherein the stopper has a CTE equal to or greater than a CTE of the flange. 
     Clause 26. The sealed pharmaceutical container of any of clauses 14-25, wherein a glass transition temperature of the stopper is less than or equal to -10° C. 
     Clause 27. The sealed pharmaceutical container of any of clauses 14-26, wherein the stopper comprises a low T g  elastomer in contact with the upper sealing surface, the low Tg elastomer comprising one or more of a polybutadiene, silicone, a fluorosilicone, a nitrite, and an EPDM elastomer. 
     Clause 28. The sealed pharmaceutical container of clause 19, wherein the sealed pharmaceutical container maintains the helium leakage rate at less than or equal to 1.4×10 -6  cm 3 /s. 
     Clause 29. The sealed pharmaceutical container of any of clauses 14-28, wherein the metal-containing cap maintains continuous compression of the stopper against the flange as the sealed pharmaceutical container is cooled. 
     Clause 30. The sealed pharmaceutical container of clause 19, wherein the sealing assembly maintains the 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 31. The sealed pharmaceutical container of clause 19, wherein the sealing assembly maintains the 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 32. 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; providing a stopper including a sealing portion extending over the upper sealing surface of the flange and covering the opening, and a rim extending at least partially along the outer surface of the flange; and crimping a metal-containing cap over the stopper and against flange to compress the stopper against the upper sealing surface. 
     Clause 33. The method of clause 32, 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 34. The method of clause 32, wherein the rim of the stopper extends along the entire outer surface of the flange. 
     Clause 35. The method of clause 32, wherein a cutout portion is formed in the outer surface of the flange extending in an inward radial direction, the rim of the stopper having a shape configured to nest within the cutout portion. 
     Clause 36. The method of clause 32, wherein the stopper includes a lip extending radially inwardly from an end of the rim opposite the sealing portion and along the underside surface of the flange. 
     Clause 37. The method of clause 32, wherein adhering a polymer ring along an outer edge of the stopper. 
     Clause 38. A sealed 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 and an inner surface defining an opening in the sealed pharmaceutical container, wherein a cutout portion is formed in the outer surface of the flange extending in an inward radial direction. 
     Clause 39. The sealed pharmaceutical container of clause 38, wherein the outer surface of the flange comprises: an upperside surface portion opposite the underside surface and extending from an outermost edge of the flange; and a vertical surface portion extending from a joining surface portion at the upperside surface portion to the upper sealing surface. 
     Clause 40. The sealed pharmaceutical container of clause 39, wherein the vertical surface portion extends perpendicular to the upperside surface portion. 
     Clause 41. The sealed pharmaceutical container of clause 39 or clause 40, wherein the upperside surface portion, the outermost edge, and the underside surface of the flange cooperate to define a ledge. 
     Clause 42. The sealed pharmaceutical container of any of clauses 39-41, wherein the joining surface portion forms a chamfer. 
     Clause 43. The sealed pharmaceutical container of any of clauses 39-41, wherein the joining surface portion is arcuate. 
     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.