Container closure assembly for maintaining seal integrity at low storage temperatures

Abstract

A sealed pharmaceutical container includes a flange including a lower side surface, an outer surface extending from the lower side surface, the outer surface defining an outer radius r o ; and an upper surface extending between the outer surface and an inner surface defining an opening in the sealed pharmaceutical container. The upper surface includes a sealing region extending between the opening and the outer surface and including a radius r sr smaller than r o . The sealed pharmaceutical container also includes a sealing assembly including a sealing portion (contacting the upper surface at a lower surface of the sealing portion) and a cap (including a plug abutting against the upper surface). Upon compression, a compressed radius r sc included by the sealing portion of the plug is smaller than r sr adjacent the upper surface.

Description

[0001] Cross-reference of related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 239,226, filed August 31, 2021, pursuant to 35 U.S. SC §119, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This specification generally relates to container closure systems, such as glass containers for storing pharmaceutical compositions and stoppers for sealing glass containers. Background Technology

[0004] Drug containers (e.g., bottles and syringes) are typically sealed with stoppers or other closures to maintain the integrity of the contained material. Closures are usually made of synthetic rubber and other elastomers. These materials advantageously possess high impermeability and elasticity, facilitating insertion into the container to seal its interior. However, the elasticity of commonly used closure materials can decrease at low temperatures. For example, synthetic rubber currently used as closure material may have a transition temperature greater than or equal to -70°C and less than or equal to -30°C. Below the transition temperature, closures constructed from such synthetic rubber may exhibit solid behavior and may not be able to compensate for the large difference in coefficients of thermal expansion between the glass and the roll-top used to secure the closure to the container through elastic expansion. Consequently, existing sealing assemblies for drug containers may fail at temperatures below or equal to -30°C.

[0005] Some biological materials (e.g., blood, serum, proteins, stem cells, and other perishable biological fluids) need to be stored at temperatures below the glass transition temperature at which conventional elastomers remain usable. 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 maintain their activity. Such low temperatures can cause dimensional changes in enclosed components (e.g., glass or polymer containers, stoppers, aluminum caps), leading to issues with seal integrity and potential contamination of the materials stored within. Summary of the Invention

[0006] A first aspect of this disclosure includes a sealed drug container comprising: a shoulder; a neck extending from the shoulder; and a flange extending from the neck, the flange comprising: a lower surface extending from the neck; and an outer surface extending from the lower surface, the outer surface defining an outer radius r of the flange. o; and an upper surface extending between an outer surface and an inner surface defining an opening in a sealed drug container, wherein the upper surface includes: a sealing region extending between the opening and the outer surface, wherein the sealing region includes a radius r sr Less than r o ; and a transition region extending between the sealing area and the outer surface; and a sealing assembly comprising: a plug including an insertion portion inserted into an opening and a sealing portion contacting the upper surface at the lower surface of the sealing portion; and a cap that compresses the plug against the upper surface, wherein the sealing portion of the plug includes a compression radius r sc Less than r adjacent to the upper surface sr .

[0007] The second aspect of this disclosure includes a sealed drug container according to the first aspect, wherein the sealing portion includes a sealing surface disposed on a sealing area on the upper surface, said sealing surface including at least a portion whose shape conforms to the sealing area as a result of a cap compressing a stopper against the upper surface.

[0008] A third aspect of this disclosure includes a sealed drug container according to any one of the first to second aspects, wherein the sealing surface includes an outer peripheral edge disposed radially inside a transition region on the sealing area.

[0009] The fourth aspect of this disclosure includes a sealed drug container according to any one of the first to third aspects, wherein the outer peripheral edge of the sealing surface is arranged radially outside the inner edge of the sealing region.

[0010] A fifth aspect of this disclosure includes a sealed drug container according to any one of aspects 1 to 4, wherein the sealed drug container maintains compression on its upper surface when cooled to a temperature less than or equal to -45°C, such that the helium leakage rate of the sealed drug container at that temperature is less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

[0011] The sixth aspect of this disclosure includes a sealed drug container according to any one of the first to fifth aspects, wherein the cap compresses the stopper against the upper surface, thereby applying a residual sealing force of less than 20 lbf to the upper surface.

[0012] The seventh aspect of this disclosure includes a sealed drug container according to any one of the first to second aspects, wherein the cap compresses the stopper against the upper surface, thereby applying a residual sealing force of less than 15 lbf to the upper surface.

[0013] The eighth aspect of this disclosure includes a sealed drug container according to any one of the first to seventh aspects, wherein the second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -80°C is at least about 10% of the first contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature.

[0014] The ninth aspect of this disclosure includes a sealed drug container according to any one of the first to eighth aspects, wherein the second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -180°C, and the second contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature, is greater than or equal to 10.0%.

[0015] The tenth aspect of this disclosure includes a sealed drug container according to any one of aspects 1 to 9, wherein the sealing portion includes a non-uniform radial dimension.

[0016] The eleventh aspect of this disclosure includes a sealed drug container according to any one of the first to tenth aspects, wherein the sealing portion includes a stepped transition on a radial scale at a location axially offset from the upper surface.

[0017] The 12th aspect of this disclosure includes a sealed drug container according to any one of the first to second aspects, wherein the sealing portion of the stopper includes: a lower contact portion that contacts the upper surface of the flange; and an upper contact portion that directly contacts the cap, wherein: the radial dimension r of the upper portion is... up Greater than the compressed radius r sc Thus, at least a portion of the upper part extends axially above the transition region, and the radial dimension of the contacting lower part is less than r. up .

[0018] The 13th aspect of this disclosure includes a sealed drug container according to any one of aspects 1 to 12, wherein: the outer radius r of the flange o The contact area between the upper surface of the sealed drug container and the sealing portion is greater than or equal to 75 mm² when the container is cooled to a temperature less than or equal to -80°C. 2 .

[0019] A 14th aspect of this disclosure includes a sealed drug container comprising: a central axis; an opening; and a flange circumferentially surrounding the opening, the flange including: a lower surface extending from a neck; and an outer surface extending from the lower surface, the outer surface defining an outer radius r of the flange. oThe upper surface, wherein, for a cross-section of a sealed drug container taken along a plane extending parallel to and through the central axis, comprises a first linear segment disposed on a first side of the opening and a second linear segment disposed on a second side of the opening, wherein, in a direction perpendicular to the central axis, the outer ends of the first and second linear segments are arranged to be spaced apart from each other by a distance of 2*r. sr ; and a transition region extending between the upper and outer surfaces; and a sealing assembly comprising: a plug including an insertion portion inserted into an opening and a sealing portion contacting the upper surface; and a cap that compresses the plug against the upper surface, wherein the sealing portion includes a compression radius r sc Less than r adjacent to the upper surface sr .

[0020] The 15th aspect of this disclosure includes a sealed drug container according to the 14th aspect, wherein the first and second linear segments of the cross-section extend at an angle relative to a plane perpendicular to the central axis and are part of a conical segment of the upper surface.

[0021] The 16th aspect of this disclosure includes a sealed drug container according to any one of the 1st to 16th aspects, wherein the sealing portion includes a sealing surface disposed on the first and second linear segments.

[0022] The 17th aspect of this disclosure includes a sealed drug container according to any one of the 14th to 15th aspects, wherein the sealing surface includes an outer peripheral edge disposed radially inside the transition region.

[0023] The 18th aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 17, wherein the outer peripheral edge of the sealing surface is arranged radially outward of the inner end of the first and second linear segments.

[0024] The 19th aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 18, wherein the sealed drug container maintains compression on its upper surface when cooled to a temperature less than or equal to -45°C, such that the helium leakage rate of the sealed drug container at that temperature is less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

[0025] The 20th aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 19, wherein the cap compresses the stopper against the upper surface, thereby applying a residual sealing force of less than 20 lbf to the upper surface.

[0026] The 21st aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 20, wherein the cap compresses the stopper against the upper surface, thereby applying a residual sealing force of less than 15 lbf to the upper surface.

[0027] The 22nd aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 21, wherein the second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -80°C is at least about 10% of the first contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature.

[0028] The 23rd aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 22, wherein the second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -180°C, and the second contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature, is greater than or equal to 10.0%.

[0029] The 24th aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 23, wherein the sealing portion includes a non-uniform radial dimension.

[0030] The 25th aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 4, wherein the sealing portion includes a stepped transition on a radial scale at a location axially offset from the upper surface.

[0031] The 26th aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 25, wherein the sealing portion of the stopper includes: a lower contact portion that contacts the upper surface of the flange; and an upper contact portion that directly contacts the cap, wherein: the radial dimension r of the upper portion is... up Greater than the compressed radius r sc Thus, at least a portion of the upper part extends axially above the transition region, and the radial dimension of the contacting lower part is less than r. up .

[0032] The 27th aspect of this disclosure includes a sealed drug container according to any one of aspects 14 to 26, wherein: the outer radius r of the flange o The contact area between the upper surface of the sealed drug container and the sealing portion is greater than or equal to 75 mm² when the container is cooled to a temperature less than or equal to -80°C. 2 .

[0033] The 28th aspect of this disclosure includes a sealing method for a sealed drug container, the method comprising the steps of: providing a sealed drug container including a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange including: a lower surface extending from the neck; an outer surface extending from the lower surface, the outer surface defining an outer diameter of the flange; and an upper surface extending from the outer surface of the sealed drug container to an inner surface defining an opening, the upper surface including a radius r sr The sealing area; inserting a pharmaceutical composition into a sealed pharmaceutical container; providing a sealing assembly including a stopper, the stopper comprising an insertion portion and a sealing portion; such that a metal cap is positioned above the stopper and abuts against a flange curled to compress the sealing portion against an upper surface, wherein, prior to compression by the metal cap, the uncompressed radius r at the lower edge of the sealing portion included in the sealing portion... uc Less than or equal to 0.85*r sr ; and cooling the sealed drug container to a temperature less than or equal to -45°C, wherein, after cooling, the compression on the upper surface is maintained, such that the helium leakage rate of the sealed drug container at that temperature is less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

[0034] The 29th aspect of this disclosure includes the method according to the 28th aspect, wherein, once compressed by the metal cap, the compressed radius r of the sealing portion is... sc Less than r o .

[0035] The 30th aspect of this disclosure includes a method according to any one of aspects 28 to 29, wherein the curling of the metal cap causes the stopper to be compressed against the upper surface to provide a residual sealing force of less than or equal to 20 lbf.

[0036] The 31st aspect of this disclosure includes a method according to any one of aspects 28 to 30, wherein the second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -80°C is at least about 10% of the first contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature.

[0037] The 32nd aspect of this disclosure includes a method according to any one of aspects 28 to 31, wherein the second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -180°C and the second contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature are greater than or equal to 10.0%.

[0038] The 33rd aspect of this disclosure includes a method according to any one of aspects 28 to 32, wherein the temperature is less than or equal to -80°C.

[0039] The 34th aspect of this disclosure includes a method according to any one of aspects 28 to 33, wherein the temperature is less than or equal to -180°C.

[0040] The 35th aspect of this disclosure includes a method according to any one of aspects 28 to 34, wherein: the upper surface further includes a transition region extending between the sealing portion and the outer surface of the flange, and the sealing portion includes a sealing surface in contact with the sealing region, and as a result of plug compression, the outer peripheral edge of the sealing surface does not contact the transition region.

[0041] The 36th aspect of this disclosure includes a method according to any one of aspects 28 to 35, wherein the sealing portion includes a non-uniform radial dimension.

[0042] The 37th aspect of this disclosure includes a method according to any one of aspects 28 to 36, wherein the sealing portion includes a stepped transition of radial dimensions at a location axially offset from the upper surface.

[0043] The 38th aspect of this disclosure includes a sealed drug container according to any one of aspects 28 to 37, wherein the sealing portion of the stopper includes: a lower contact portion that contacts the upper surface of the flange; and an upper contact portion that directly contacts the cap, wherein: the radial dimension r of the upper portion is... up Greater than the compressed radius r sc Thus, at least a portion of the upper part extends axially above the transition region, and the radial dimension of the contacting lower part is less than r. up . Attached Figure Description

[0044] The embodiments illustrated in the accompanying drawings are illustrative and exemplary in nature and are not intended to limit the subject matter defined by the claims. A detailed description of the illustrative embodiments can be understood by reading the following drawings, in conjunction with which the same structures are indicated by the same reference numerals, wherein:

[0045] Figure 1A A schematic cross-sectional view of a sealed drug container according to one or more embodiments described herein;

[0046] Figure 1B Schematic illustration of one or more embodiments described herein Figure 1A A cross-sectional view of a portion of a sealed drug container;

[0047] Figure 1CSchematic illustration of one or more embodiments described herein Figure 1A The dimensional relationship between the upper surface of the stopper and the outer surface of the flange of a sealed drug container;

[0048] Figure 2 A schematic cross-sectional view of a portion of a sealed drug container according to one or more embodiments described herein;

[0049] Figure 3A The simulation results show the compression of a first plug abutting against the flange of a first glass container at a temperature of 25°C according to one or more embodiments described herein;

[0050] Figure 3B The display shows that, according to one or more embodiments described herein, compression is applied at a temperature of -80°C. Figure 3A Simulation results of the first stopper on the flange of the first glass container;

[0051] Figure 3C The display shows that, according to one or more embodiments described herein, compression is applied at a temperature of -180°C. Figure 3A Simulation results of the first stopper on the flange of the first glass container;

[0052] Figure 4A The simulation results show the results of compressing a second plug against the flange of a second glass container at a temperature of 25°C according to one or more embodiments described herein;

[0053] Figure 4B The display shows that, according to one or more embodiments described herein, compression is applied at a temperature of -80°C. Figure 4A Simulation results of the second stopper on the flange of the second glass container;

[0054] Figure 4C The display shows that, according to one or more embodiments described herein, compression is applied at a temperature of -180°C. Figure 4A Simulation results of the second stopper on the flange of the second glass container;

[0055] Figure 5 This demonstrates, according to one or more embodiments described herein, at various temperatures. Figures 3A-4C A diagram showing the contact area between the first and second stoppers and the first and second glass containers. Detailed Implementation

[0056] Specific embodiments of sealed pharmaceutical containers will now be referenced, which include a sealing assembly that maintains the integrity of the sealed contents at lower 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, -180°C). To help maintain the integrity of the sealed contents at such low storage temperatures, the sealed glass containers described herein may include a glass container and a stopper specifically designed based on the structure of the glass container to provide improved sealing performance compared to certain existing container and stopper combinations. The stopper according to this disclosure may include: an insertion portion designed to insert into an opening in the glass container, and a sealing portion that contacts the upper surface of the glass container to form a seal. The sealing portion may include a selected radial dimension such that when the plug is compressed against the upper surface after capping, the radial dimension r included in the sealing portion... sc Less than or equal to the radial dimension r associated with the sealing area on the upper surface of the glass container. sr As a result, the outer peripheral edge of the sealing portion adjacent to the flange can be arranged radially inward of the outer edge of the sealing region. The outer peripheral edge can be arranged to contact the sealing region of the upper surface. The sealing region can be configured such that its properties (e.g., including a Ra value less than or equal to 5 nm and / or no surface height deviation greater than or equal to 5 μm) are conducive to establishing a uniform distribution of contact pressure between the stopper and the upper surface. Such uniform contact pressure can help maintain a high contact area between the stopper and the upper surface when the container is cooled to a lower storage temperature (e.g., greater than or equal to 75 mm for a 13 mm bottle). 2 This increases the likelihood of maintaining the integrity of the sealed object within the container.

[0057] The stopper described herein can also help maintain container closure integrity at low storage temperatures with lower stopper compression during crimping compared to some existing sealed containers. Existing pharmaceutical containers may result in residual seal forces greater than 20 lbf (e.g., greater than or equal to 25 lbf, resulting in stopper compression greater than 10% and less than or equal to 20%) during crimping. The seal improvement provided by the stopper described herein allows for maintaining container closure integrity with lower residual forces (e.g., resulting in stopper residual nominal strain less than or equal to 8% after crimping). This reduction in residual seal forces can facilitate the use of simpler and more efficient crimping processes, thereby reducing production costs. Using lower residual forces during crimping also reduces the risk of stopper overcompression during capping. Existing sealing assemblies may rely on increased stopper compression to maintain container closure integrity at low storage temperatures. Such increased stopper compression can lead to bottle breakage. By promoting a quality seal without excessive stopper compression, the sealing assembly described herein reduces the risk of bottle breakage.

[0058] As used herein, the term "surface roughness" refers to the Ra value or Sa value. The Ra value is a measurement of the arithmetic mean of the filtered roughness distribution, determined by the deviation relative to the centerline of the filtered roughness. For example, the Ra value can be determined based on the following relationship:

[0059]

[0060] In the formula, H i It is the measurement of the surface height, and H CL The surface height is measured corresponding to the centerline of the data points in the filtered distribution (e.g., the center between the maximum and minimum surface height values). The Sa value can be determined by extrapolation of the real part of Equation 1 herein. The filter value (e.g., the cutoff wavelength) used to determine the Ra or Sa value described herein can be found in ISO 25718 (2012). Surface height can be measured using various tools (e.g., optical interferometers, stylus-based profilometers, or laser confocal microscopes). To assess the roughness of the surface described herein (e.g., a sealed surface or a portion thereof), the largest possible measurement area in practice should be used to assess the variability that may exist on a large spatial scale.

[0061] As used herein, the term "container closure integrity" refers to maintaining a seal at the interface between the glass container and the sealing assembly (e.g., between the sealing surface of the glass container and the stopper), based on the material stored in the glass container, that the seal does not contain gaps larger than a threshold size for maintaining the likelihood of contaminant intrusion or reduces the likelihood of gas permeability falling below a predetermined threshold. For example, in an embodiment, if in USP <1207> The helium leakage rate during the helium leakage test process described in (2016) is less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s maintains the integrity of the enclosed object in the container.

[0062] As used herein, the term "about" indicates that a quantity, size, formulation, parameter, and other variable and characteristic is not, and does not need to be, exact, but may be approximate and / or larger or smaller as required, reflecting tolerances, conversion factors, rounding and measurement errors, and other factors known to those skilled in the art. When the term "about" is used to describe a value or endpoint of a range, the specific value or endpoint referenced is included. Whether or not the numerical values ​​or endpoints of a range in the specification are described with "about," there are two implementations: one modified with "about" and one not modified with "about." It will also be understood that each endpoint of a range is important both in relation to and independently of another endpoint.

[0063] The directional terms used in this article, such as up, down, right, left, front, back, top, and bottom, are only for reference to the accompanying drawings and are not intended to imply absolute orientation.

[0064] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” used herein include plural references. Thus, for example, a reference to a “one” component includes aspects having two or more such components, unless otherwise explicitly stated in the text.

[0065] See now Figure 1A The image schematically shows one embodiment of a sealed pharmaceutical container 100 for storing pharmaceutical preparations in cross-section. The sealed pharmaceutical container 100 includes a glass container 102 and a sealing assembly 104 connected to the glass container 102 via an opening 105. The glass container 102 generally includes a body 112. The body 112 extends between an inner surface 114 and an outer surface 116 of the glass container 102, includes a central axis A, and substantially encloses an internal volume 118. Figure 1AIn the illustrated embodiment of the glass container 102, the body 112 generally includes a wall portion 120 and a base portion 122. The wall portion 120 transitions to the base portion 122 via a heel portion 124. In the illustrated embodiment, the glass container 102 includes: 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. In the embodiment, the glass container 102 is axially symmetric about a central axis A, and each of the barrel 115, the neck 128, and the flange 126 is substantially cylindrical. The body 112 has a wall thickness T. w It extends between the inner surface 114 and the outer surface 116, such as Figure 1A As shown.

[0066] In this embodiment, the glass container 102 can be made of materials such as USP <660> The defined Type I, Type II, or Type III glass formations include borosilicate glass compositions, such as USP <660> The glass container 102 may be formed from a Type I borosilicate glass composition. Alternatively, the glass container 102 may be formed from any other alkaline aluminosilicate glass composition that meets the Type I standard, such as those described in U.S. Patent No. 8,551,898 (the entire contents of which are incorporated herein by reference) or from alkaline earth aluminosilicate glass, such as those described in U.S. Patent No. 9,145,329 (the entire contents of which are incorporated herein by reference). In embodiments, the glass container 102 may include a coating, such as the heat-resistant coating disclosed in U.S. Patent No. 10,0273,049, the entire contents of which are incorporated herein by reference. In embodiments, the glass container 102 may be constructed from a soda-lime silicate glass composition. In embodiments, the glass container 102 has a coefficient of thermal expansion greater than or equal to 0 x 10⁻⁶. -7 / K and less than or equal to 100x10 -7 / K (e.g., greater than or equal to 30x10) -7 / K and less than or equal to 70x10 -7 The glass composition is constructed of / K).

[0067] The wall thickness T of glass container 102 W This can vary depending on the practice. In one implementation, the wall thickness T of the glass container 102 is... W It can be less than or equal to 6 millimeters (mm), for example: 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 wIt can 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 the embodiment, the wall thickness T W The wall thickness T can be greater than or equal to 0.9 mm and less than or equal to 1.8 mm. W It can vary depending on the axial position within the glass container 102.

[0068] like Figure 1A As shown, flange 126 includes a lower surface 132, an outer flange surface 136, and a upper surface 138. The outer flange surface 136 is part of the outer surface 116 of the glass container 102. The outer flange surface 136 may define the outer diameter of flange 126. In embodiments, the outer diameter is 13 mm, 20 mm, or between 13 mm and 20 mm. Any size glass container (e.g., 2R, 4R, 8R, 15R, 20R, 25R, 30R, 50R, and 100R bottles according to ISO 8362-1). The upper surface 138 may define a sealing region 180 of the outer surface 116 of the glass container 102. The sealing region 180 may extend radially between the inner edge 140 and the outer edge 142 of the upper surface 138. In one embodiment, the sealing region 180 includes a conical region of an outer surface 116 extending between the inner and outer edges 140, 142 (e.g., where the outer surface 116 conforms to a conical profile). In another embodiment, within the sealing region 180, the upper surface 138 contains a low surface roughness (e.g., Ra value less than or equal to 5 μm) and is free of surface defects and surface height deviations greater than or equal to 5 μm. This uniformity of the upper surface 138 advantageously facilitates maintaining contact between the upper surface 138 and the stopper (e.g., stopper 106 as described herein), thereby maintaining a seal when the glass container 102 is cooled to lower temperatures (e.g., less than or equal to -45°C, less than or equal to -80°C, less than or equal to -180°C). In another embodiment, the sealed pharmaceutical container can be cooled to the low storage temperatures described herein at a rate less than or equal to 3°C per minute.

[0069] In one embodiment, flange 126 further includes a transition region 144 extending between upper surface 138 and outer flange surface 136. In another embodiment, in transition region 144, outer surface 116 of glass container 102 transitions between the surface profile of sealing region 180 (e.g., a conical surface profile) and outer flange surface 136 (e.g., a cylindrical surface profile). Depending on the practice, transition region 144 can have various forms. In one embodiment, transition region 144 includes a corner, such that outer surface 116 transitions directly from upper surface 138 to outer flange surface 136. In another embodiment, transition region 144 includes a chamfer extending from upper surface 138 at a chamfer angle. In yet another embodiment, transition region 144 includes a fillet containing a radius of curvature. As will be described in more detail herein, the relative position of transition region 144 to the sealing surface of a stopper (e.g., stopper 106 described herein) is an important factor in ensuring that the sealed medicine container 100 maintains the integrity of the sealed object at lower storage temperatures.

[0070] See now Figure 1A and 1B In one embodiment, each cross-section of the upper surface 138 of the flange 126, taken with respect to a plane extending through and parallel to the central axis A, includes a first linear portion 170 and a second linear portion 172. The first and second linear portions 170, 172 are arranged on opposite sides of the opening 105 of the glass container 102. Figure 1B As shown, the first linear portion 170 may include a first outer end portion 174 (e.g., disposed on the outer edge 142 of the upper surface 138, see [reference]). Figure 1A The second linear portion 172 may include a second outer end portion 176 (e.g., also disposed on the outer edge 142 of the upper surface 138, see [reference]). Figure 1A The first outermost end 174 and the second outermost end 176 are 2*r with a length equal to the upper surface 138. sr The end of the diameter. The sealing area 180 of the upper surface 138 may include a radius r sr Its measurement is the radial distance extending radially outward from a point perpendicular to the central axis A to the outer edge 142 (see [reference]). Figure 1A Radius r sr This can correspond to the radial distance between the inner end of the transition region 144 (where the outer surface 116 deviates from the cylindrical profile of the upper surface 138) and the central axis A.

[0071] like Figure 1B As shown, the first linear portion 170 includes a first inner end portion 182, and the second linear portion 172 includes a second inner end portion 184. The first inner end portion 182 and the second inner end portion 184 have a length equal to 2*r. irThe diameter of the end of the upper surface 138 is defined by the inner boundary of the upper surface 138. The first and second inner ends 182 and 184 can define the inner radius r of the sealing region 180. ir On the radially inner side of the first and second inner ends 182, 184, the upper surface 138 may be offset relative to the surface profile of the sealing region 180 and transition to the inner surface 114 (see...). Figure 1A And form the end of the opening 105.

[0072] See Figure 1A and 1B The sealing assembly 104 includes a plug 106 and a cap assembly 108. In one embodiment, the plug 106 can be constructed from a suitable elastomeric material (e.g., butyl rubber). In another embodiment, the plug 106 can be made of silicone or other low-T materials. g Elastomers (e.g., glass transition temperature T) g The stopper may be constructed at a temperature less than or equal to -20°C, less than or equal to -30°C, or less than or equal to -40°C, for example, fluorosilicone, ethylene propylene diene monomer (EPDM) elastomer, polydimethylsiloxane (PDMS), and polybutadiene. In other words, this disclosure is not limited to stoppers constructed from specific materials.

[0073] exist Figure 1A and 1B In the illustrated embodiment, the stopper 106 includes an insertion portion 117 and a sealing portion 119 containing a sealing surface 121. During the sealing process of the glass container 102, the insertion portion 117 is inserted into the opening 105 until the sealing surface 121 contacts the upper surface 138 of the flange 126 of the glass container 102. Then, the sealing portion 119 is pressed against the upper surface 138 by the curling of the cap assembly 108, thereby forming a seal between the sealing surface 121 and the upper surface 138. In this embodiment, the insertion portion 117 may be omitted and the stopper 106 may consist only of the sealing portion 119.

[0074] The display cap assembly 108 includes a metal portion 148 and a plastic portion 150. The metal portion 148 is curled around the lower surface 132 of the flange 126 so that its lower bottom portion 152 contacts the lower surface 132 (see...). Figure 1AIn one embodiment, the length of the lower portion 148, which directly contacts the lower surface 132 of the flange 126, is greater than or equal to 1 mm, thereby helping to maintain residual sealing force within the stopper 106 at storage temperatures less than or equal to -80°C. In another embodiment, the plastic portion 150 includes retaining features 154 (e.g., grooves, cavities, recesses, or holes) that receive the inner edge 156 of the metal portion 148 such that the upper portion 158 of the metal portion 148 is held on the upper surface 160 of the stopper 106. In yet another embodiment, the stopper 106 is inserted into the opening 105 during the curling process, and a compressive force is applied to the metal portion 148 during the curling process. The compression of the stopper 106 creates a residual sealing force within the flange 126, which maintains the compression of the stopper 106 after the metal portion 148 has curled into place. In implementation, the residual sealing force can vary from 5 lbf to 25 lbf or can be greater than 25 lbf, resulting in a nominal plug strain of 5% to 19% or higher (if the residual sealing force is higher).

[0075] In this embodiment, various aspects of the glass container 102 and the cap assembly 108 are designed to maintain the integrity of the sealed contents at lower storage temperatures. For example, Figure 1B The stopper 106 is shown in its uncompressed state before the cap assembly 108 is rolled into the glass container 102. As shown, the sealing portion 119 includes an uncompressed radius r. uc In an embodiment, the plug 106 is constructed such that it has a radius r when at (room temperature). uc Less than or equal to 0.95*r sr In its uncompressed state, the sealing portion 119 is a flange with a generally cylindrical shape. That is, when in its uncompressed state, the radius r encompassed by the sealing portion 119 is... uc It can be a sealing portion with a radius r of up to 180 on the outer surface of 116. sr 95%. In the implementation method, for r uc Make a selection such that it is less than r sr And greater than or equal to (r) ir +r sr ) / 2. This dimension of the sealing portion 119 advantageously prevents contact between the sealing surface 121 and the transition region 144 when the sealing portion 119 is compressed against the upper surface 138 during capping, while still providing sufficient contact area to form a reliable seal.

[0076] like Figure 1AAs shown, when compressed against the upper surface 138, the sealing surface 121 of the stopper 106 includes an outer peripheral edge 164. In this embodiment, the outer peripheral edge 164 marks the transition between the sealing surface 121 and the outer surface 166 of the stopper 106 when the stopper 106 is in a compressed state. It will be understood that this text is relative to... Figure 1A The exact endpoints of the various surfaces of the described plug 106 (e.g., sealing surface 121 and outer surface 166) may not exactly correspond to the shape of the plug 106 when it is in an uncompressed state. Figure 1A As shown, as a result of the dimensions of the plug 106 described herein (e.g., the perimeter shape of the sealing portion 119 substantially corresponds to the perimeter shape of the flange 126 and the included uncompressed radius r), uc Less than or equal to 0.85*r sr The outer peripheral edge 164 of the sealing surface 121 is arranged radially inside the transition region 144 on the upper surface 138. That is, after compression during the curling process, the outer peripheral edge 164 is arranged on the sealing region 180 of the outer surface 116.

[0077] Because the sealing region 180 has a low surface roughness and no surface height deviation of 5.0 μm or greater, such a location of the outer peripheral edge 164 facilitates a uniform compression distribution at the interface between the sealing portion 119 and the upper surface 138. As a result, the dimensions of the stopper 106 described herein advantageously avoid compression concentration of the stopper 106 at specific points along the interface (e.g., where the contact pressure between a specific segment of the sealing surface 121 and a specific segment of the upper surface 138 is greater than 200% of the contact pressure at other segments of the interface). Such concentration of contact pressure may tend to reduce the contact area between the sealing portion 119 and the upper surface 138, increasing the likelihood of seal rupture at lower storage temperatures.

[0078] What has been confirmed is that Figure 1A and 1B The stopper 106 shown offers improved performance compared to stoppers designed with the radial dimensions of the included sealing portion comparable to the outer flange surface 136 of the flange 126. Such comparable dimensions may result in contact between this type of stopper and the transition region 144. Studies have shown that contact between the transition region 144 and the stopper causes contact pressure to concentrate at the interface between the stopper and the transition region 144, which tends to reduce the contact area with the upper surface 138 at lower storage temperatures. Figure 1A and 1B The plug 106 shown provides a counterintuitive and unexpected result: reducing the overlap between the sealing surface 121 and the flange 126 potentially increases the contact area at low storage temperatures.

[0079] Figure 1C The schematic diagram shows the radial dimensions of the outer flange surface 136, the transition region 144, and the upper surface 138 of the flange 126, as well as the compressed radial dimension r of the plug 106. sc The sealing area 180 can be located at a radial position r. ir (For example, containing) Figure 1B The first and second inner ends 182 and 184 shown are related to the radial position r sr (For example, containing) Figure 1B The first and second outermost ends 174 and 176, as shown, extend radially. In an embodiment, the upper surface 138 conforms to r. ir With r sr The conical profile between [the two points]. Radius r sr The inner boundary of the transition region 144 can be depicted. For example... Figure 1C As shown, the radial dimension r after compression sc This can represent the radial dimension of the sealing portion 119 when compressed against the upper surface 138 by the cap assembly 108. In an embodiment, the compressed radial dimension r sc This represents the relationship between the central axis A and the outer peripheral edge 164 of the sealing surface 121 when the sealing portion 119 is in a compressed state (see...). Figure 1A The radial distance between ) . It will be understood that compression of the sealing portion 119 can cause the sealing portion 119 to include as a distance from the sealing surface 121 (see Figure 1A A non-constant radial scale that is a function of the axial distance of ). The compressed radial scale r shown is... sc This represents the radial dimension of the area where the sealing portion 119 contacts or is adjacent to the upper surface 138. For example... Figure 1C As shown, the outer radius r of the flange 126 (defined by the outer flange surface 136) o The radius r is greater than that of the sealing area 180 defined by the upper surface 138. sr (It is still larger than the compressed radial dimension r) sc In this embodiment, regardless of the degree of compression of the plug 106 via the cap assembly 108, after compression via the cap assembly 108, the outermost point of the sealing portion 119 is located radially inside the transition region 144 to ensure no contact between the sealing portion 119 and the transition region 144.

[0080] Figure 2 A portion of another sealed drug container 200 is schematically shown in cross-section. The sealed drug container 200 may include components that, relative to this text, [are related to the previous paragraph]. Figure 1A-1C The sealed drug container 100 is a similar component. Therefore, in Figure 2Similar reference numerals are included to indicate the incorporation of such similar components. The sealing assembly 202 included in the sealed drug container 200 is structurally different from that described herein. Figure 1A-1C The sealing assembly 104 is described above. The sealing assembly 202 includes a plug 204 and a cap assembly 108. The plug 204 includes an insertion portion 206 and a sealing portion 208. The insertion portion 206 is configured to insert into the opening 105 of the sealing drug container 100, while the sealing portion 208 compresses against the upper surface 138 of the flange 126.

[0081] In one embodiment, when in an uncompressed state, the sealing portion 208 includes a non-uniform radial dimension. For example, as... Figure 2 As shown, the sealing portion 208 includes a stepped transition 214 in the radial dimension. The stepped transition 214 defines the boundary between the upper portion 210 and the contacting lower portion 212 of the sealing portion 208. Although the stepped transition 214 included in the illustrated embodiment makes the contacting lower portion 212 and the upper portion 210 different from each other (e.g., each containing a substantially uniform radial dimension), it should be understood that embodiments without the stepped transition 214 are also contemplated and fall within the scope of this disclosure. For example, in an embodiment, the radial dimension of the sealing portion 208 gradually decreases as it approaches the insertion portion 206. In such embodiments, at least a portion of the outer surface 230 of the sealing portion 208 may conform to a tapered or conical profile. In an embodiment, the outer surface 230 curves inward toward the geometric center of the plug 204. In an embodiment, the sealing portion 208 includes multiple transitions in the radial dimension, so that the sealing portion 208 includes more than two segments with different radial dimensions. In one embodiment, the radial dimension of the sealing portion 208 varies as a function of its longitudinal position according to a periodic or aperiodic function, such that the radial dimension of the sealing portion 208 at its sealing surface 218 is smaller than that at the point where the sealing portion 208 contacts the metal portion 148 of the cap assembly 108. Various plugs with non-uniform radial dimensions are considered and fall within the scope of this disclosure.

[0082] exist Figure 2 In the illustrated embodiment, the lower contact portion 212 contacts the upper surface 138 of the flange 126 to form a seal. During the sealing of the cap of the drug container 200, the upper portion 210 can compress against the metal portion 148 of the cap assembly 108. Figure 2 As shown, as a result of the stepped transition 214, when in an uncompressed state, the radial dimension r contained in the lower part 212 of the contact area... cp The radial dimension r is smaller than the upper part of 210. up In the implementation, the radius r of the upper portion 210up This corresponds to the case associated with stoppers conventionally used for bottles of a specific size in glass container 102 (e.g., r up It can be greater than or equal to 6.5 mm and less than or equal to 10 mm.

[0083] In the implementation, the increased radial dimension r of the upper portion 210 up The capping process facilitates the use of existing capping techniques by centering the cap assembly 108 relative to the glass container 102 during the capping process. The difference in radial dimensions between the sealing portion 208 and the metal portion 148 of the cap assembly 108 can make capping more difficult, for example, by making the compression of the stopper 204 more sensitive to the alignment of the capping system (not shown) relative to the central axis A. The upper portion 210 reduces the extent of the radial gap 216 extending between the metal portion 148 and the stopper 204, thereby facilitating the alignment of the cap assembly 108 during the capping process.

[0084] The radial dimension r of the lower contact portion 212 cp The choice can be based on the text relative to... Figure 1A-1C The uncompressed radial dimension r of the sealing portion 119 of the plug 106 uc Similar standards. For example, in implementation, r cp It can be less than or equal to 0.85*r sr (For example, less than or equal to 0.80*r) sr Less than or equal to 0.75*r o Less than or equal to 0.70*r o Less than or equal to 0.65*r or Less than or equal to 0.60*r sr Less than or equal to 0.55*r o Less than or equal to 0.50*r sr The reduced radial dimension of the lower contact portion 212 relative to the sealing portion 180 advantageously facilitates the arrangement of the outer peripheral edge 220 of the sealing surface 218 of the plug 204 on the sealing region 180 and radially inward of the transition region 144. This placement of the outer peripheral edge 220 can result in a uniform distribution of contact pressure after the cap and help maintain a high-quality seal at lower storage temperatures.

[0085] like Figure 2As shown, when in an uncompressed state, the lower contact portion 212 may include an axial dimension 232. In an embodiment, the axial dimension 232 is selected to be large enough that the stepped transition 214 does not contact the glass container 102 after the stopper 204 is compressed during capping. In an embodiment, the axial dimension 232 is greater than or equal to 10% (e.g., greater than or equal to 15%, greater than or equal to 20%) of the axial dimension 234 of the sealing portion 208. Such an axial dimension 232 can advantageously prevent the stepped transition 214 from contacting the upper surface 138 of the flange 126, which could cause deformation of the sealing portion 208 and interfere with its contact area.

[0086] Figures 3A-3C Simulation results show the performance of a sealed drug container 300 according to an exemplary embodiment of this disclosure. The sealed drug container 300 shows a glass container 302 and a stopper 304. The stopper 304 is coiled against a flange 306 of the glass container 302 via a cap assembly (not shown), the cap assembly having a structure similar to that described herein with respect to... Figure 1A-1C The cap assembly 108 is described. The display flange 306 includes an outer surface 308, an upper surface 310, and a transition region 312 extending between the outer surface 308 and the upper surface 310. In an embodiment, the upper surface 310 has a structure similar to that described herein with respect to... Figure 1A-1C The upper surface 138 of the flange 126 defines a conical region. The transition region 312 includes rounded corners, where the outer surface of the glass container 302 curves between the outer surface 308 and the upper surface 310. The transition region 312 includes an inner end portion 314 that delineates the outer peripheral edge of the upper surface 310. Figure 3A As shown, the plug 304 is configured such that after being compressed against the upper surface 310, the outer surface 316 of the plug is larger than the conical region defined by the upper surface 310 of the flange 306. As a result, the sealing surface 317 of the plug 304 includes an outer peripheral edge 319 disposed on the transition region 312.

[0087] Figures 3A-3C The simulation shown predicts a residual sealing force of approximately 25 lbf (e.g., greater than or equal to 24.7 lbf and less than or equal to 25.6 lbf) when the stopper 304 is compressed against the flange 306 via the cap assembly (not shown). Finite element analysis is then performed to simulate the cooling process. During cooling, the drug container 300 and the stopper 304 are cooled to -80°C and -180°C at a cooling rate of 1°C / min. The contact state of the stopper 304 against the flange 306 at 25°C, -80°C, and -180°C, respectively, illustrates the sealing state. Figure 3AAs shown, at 25°C, the compression of the stopper 304 results in a continuous contact area covering the entire upper surface 310, indicating an effective seal of the glass container 302 at this temperature. However, as the simulation results show, the contact pressure is non-uniform at the inner end 314 of the transition region 312 and includes a first peak region 318. Figure 3B As shown, when the sealed drug container is cooled to -80°C, the contact pressure between the stopper 304 and the flange 306 exhibits a non-uniform radial distribution. The contact pressure includes a first peak region 318 extending radially outward from the inner end 314 of the transition region 312 and a second peak region 320 offset from the first peak region 318 (e.g., at the inner edge of the upper surface 310). Consequently, a region 321 with lower contact pressure exists along the upper surface 310 extending between the first peak region 318 and the second peak region 320. It is not intended to be theoretically limited, but it is believed that this region 321 originates from deformation of the stopper 304 due to contact between the sealing surface 317 and the transition region 312 (e.g., as a result of the stopper 304 bending around the inner end 314 when compressed against the flange 306). The region 321 with lower contact pressure may indicate a reduction in the contact area between the stopper 304 and the flange 306 compared to when the temperature is 25°C, increasing the likelihood of container closure failure at -80°C. Figure 3C As shown, the contact area decreases even more when the sealed drug container 300 is cooled to -180°C. The second peak region 320 present in the contact pressure distribution at -80°C is absent at -180°C. Unwilling to be limited by theory, this is likely due to the volume shrinkage of the stopper 304 and the decreased shape recovery capability of the stopper 304 due to its temperature being below the glass transition temperature. It is believed that the non-uniform contact pressure distribution (including the first peak region 318 of higher contact pressure on the transition region 312) contributes to the reduction in contact area at lower storage temperatures as a result of the deformation of the stopper 304.

[0088] Figures 4A-4C Simulation results show the performance of a sealed drug container 400 according to an exemplary embodiment of this disclosure. The sealed drug container 400 shows a glass container 402 and a stopper 404. The stopper 404 is rolled against a flange 406 of the glass container 402 via a cap assembly (not shown), the cap assembly having a structure similar to that described herein with respect to... Figure 1A-1C The cap assembly 108 is described. The flange 406 includes an outer surface 408, an upper surface 410, and a transition region 412 extending between the outer surface 408 and the upper surface 410. In an embodiment, the upper surface 410 has a structure similar to that described herein with respect to... Figure 1A-1CThe upper surface 138 of the flange 126 defines a conical region. The transition region 312 shows a rounded corner where the outer surface of the glass container 402 curves between the outer surface 408 and the upper surface 410. The transition region 412 includes an inner end portion 414 that delineates the outer peripheral edge of the upper surface 410. Figure 4A As shown, the plug 404 is constructed such that after being compressed against the upper surface 410, the radial dimension of the outer surface 416 of the plug 404 is smaller than that associated with the upper surface 410. As a result, the outer peripheral edge 419 of the sealing surface 417 of the plug 404 can be positioned on the upper surface 410 after compression.

[0089] Figures 4A-4C The simulation shown predicts the scenario where the plug 404, when rolled up via the cap assembly (not shown) to provide a residual sealing force of approximately 17 lbf, compresses against the flange 406. Finite element analysis is then performed to simulate the compression of the plug 404 against the flange 406 at 25°C, -80°C, and -180°C, respectively. Figure 4A As shown, at 25°C, the predicted contact pressure between the sealing surface 417 and the upper surface 410 is relatively uniform across the entire upper surface 410, indicating a high-quality seal. Unlike... Figure 3A The compression of the stopper 304 against the flange 406, as shown, does not result in any contact pressure peak on the upper surface 410. It is not desirable to be bound by theory and believe that a uniform contact pressure distribution is a result of the sealing surface 417 not contacting the transition region 412 or not extending above the transition region 412, which could cause the shape of the stopper 404 to deviate from the upper surface 410, especially at lower storage temperatures.

[0090] like Figure 4B-4C As shown, even when the sealed drug container is cooled to -80°C and -180°C respectively, the contact area between the stopper 404 and the flange 406 remains relatively consistent. The contact pressure between the stopper 404 and the flange 406 is greater than 0.001 MPa over essentially the entire upper surface 410, with no relative pressure. Figures 3A-3C The gap present in the plug 304. As these simulation results show, avoiding contact between the sealing surface 417 and the transition region 412 advantageously provides a difference compared to the previous method. Figures 3A-3C The stopper 303 exhibits a more uniform contact pressure distribution compared to the sealing surface 317 contacting the transition region 412. These results confirm the effectiveness of the stopper described herein in providing a more robust seal, which is more likely to maintain the integrity of the sealed object at low storage temperatures compared to some existing stoppers.

[0091] Figure 5 This article shows that it is relative to Figures 3A-4C Performance simulations of the stoppers 304 and 404 cooled to various storage temperatures are shown in Figure 500, with the stoppers 304 and 404 curled against upper surfaces 310 and 410 using a cap assembly (not shown). In the simulations that produced Figure 500, flanges 306 and 406 comprise an outer diameter of 13 mm. The stopper 304 curled against the outer surface 310 provides a residual sealing force of 25.1 lbf. Simulations of the stopper 404 were performed twice, with residual sealing forces of 17.7 lbf and 14.1 lbf. Trace 502 shows the simulation results for stopper 304, while traces 504 and 506 show the simulation results for stopper 404 curled against the upper surface 410, providing residual sealing forces of 17.1 lbf and 14.1 lbf, respectively. As shown in Figure 502, stopper 304 provides a residual sealing force of over 175 mm at temperatures above -75°C. 2 The contact area, approximately 200 mm² at room temperature. 2 The contact area. However, at temperatures below -75°C, this contact area decreases to below 25 mm. 2 And below 20mm at temperatures below -120℃ 2 Such results indicate a higher probability of container-sealed object integrity failure at temperatures below or equal to -80°C.

[0092] like Figure 5 As shown, the 404 plug provides a slightly lower contact area at room temperature (approximately 150 mm²). 2 This is expected to be due to the reduced radial dimensions and the use of a smaller residual sealing force. However, at temperatures below -75°C, the contact area remains above 75 mm². 2 The two residual sealing forces result in a relatively consistent approximate 80mm at temperatures less than or equal to -80°C. 2 The contact area. For stopper 404, the ratio of the contact area or sealing area at -80°C to that at room temperature is greater than 63%. This is significantly different from the results obtained for stopper 304 (where the ratio is less than 5% (e.g., approximately 4.4%)). In the embodiment, regardless of the storage temperature, the contact area between stopper 404 and flange 406 is maintained at 10% or greater than the surface area of ​​upper surface 410. In the embodiment, at temperatures less than or equal to -80°C or -180°C, the contact area is maintained at 75 mm. 2 Compared to Figures 3A-3CThe stopper 304 shown has a significantly increased contact area, which greatly increases the likelihood of maintaining the integrity of the sealed contents at low storage temperatures. These results demonstrate the effectiveness of the stopper described herein. Furthermore, the stopper 404 provides this performance improvement with less stopper compression (manifested as reduced residual sealing force). Therefore, the stopper of this disclosure can facilitate capping of drug containers using a simplified capping process compared to those used with existing assemblies, thereby improving production efficiency.

[0093] Based on the foregoing, it should be understood that a sealed glass container capable of maintaining the integrity of the sealed object at storage temperatures less than or equal to -70°C has been disclosed. The improved seal can be achieved entirely through a structural stopper used to seal the glass container, thereby avoiding contact with non-conical areas of the outer surface of the glass container. By avoiding contact between the stopper and transition areas (e.g., bevels, flanges, corners) on the outer surface of the glass container, a uniform contact pressure distribution can be achieved, which helps maintain a higher contact area at low storage temperatures.

[0094] Unless otherwise expressly stated, no method described herein should be construed as requiring its steps to be performed in a specific order or requiring any device to have a particular orientation. Therefore, if a method claim does not actually describe the order in which its steps are to be followed, or any device claim does not actually describe the order or orientation of the components, or the claims or description do not otherwise specifically state that the steps are limited to a specific order, or do not describe a specific order or orientation of the device components, then in no way should the order or orientation be inferred. This also applies to any possible unexpressed basis for interpretation, including: the logic regarding setup steps, operational flow, component order, or component orientation; the general meaning obtained from grammatical structures or punctuation; and the number or type of embodiments described in the specification.

[0095] 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 spirit and scope of the claimed subject matter. Therefore, this specification is intended to cover modifications and variations of the various embodiments described herein, provided that such modifications and variations fall within the scope of the appended claims and their equivalents.

Claims

1. A sealed pharmaceutical container, comprising: Shoulders; The neck extending from the shoulders; as well as A flange extending from the neck, the flange comprising: The lower surface extending from the neck; An outer surface extending from the lower surface defines the outer radius r of the flange. o ;as well as An upper surface extending between an outer surface and an inner surface defining an opening in a sealed drug container, wherein the upper surface comprises: A sealing region extends between the opening and the outer surface, wherein the radius r encompassed by the sealing region is... sr Less than r o ;as well as The transition area extending between the sealing area and the outer surface; and A sealing assembly comprising: A plug comprising an insertion portion inserted into an opening and a sealing portion that contacts an upper surface at a lower surface of a sealing portion, wherein the sealing portion includes a stepped transition of a radial dimension at a location axially offset from the upper surface; and The cap, with its compression plug abutting against the upper surface, wherein the sealing portion of the plug contains a compression radius r. sc Smaller than the radius r of the sealed area sr .

2. The sealed drug container as claimed in claim 1, wherein, The sealing portion includes a sealing surface disposed on a sealing area on the upper surface, the sealing surface including at least a portion whose shape conforms to the sealing area as a result of the cap compressing the plug against the upper surface.

3. The sealed drug container as described in claim 2, wherein, The sealing surface includes an outer peripheral edge, which is arranged radially inside the transition region on the sealing area.

4. The sealed drug container as described in claim 3, wherein, The outer peripheral edge of the sealing surface is arranged radially outside the inner edge of the sealing area.

5. The sealed drug container as claimed in claim 1, wherein, When the sealed glass container is cooled to a temperature below or equal to -45°C, compression is maintained on the upper surface, resulting in a helium leakage rate of less than or equal to 1.4 x 10⁻⁶ at that temperature. -6 cm 3 / s.

6. The sealed drug container as claimed in claim 5, wherein, By compressing the cap against the upper surface, a residual sealing force of less than 20 lbf is applied to the upper surface of the cap.

7. The sealed drug container as claimed in claim 1, wherein, The second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -80°C is at least 10% of the first contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature.

8. The sealed drug container as claimed in claim 1, wherein, The sealing part of the plug includes: The lower portion of the contact area that contacts the upper surface of the flange; and The upper part that is in direct contact with the cap, including: The radial dimension r contained in the upper part up Greater than the compressed radius r sc Thus, at least a portion of the upper part extends axially above the transition region, and The radial dimension of the lower part of the contact is less than r. up .

9. The sealed drug container as claimed in claim 1, wherein: outer radius r of the flange o Equal to 6.5 mm, and When the sealed drug container is cooled to a temperature less than or equal to -80°C, the contact area between the upper surface and the sealing part is greater than or equal to 75 mm². 2 .

10. A sealed pharmaceutical container, comprising: Central axis; Opening; A flange circumferentially surrounding the opening, the flange comprising: The lower surface extending from the neck; An outer surface extending from the lower surface defines the outer radius r of the flange. o ; The upper surface, the upper surface including a radius r sr The sealed area, wherein, for a cross-section of the sealed drug container taken along a plane parallel to and passing through the central axis, the upper surface includes a first linear segment arranged on a first side of the opening and a second linear segment arranged on a second side of the opening, wherein, in a direction perpendicular to the central axis, the outer ends of the first and second linear segments are arranged to be spaced apart from each other by a distance of 2. r sr ;as well as The transition region extending between the upper and outer surfaces; and A sealing assembly comprising: A plug, comprising an insertion portion inserted into an opening and a sealing portion contacting an upper surface, wherein the sealing portion includes a stepped transition of a radial dimension at a location axially offset from the upper surface; and The cap, with its compression plug abutting against the upper surface, wherein the sealing portion includes a compression radius r sc Smaller than the radius r of the sealed area sr .

11. The sealed drug container as claimed in claim 10, wherein, The first and second linear segments of the cross section extend at an angle relative to the plane perpendicular to the central axis and are part of the conical segment of the upper surface.

12. The sealed drug container as claimed in claim 10, wherein, The sealing portion includes sealing surfaces arranged on the first and second linear sections.

13. The sealed drug container as claimed in claim 12, wherein, The sealing surface includes an outer peripheral edge, which is arranged radially inside the transition region.

14. The sealed drug container as claimed in claim 13, wherein, The outer peripheral edge of the sealing surface is arranged radially outward from the inner end of the first and second linear sections.

15. The sealed drug container as claimed in claim 10, wherein, When the sealed glass container is cooled to a temperature below or equal to -45°C, compression is maintained on the upper surface, resulting in a helium leakage rate of less than or equal to 1.4 x 10⁻⁶ at that temperature. -6 cm 3 / s.

16. The sealed drug container as claimed in claim 15, wherein, By compressing the cap against the upper surface, a residual sealing force of less than 20 lbf is applied to the upper surface of the cap.

17. The sealed drug container as claimed in claim 10, wherein, The second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -80°C is at least 10% of the first contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature.

18. The sealed drug container as claimed in claim 10, wherein, The sealing part of the plug includes: The lower portion of the contact area that contacts the upper surface of the flange; and The upper part that is in direct contact with the cap, including: The radial dimension r contained in the upper part up Greater than the compressed radius r sc Thus, at least a portion of the upper part extends axially above the transition region, and The radial dimension of the lower part of the contact is less than r. up .

19. A method for sealing a sealed drug container, the method comprising the following steps: A sealable drug container is provided, comprising a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange comprising: The lower surface extending from the neck; An outer surface extending from the lower surface defines the outer diameter of the flange; as well as An upper surface extending from the outer surface of a sealed drug container to the inner surface defining an opening, the upper surface including a radius r sr The sealed area; Insert the pharmaceutical composition into a sealed pharmaceutical container; A sealing assembly comprising a plug, the plug including an insertion portion and a sealing portion, wherein the sealing portion includes a stepped transition of a radial dimension at a location axially offset from an upper surface; The metal cap is positioned above the stopper and abuts against the flange, causing the sealing portion to curl and compress against the upper surface. Prior to compression by the metal cap, the uncompressed radius r at the lower edge of the sealing portion is... uc Less than or equal to 0.85 r sr ;as well as The sealed drug container is cooled to a temperature less than or equal to -45°C, wherein, after cooling, the compression on the upper surface is maintained, such that the helium leakage rate of the sealed drug container at this temperature is less than or equal to 1.4 x 10⁻⁶. -6 cm 3 / s.

20. The method of claim 19, wherein, Once compressed by the metal cap, the compressed radius r of the sealed portion... sc Smaller than the outer radius r of the flange o .

21. The method of claim 19, wherein, The curling of the metal cap compresses the plug against the upper surface, providing a residual sealing force of less than or equal to 20 lbf.

22. The method of claim 19, wherein, The second contact area between the sealing portion and the upper surface when the sealed drug container is cooled to -80°C is at least 10% of the first contact area between the sealing portion and the upper surface when the sealed drug container is at room temperature.

23. The method of claim 19, wherein, The temperature is less than or equal to -80°C.

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