Medicament container assembly comprising sealing assembly for cryogenic storage

Abstract

A medicament container assembly includes a medicament container and a sealing assembly. In a sealed state, an insertion portion of the sealing assembly is inserted into an opening of the medicament container to define a seal. In the sealed state, an upper portion of the seal assembly extends over an upper surface of a flange of the medicament container and covers the opening. In a non-sealed state in which the insertion portion is not inserted into the opening, an outer diameter of a portion of the insertion portion is greater than a diameter of a corresponding portion of the opening by an amount equal to or greater than 3% and equal to or less than 15%.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority benefit under 35 U.S.C. §119 to U.S. Provisional Application No. 63 / 504,835, filed May 30, 2023, the contents of which are relied upon and incorporated herein by reference in its entirety. TECHNICAL FIELD

[0003] The present specification generally relates to containers, such as glass containers for storing pharmaceutical compositions, and more particularly, to pharmaceutical container assemblies comprising a sealing assembly that is used in conjunction with a glass container to maintain container closure integrity at relatively low storage temperatures. BACKGROUND

[0004] Pharmaceutical containers, such as vials and syringes, are often sealed via a stopper or other closure to maintain the integrity of the contained material. The closure is often made of synthetic rubber and other elastomers. Such materials are best with moderate and / or high resistance to permeation and elasticity to facilitate insertion into the container to seal the interior of the container. However, the elasticity of the closure materials commonly used can decrease at low temperatures. For example, synthetic rubbers currently used as closure materials can include a transition temperature greater than or equal to -70 °C and less than or equal to -10 °C. Below the transition temperature, the closure made from such synthetic rubbers can behave as a solid and not be able to elastically expand to compensate for the relatively large difference between the thermal expansion coefficients of the glass and the crimped cap used to secure the closure to the container. In view of this, existing pharmaceutical container sealing assemblies can fail at temperatures less than or equal to -20 °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 conventional elastomer glass transition temperature to continue to function. For example, certain RNA-based vaccines can need to be stored at dry ice temperatures (e.g., about -80 °C) or liquid nitrogen temperatures (e.g., about -180 °C) to remain active. Such low temperatures can cause dimensional changes in the closure components (e.g., glass or plastic containers, stoppers, aluminum caps), leading to problems with the seal integrity and possible contamination of the material stored therein. SUMMARY

[0006] In one embodiment, a drug container assembly includes a drug container and a seal assembly. The drug container includes a shoulder, a neck extending from the shoulder, and a flange extending from the neck. The flange includes a lower side surface extending from the neck, an outer surface extending from the lower side surface, an upper surface opposite the lower side surface, the upper surface extending between the outer surface and an inner surface defining an opening in the drug container, and a seal assembly. The seal assembly includes a stopper including an upper portion comprising an upper surface and an insertion portion including an outer surface. The insertion portion extends from the upper portion. In a sealed state, the insertion portion is inserted into the opening to define a seal between the insertion portion and the inner surface of the flange. In the sealed state, the upper portion extends above the upper surface of the flange and covers the opening. In a non-sealed state in which the insertion portion is not inserted into the opening, an outer diameter of a portion of the insertion portion is greater than a diameter of a corresponding portion of the opening by an amount equal to or greater than 3% and less than or equal to 15%.

[0007] In another embodiment, a method of sealing a drug container includes inserting a drug composition into the drug container. The drug container includes a shoulder, a neck extending from the shoulder, and a flange extending from the neck. The flange includes a lower side surface extending from the neck, an outer surface extending from the lower side surface, and an upper surface opposite the lower side surface. The upper surface extends between the outer surface and an inner surface defining an opening in the drug container. The method additionally includes inserting a stopper through the opening in the drug container to form a drug container assembly. The stopper includes an upper portion and an insertion portion extending from the upper portion. When in a sealed state, the upper portion extends above the upper surface of the flange and covers the opening. The insertion portion extends within the opening to define a seal between the insertion portion and the inner surface of the flange. The insertion portion includes an outer surface. Prior to inserting the stopper into the opening of the drug container, in a non-sealed state, an outer diameter of a portion of the insertion portion is greater than a diameter of a corresponding portion of the opening by an amount equal to or greater than 3% and less than or equal to 15%.

[0008] These and additional features provided by the embodiments described herein will be more fully understood in view of the following detailed description, taken with the drawings, in which: BRIEF DESCRIPTION OF DRAWINGS

[0009] The following detailed description of the illustrative embodiments can best be understood when read in conjunction with the following drawings, in which the same structure is identified using the same reference numerals and in which: The detailed description set forth below in connection with the appended drawings describes exemplary embodiments and does not represent the only embodiments that can be implemented.

[0010] Figure 1 schematically depicts a cross-sectional view of a drug container assembly in a non-sealed state, in accordance with one or more embodiments shown and described herein;

[0011] Figure 2 schematically depicts a partial cross-sectional view of a drug container in a sealed state and capped with a low residual seal force, in accordance with one or more embodiments shown and described herein;

[0012] Figure 3 schematically depicts a partial cross-sectional view of a drug container in a sealed state and capped with a maximum residual seal force, in accordance with one or more embodiments shown and described herein;

[0013] Figure 4 schematically depicts a cross-sectional view of another drug container assembly in a capped state, in accordance with one or more embodiments shown and described herein;

[0014] Figure 5 schematically depicts a cross-sectional view of a drug container assembly in a capped state, in accordance with one or more embodiments shown and described herein; Figure 4 Figure 4

[0015] Figure 6 schematically depicts a cross-sectional view of another drug container assembly in a capped state, in accordance with one or more embodiments shown and described herein;

[0016] Figure 7 schematically depicts a cross-sectional view of a drug container assembly in a capped state, in accordance with one or more embodiments shown and described herein; Figure 6 Figure 6

[0017] Figure 8 a graph representing the relationship between an interference fit and a required stopper insertion force, in accordance with one or more embodiments shown and described herein; and

[0018] Figure 9 a graph representing the relationship between an interference fit and an oxygen concentration, in accordance with one or more embodiments shown and described herein. DETAILED DESCRIPTION

[0019] ​​​​Reference will now be made in detail to embodiments of a drug container assembly comprising a sealing assembly that maintains container closure integrity at relatively low storage temperatures (e.g., less than or equal to -80°C, less than or equal to -100°C, less than or equal to -125°C, less than or equal to -150°C, less than or equal to -175°C, less than or equal to -180°C). In embodiments, the structure of the drug container assembly described herein can differ in one or more aspects from the structure of existing drug container assemblies in order to facilitate maintenance of a seal at the interface between the drug container and a sealing assembly inserted therein. For example, embodiments of the drug container described herein can be a vial (although other container shapes are within the scope of the present disclosure) that comprises a shoulder, a neck, and a flange comprising an upper surface against which a stopper of a sealing assembly is pressed by a cap. Various characteristics of the mating drug container and sealing assembly that define a sealing surface can be adapted to maintain a seal when the drug container assembly is cooled to such low storage temperatures. For example, in embodiments, a portion of the insertion portion of the sealing assembly has an outer diameter that is greater than the diameter of the corresponding portion of the drug container by an amount equal to or greater than 3% and less than or equal to 15% in the non-sealing state in which the sealing assembly is not inserted into the drug container. In embodiments, various other characteristics of the sealing assembly (e.g., the outer diameter of the upper portion of the stopper, the geometry of the outer surface of the insertion portion, etc.) can be tailored to improve seal integrity.

[0020] As used herein, the term“container closure integrity” refers to maintenance of a seal at the interface between a drug container and a sealing assembly (e.g., between the inner surface of the flange of the drug container and the outer surface of the insertion portion of the stopper) that does not contain a gap above a threshold size to maintain a probability of contamination ingress or a gas permeation likelihood below a predetermined threshold based on the material stored in the drug container. For example, in embodiments, container closure integrity is maintained if the helium leak rate during the helium leak test described in USP <1207> (2016) (particularly <1207.1>, <1207.2>, and <1207.3>) is maintained at less than or equal to 1.4 x 10 -6 cm 3 / s.

[0021] In embodiments of the drug container described herein, the concentrations of constituent ingredients (e.g., Si02, AI2O3, B2O3, etc.) of the glass composition forming the drug container are specified as expressed in mole percent (mol.%) on an oxide basis, unless otherwise specified.

[0022] The term "substantially free of," 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 can contain trace amounts of the constituent component as a contaminant or impurity in an amount less than 0.05 mol.%.

[0023] The term "CTE," as used herein, unless otherwise indicated, means the coefficient of thermal expansion over a temperature range of about -200 °C to about 300 °C.

[0024] As used herein, the term "about" means amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximated and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and other factors that are expected to be within the scope of one of ordinary skill in the art. When the term "about" is used in reference to a value or range of endpoints, the specific value or endpoint is encompassed. Whether the numerical values of the ranges' endpoints are "about" the recited criterion or not, both embodiments are described - one with "about" and one without "about." It is further understood that the endpoints of the ranges are specific values included within the ranges, unless the context clearly dictates otherwise.

[0025] Directional terms as used herein - for example up, down, right, left, front, back, top, bottom, over, under, and the like - are made only with reference to the figures as drawn and not in an absolute sense, unless specifically so noted.

[0026] 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" or "the" component includes aspects having two or more such components unless the context clearly indicates otherwise.

[0027] Reference is now made to Figures 1-3 One embodiment of a drug container assembly 100 for storing a drug formulation is schematically depicted in cross-section. The drug container assembly 100 includes a drug container 102 and a seal assembly 104. The drug container assembly 100 is depicted in Figure 1 a non-sealed state, in which the seal assembly 104 is not inserted into the drug container 102, and in Figure 2 and 3 a sealed state, in which the seal assembly 104 is inserted into the drug container 102. More specifically, as discussed in greater detail herein, the drug container assembly 100 is depicted in Figure 2In the Figure 3 In the

[0028] Referring again to Figure 1 The drug container 102 generally includes a body 112. The body 112 has a wall thickness T W containing a central axis A, and generally encloses an interior volume 118. The wall thickness T W may vary depending on the embodiment. In embodiments, the wall thickness T W may be less than or equal to 6 millimeters (mm), such as less than or equal to 4 mm, less than or equal to 2 mm, less than or equal to 1.5 mm, or less than or equal to 1 mm. In some embodiments, the wall thickness T w may be greater than or equal to 0.1 mm and less than or equal to 6 mm, greater than or equal to 0.3 mm and less than or equal to 4 mm, greater than or equal to 0.5 mm and less than or equal to 4 mm, greater than or equal to 0.5 mm and less than or equal to 2 mm, or greater than or equal to 0.5 mm and less than or equal to 1.5 mm. In embodiments, the wall thickness T W may be greater than or equal to 0.9 mm and less than or equal to 1.8 mm. The wall thickness T W may vary depending on the axial position within the drug container 102.

[0029] In the embodiments of the drug container 102 shown in Figure 1 In the embodiments of the drug container 102 shown in

[0030] As Figure 1As depicted, flange 126 includes a lower surface 132, an outer surface 134 extending from the lower surface 132, and an upper surface 136 opposite to the lower surface 132. Inner surface 114 of body 112 extends along each of cylinder 115, flange 126, and neck 128, and defines an opening 105 at the upper surface 136 of flange 126.

[0031] More specifically, in Figures 1-3 In the embodiment of the drug container 102 depicted herein, a lip 138 is formed at the flange 126 on the inner surface 114 of the body 112. For example... Figure 1 As shown, the lip 138 is depicted on the opposite side of the inner surface 114 of the body 112 at the flange 126. Therefore, it should be understood that the lip 138 may be formed to extend along the entire circumference of the inner surface 114 of the body 112, or in other embodiments, a plurality of separate lip portions spaced apart from each other and formed at intervals along the circumference of the inner surface 114 of the body 112. The lip 138 prevents backlash of the sealing assembly 104 when inserted into the opening 105 of the drug container 102. The inner surface 114 of the body 112, extending from the lip 138 along the flange 126 and neck 128, extends parallel to the central axis A. The inner surface 114 of the body 112 immediately below the lip 138 defines a flange sealing position 140 with an inner diameter D1. As described in more detail herein, the sealing assembly 104 contacts the flange sealing position 140 when inserted into the drug container 102 to define a seal between the sealing assembly 104 and the drug container 102. However, in embodiments without the lip 138, it should be understood that the flange sealing position 140 may be located along the flange 126 or neck 128 at any point on the inner surface 114 of the body 112 that contacts the sealing assembly 104 when in a sealed state.

[0032] In this embodiment, the drug container 102 may be made of USP <660> Type I, Type II, or Type III glass formation as defined in [reference needed], comprising borosilicate glass compositions, such as those according to USP [reference needed]. <660> The drug container 102 may be formed of a type 1B borosilicate glass composition. Alternatively, the drug container 102 may be formed of an alkaline aluminosilicate glass composition, such as those disclosed in U.S. Patent No. 8,551,898, which is incorporated herein by reference in its entirety, or of an alkaline earth aluminosilicate glass, such as those described in U.S. Patent No. 9,145,329, which is incorporated herein by reference in its entirety. In an embodiment, the drug container 102 may be made of a soda-lime glass composition. In an embodiment, the drug container 102 has a coefficient of thermal expansion greater than or equal to 0 × 10⁻⁶. -7 / K and less than or equal to 100 × 10 -7 / K (e.g., greater than or equal to 30 x 10 -7 / K and less than or equal to 70 x 10 -7 / K) comprise.

[0033] While the drug container 102 is depicted in Figure 1 as having a particular form factor (i.e., a vial), it should be appreciated that the drug container 102 can have other form factors, including but not limited to Vacutainers®, cartridges, syringes, ampoules, bottles, flasks, vials, tubes, beakers, and the like, as discussed in greater detail herein. Moreover, it should be appreciated that the drug containers described herein can be used for a variety of applications, including but not limited to pharmaceutical packaging, beverage containers, and the like.

[0034] While referred to herein as a drug container 102, it should be appreciated that the drug container 102 can be formed from materials other than glass, such as polymers, metals, ceramics, and the like. Moreover, the coefficient of thermal expansion of these materials can be greater than or equal to 0 x 10 -7 / K and less than or equal to 8,000 x 10 -7 / K.

[0035] The seal assembly 104 includes a stopper 106 and a metal-containing cap 108. The stopper 106 includes an upper portion 142 and an insertion portion 144 extending from the upper portion 142. In embodiments, the stopper 106 is composed of a polymer-based material (e.g., butyl or other synthetic rubber). The upper portion 142 includes an upper surface 146, a lower surface 148 opposite the upper surface 146, and an outer surface 150 extending between the upper surface 146 and the lower surface 148. The outer surface 150 of the upper portion 142 defines an outer diameter D2.

[0036] The insertion portion 144 extends from the upper portion 142 in a direction opposite to the upper surface 146 of the upper portion 142. The insertion portion 144 includes an upper end 152 at the upper portion 142, a lower end 154 opposite to the upper end 152, and an outer surface 156 extending between the upper end 152 and the lower end 154. The outer surface 156 of the insertion portion 144 includes an upper outer surface portion 158 and a lower outer surface portion 160. The upper outer surface portion 158 extends from the upper end 152 of the insertion portion 144, and the lower outer surface portion 160 extends from the upper outer surface portion 158 to the lower end 154 of the insertion portion 144. In embodiments where the drug container 102 includes a lip 138, as described herein, a groove 162 may be formed at the upper end 152 of the insertion portion 144 in the upper outer surface portion 158 of the insertion portion 144. In one embodiment, the groove 162 may form a plurality of individual groove portions, which are spaced apart from each other and formed at intervals along the circumference of the upper outer surface portion 158 of the insertion portion 144. In other embodiments, the groove 162 surrounds the entire circumference of the insertion portion 144.

[0037] In one embodiment, the insertion portion 144 includes a protrusion 164 formed on an upper outer surface portion 158 of the insertion portion 144, where the upper outer surface portion 158 is in contact with a lower outer surface portion 160. In an embodiment where a recess 162 is provided, the protrusion 164 may be formed immediately below the recess 162, opposite the upper portion 142 of the plug 106. However, it should be understood that the protrusion 164 may be located at any position on the outer surface 156 of the insertion portion 144, for example, on the lower outer surface portion 160. The protrusion 164 defines an insertion sealing position 166 and has an outer diameter D3. The outer diameter D3 of the insertion sealing position is larger than the outer diameter of the insertion portion at any other point along the outer surface of the insertion portion.

[0038] In the unsealed state where the insertion portion 144 is not inserted into the opening 105 of the drug container 102, such as Figure 1As shown in FIG. 1 1, the outer diameter D3 of the insertion portion 144 defined by the protrusion 164 at the insertion seal location 166 is greater than the inner diameter Dl of the inner surface 114 of the body 112 at the flange seal location 140 by an amount equal to or greater than 3% and less than or equal to 15%. In embodiments, the outer diameter D3 of the insertion portion 119 defined by the protrusion 164 at the insertion seal location 166 is greater than the inner diameter Dl of the inner surface 114 of the body 112 at the flange seal location 140 by an amount equal to or greater than 5.8% and less than or equal to 13.5%. In embodiments, the outer diameter D3 of the insertion portion 144 defined by the protrusion 164 at the insertion seal location 166 is greater than the inner diameter Dl of the inner surface 114 of the body 112 at the flange seal location 140 by an amount equal to or greater than 7% and less than or equal to 13%. In embodiments, the outer diameter D3 of the insertion portion 144 defined by the protrusion 164 at the insertion seal location 166 is greater than the inner diameter Dl of the inner surface 114 of the body 112 at the flange seal location 140 by an amount equal to or greater than 9% and less than or equal to 11%. The percentage difference between the outer diameter D3 of the insertion portion 144 defined by the protrusion 164 at the insertion seal location 166 and the inner diameter Dl of the inner surface 114 of the body 112 at the flange seal location 140 can be referred to herein as an interference fit. Thus, the greater the percentage difference between the outer diameter D3 of the insertion portion 144 and the inner diameter Dl of the inner surface 114 of the body 112, the greater the interference fit. Thus, the interference fit refers to the compressive force exerted by the drug container 102 against the insertion portion 144 of the stopper 106 when the insertion portion 144 of the stopper 106 is inserted into the opening 105 of the drug container 102.

[0039] In embodiments, the lower outer surface portion 160 of the insertion portion 144 tapers from the upper outer surface portion 158 toward the lower end 154 of the insertion portion 144. In embodiments where the recess 162 and / or the protrusion 164 are not provided on the outer surface 134 of the insertion portion 144, the upper outer surface portion 158 of the insertion portion 144 can also taper from the upper end 152 to the lower outer surface portion 160, which can continue to taper toward the lower end 154 of the insertion portion 144.

[0040] The insertion portion 144 includes a lower surface 168 at the lower end 154 of the insertion portion 144. In embodiments, a cutout 170 is formed in the lower surface 168 and extends in a direction toward the lower surface 148 of the upper portion 142. The cutout 170 can have any suitable shape, such as concave. However, it should be appreciated that the cutout 170 can have any other suitable shape, such as tubular, rectangular, etc.

[0041] Still referring to FIG. 1 1, the protrusion 164 can include a lower surface 172. In embodiments, the lower surface 172 of the protrusion 164 is substantially planar. In embodiments, the lower surface 172 of the protrusion 164 is substantially perpendicular to the lower surface 148 of the upper portion 142. In embodiments, the lower surface 172 of the protrusion 164 is substantially parallel to the lower surface 148 of the upper portion 142. Figure 1The metal-containing cap 108 of the seal assembly 104 includes an upper portion 172 and a side portion 174 extending from the upper portion 172. The side portion 174 has an inner diameter D4. As shown in Figure 1 With the seal assembly 104 separated from the drug container 102, the inner diameter D4 of the side portion 174 of the metal-containing cap 108 is greater than the outer diameter D2 of the upper portion 142 of the stopper 106 such that a gap 176 is defined therebetween, as shown in FIG. 3. As referred to herein, the gap 176 refers to the outer surface 150 of the upper portion 142 of the stopper 106 not being in contact with the side portion 174 of the metal-containing cap 108. As described in greater detail herein, the side portion 174 of the metal-containing cap 108, and in particular a lower terminal end 178 of the side portion 174, can be deformed by crimping to engage the lower side surface 132 of the flange 126, i.e., to seal the seal assembly 104 to the drug container 102.

[0042] In embodiments, to maintain the seal, the metal-containing cap 108 and the stopper 106 can be configured such that the shrinkage of the metal-containing cap 108 is greater than or equal to the combined shrinkage of the drug container 102 and the stopper 106. To facilitate satisfying such a relationship, in embodiments, the metal-containing cap 108 is composed of aluminum, which can have a CTE of approximately 240 x 10 -7 / K. In other embodiments, the metal-containing cap is composed of a metal alloy including at least one of Zn, Mg, and Cu. Typical rubbers composing the stopper 106 (e.g., Butyl 325, Butyl 035, etc.) can have a CTE greater than or equal to 1,400 x 10 -7 / K. That is, from the CTE differential alone, the metal-containing cap 108 is less prone to shrinkage than the stopper 106, resulting in a weakening of the seal force at lower storage temperatures. In addition to the CTE mismatch described above, the stopper 106 can have a greater volume percentage of the seal assembly 104 than the metal-containing cap 108, further exacerbating the tendency of the stopper 106 to experience greater thermal shrinkage.

[0043] Referring to Figure 2assembly 104 is coupled to the drug container 102 at the opening 105 of the drug container 102. When in the sealed state, the insertion portion 144 is inserted into the opening 105 of the drug container 102 until the upper portion 142 is in contact with the upper surface 136 of the flange 126 of the drug container 102. In the sealed state, the lower surface 148 of the upper portion 142 of the stopper 106 abuts the upper surface 136 of the flange 126 of the drug container 102. Additionally, the lip 138 formed on the inner surface 114 of the drug container 102 is received within the groove 162 formed on the upper outer surface portion 158 of the insertion portion 144. Thus, when in the sealed state, the flange seal location 140 and the insertion seal location 166 are aligned along the X-axis of the coordinate axes depicted in the figure and abut one another to define a seal. The inner surface 114 of the drug container 102 compresses the insertion portion 144 of the stopper 106 at the flange seal location 140 and the insertion seal location 166 according to a particular interference fit.

[0044] Thereafter, the upper portion 142 is pressed against the upper surface 136 of the flange 126 by crimping the metal-containing cap 108 to seal the seal assembly 104 to the drug container 102. During crimping, a compressive force is applied to the metal-containing cap 108 and the side portion 174 of the metal-containing cap 108 is deformed about the lower side surface 132 of the flange 126 to cap the drug container 102 by any suitable crimping method (e.g., a pneumatic crimping device, etc.). After crimping, the side portion 174 of the metal-containing cap 108 defines an overhang 180 at the lower terminal end 178 of the side portion 174 that contacts the lower side surface 132 of the flange 126 to force the stopper 106 to remain in a compressed state.

[0045] The compression of the stopper 106 creates an RSF within the flange 126 that maintains the compression on the stopper 106 after the metal-containing cap 108 is crimped into place. Various aspects of the drug container 102 and the seal assembly 104 are designed to ensure that the container closure integrity of the drug container 102 is maintained at low storage temperatures of less than or equal to -80°C, as described herein.

[0046] As shown in FIG. 1A, the drug container assembly 100 is depicted in a sealed state and capped at a low RSF of, for example, 5 lbf. However, as shown in FIG. 1B, a gap 176 formed between the outer surface 150 of the upper portion 142 of the stopper 106 and the side portion 174 of the metal-containing cap 108 is maintained. Thus, the outer surface 150 of the upper portion 142 of the stopper 106 is not in contact with the side portion 174 of the metal-containing cap 108. Figure 2 Figure 2 Similarly, as shown in FIG. 1C, the drug container assembly 100 is depicted in a sealed state and capped at a low RSF of, for example, 5 lbf. However, as shown in FIG. 1D, the gap 176 formed between the outer surface 150 of the upper portion 142 of the stopper 106 and the side portion 174 of the metal-containing cap 108 is maintained. Thus, the outer surface 150 of the upper portion 142 of the stopper 106 is not in contact with the side portion 174 of the metal-containing cap 108.

[0047] Similarly, as shown in FIG. 1A, the drug container assembly 100 is depicted in a sealed state and capped at a low RSF of, for example, 5 lbf. However, as shown in FIG. 1B, a gap 176 formed between the outer surface 150 of the upper portion 142 of the stopper 106 and the side portion 174 of the metal-containing cap 108 is maintained. Thus, the outer surface 150 of the upper portion 142 of the stopper 106 is not in contact with the side portion 174 of the metal-containing cap 108. Figure 3 ​As shown, the drug container assembly 100 is depicted as being in a sealed state and capped at, for example, a maximum RSF of 15 lbf. However, as Figure 3 As shown, although the stopper 106 is compressed, the gap 176 formed between the outer surface 150 of the upper portion 142 of the stopper 106 and the side portion 174 containing the metal cap 108 is maintained. Therefore, the outer surface 150 of the upper portion 142 of the stopper 106 does not contact the side portion 174 containing the metal cap 108. It should be understood that without the gap 176 between the upper portion 142 of the stopper 106 and the side portion 174 containing the metal cap 108, a failure mode may occur, causing the seal formed between the sealing assembly 104 and the drug container 102 to be compromised.

[0048] When the sealed and capped drug container assembly 100 is cooled to a relatively low storage temperature of less than or equal to -80°C (e.g., less than or equal to -80°C, less than or equal to -100°C, less than or equal to -125°C, less than or equal to -150°C, less than or equal to -175°C, -180°C), each component of the drug container assembly 100 may experience volume shrinkage depending on the thermal properties of that component. If the combined shrinkage of the stopper 106 is greater than the shrinkage of the flange 126, the compression provided by the flange 126 on the stopper 106 can be reduced, thereby increasing the likelihood that the seal formed at the flange sealing position 140 and the insertion sealing position 166 will be compromised. However, the increased interference fit, i.e., when in a non-sealed state ( Figure 1 When the outer diameter D3 of the insertion portion 144 is greater than the inner diameter D1 of the flange 126, it allows for greater shrinkage while reducing the possibility of the seal being damaged.

[0049] Although not shown in this article, it should be understood that the information presented herein may be used to illustrate this point. Figures 1-3 An alternative to the described drug container assembly 100, while maintaining container closure integrity at storage temperatures less than or equal to -80°C. For example, in Figure 4 and 5 Another embodiment of the drug container assembly 200 is depicted. It should be understood that the drug container assembly 200 is similar to the drug container assembly 100. Therefore, similar reference numerals will be used to refer to similar parts.

[0050] like Figure 4 and 5 As shown, the drug container assembly 200 includes a drug container 202 and a sealing assembly 204. Similar to... Figures 1-3The drug container 202 includes a body 212 that includes a flange 226 and a neck 128 having an inner surface 214 extending therealong. However, the drug container 202 does not include a lip 138 formed on the inner surface 214 of the drug container 202 at the flange 226, as is shown in the drug container 102 depicted in Figures 1-3 The inner surface 214 of the drug container 202 extends parallel to the central axis A from the upper surface 236 of the flange 226 along the flange 226 and the neck 128. Thus, as is shown in Figure 5 more particularly shown in, no lip is formed at the junction between the upper surface 236 of the flange 226 and the inner surface 214 of the drug container 202 at the flange 226. Thus, the inner diameter D5 of the flange 226 defining the opening 105 is uniform, i.e., does not change, along the flange 226 and the neck 128 of the drug container 202. In embodiments, the inner surface 214 extends substantially perpendicularly from the upper surface 236 of the flange 226. In embodiments, the inner surface 214 extends at an angle from the upper surface 236 of the flange 226 that is equal to or less than 3 degrees relative to the upper surface 236 of the flange 226. The inner surface 214 of the drug container 202 defines a flange seal location 240 at the flange 226.

[0051] The seal assembly 204 includes a stopper 206 that includes an upper portion 142 and an insertion portion 244 extending from the upper portion 142. As is shown in Figure 5 similar to the insertion portion 144 of the stopper 106 depicted in Figures 1-3 The insertion portion 244 includes an outer surface 256 that includes an upper outer surface portion 258 and a lower outer surface portion 260 extending from the upper outer surface portion 258 in a direction opposite the upper portion 142 of the stopper 106. However, the upper outer surface portion 258 is not provided with the upper outer surface portion 258 including the groove 162 and the protrusion 164 as is provided in the insertion portion 144 of the stopper 106 depicted in Figures 1-3 The upper outer surface portion 258 of the insertion portion 244 is planar such that it extends parallel to the central axis A of the drug container 202. Thus, the outer diameter D6 of the insertion portion 244 is uniform, i.e., does not change, along the upper outer surface portion 258. The upper outer surface portion 258 of the insertion portion 244 defines an insertion seal location 266.

[0052] similar to the insertion portion 144 of the stopper 106 depicted in Figures 1-3The drug container assembly 100 depicted, in its unsealed state where the insertion portion 244 is not inserted into the opening 105 of the drug container 202, has an outer diameter D6 at the insertion sealing position 266 that is larger than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange sealing position 240 by an amount equal to or greater than 3% and less than or equal to 15%. In an embodiment, the outer diameter D6 of the insertion portion 244 at the insertion sealing position 266 is larger than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange sealing position 240 by an amount equal to or greater than 5.8% and less than or equal to 13.5%. In another embodiment, the outer diameter D6 of the insertion portion 244 at the insertion sealing position 266 is larger than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange sealing position 240 by an amount equal to or greater than 7% and less than or equal to 13%. In the embodiment, the outer diameter D6 of the insertion portion 244 at the insertion sealing position 266 is larger than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange sealing position 240 by an amount equal to or greater than 9% and less than or equal to 11%. Although the outer diameter D6 of the insertion portion 244 is described as equal to... Figure 4 The inner diameter D5 of the inner surface 214 is greater than the inner diameter D5, but it should be understood that when the sealing assembly 204 is not inserted into the opening 105 of the drug container 202, the outer diameter D6 is greater than the inner diameter D5.

[0053] Therefore, as Figure 5 As shown, in the sealed state where the insertion portion 244 of the stopper 206 is inserted into the opening 105 of the drug container 202, the upper outer surface portion 258 of the insertion portion 244 is compressed against and flush with the inner surface 214 of the drug container 202 at the flange 226. Therefore, the flange sealing position 240 and the insertion sealing position 266 abut against each other to define a seal between the sealing assembly 204 and the drug container 202.

[0054] refer to Figure 6 and 7 Another embodiment of the drug container assembly 300 is depicted. It should be understood that the drug container assembly 300 is similar to drug container assemblies 100 and 200. Therefore, similar reference numerals will be used to refer to similar parts.

[0055] The drug container assembly 300 includes a drug container 202 and a sealing assembly 304. The sealing assembly 304 includes a stopper 306, the stopper comprising an upper portion 142 and an insertion portion 344 extending from the upper portion 142. Figure 7 As shown, similar to Figure 4 and 5The insertion portion 244 of the stopper 206 depicted in FIG. 6A includes an outer surface 256 that includes an upper outer surface portion 258 and a lower outer surface portion 260 that extends from the upper outer surface portion 258 in a direction opposite the upper portion 142 of the stopper 306. The insertion portion 244, however, includes one or more ribs 261 that surround the upper outer surface portion 258 of the insertion portion 244, which define an insertion seal location 266 having an outer diameter D7. The insertion portion 244 includes any suitable number of ribs 261, such as one, two, three, or more than three ribs 261. As shown in FIG. 6A, the insertion portion 244 includes three ribs 261 that surround the insertion portion 244. In embodiments, the ribs 261 are equally spaced apart from one another in a vertical direction extending along the upper outer surface portion 258. Each rib 261 extends the same distance from the upper outer surface portion 258. In other embodiments, the ribs 261 are spaced apart from one another in the vertical direction at different intervals, such that the distance between each rib 261 is different. Each rib 261 extends the same distance from the upper outer surface portion 258. As such, the ribs 261 define the insertion seal location 266. Figure 7 As shown in FIG. 6A, the insertion portion 244 includes three ribs 261 that surround the insertion portion 244. In embodiments, the ribs 261 are equally spaced apart from one another in a vertical direction extending along the upper outer surface portion 258. Each rib 261 extends the same distance from the upper outer surface portion 258. In other embodiments, the ribs 261 are spaced apart from one another in the vertical direction at different intervals, such that the distance between each rib 261 is different. Each rib 261 extends the same distance from the upper outer surface portion 258. As such, the ribs 261 define the insertion seal location 266.

[0056] As shown in FIG. 6A, the insertion portion 244 includes three ribs 261 that surround the insertion portion 244. In embodiments, the ribs 261 are equally spaced apart from one another in a vertical direction extending along the upper outer surface portion 258. Each rib 261 extends the same distance from the upper outer surface portion 258. In other embodiments, the ribs 261 are spaced apart from one another in the vertical direction at different intervals, such that the distance between each rib 261 is different. Each rib 261 extends the same distance from the upper outer surface portion 258. As such, the ribs 261 define the insertion seal location 266. Figures 1-5 In the non-sealed state where the insertion portion 344 is not inserted into the opening 105 of the drug container 302, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 3% and less than or equal to 15%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 5.8% and less than or equal to 13.5%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 7% and less than or equal to 13%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 9% and less than or equal to 11%. Although the outer diameter D7 of the insertion portion 344 is depicted as being equal to the inner diameter D5 of the inner surface 214 in FIG. 6A, it will be appreciated that the outer diameter D7 is greater than the inner diameter D5 when the sealing assembly 304 is not inserted into the opening 105 of the drug container 202. Figure 6 In the non-sealed state where the insertion portion 344 is not inserted into the opening 105 of the drug container 302, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 3% and less than or equal to 15%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 5.8% and less than or equal to 13.5%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 7% and less than or equal to 13%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 9% and less than or equal to 11%. Although the outer diameter D7 of the insertion portion 344 is depicted as being equal to the inner diameter D5 of the inner surface 214 in FIG. 6A, it will be appreciated that the outer diameter D7 is greater than the inner diameter D5 when the sealing assembly 304 is not inserted into the opening 105 of the drug container 202.

[0057] Thus, as shown in FIG. 6A, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 3% and less than or equal to 15%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 5.8% and less than or equal to 13.5%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 7% and less than or equal to 13%. In embodiments, the outer diameter D7 of the insertion portion 344 at the insertion seal location 366 is greater than the inner diameter D5 of the inner surface 214 of the drug container 202 at the flange seal location 240 by an amount equal to or greater than 9% and less than or equal to 11%. Figure 7As shown in FIG. 3, in the sealed condition with the insertion portion 344 of the stopper 306 inserted into the opening 105 of the drug container 202, the rib 361 extending from the upper outer surface portion 358 of the insertion portion 344 compresses against the inner surface 214 of the drug container 202 at the flange 226. Thus, the flange seal location 240 and the insertion seal location 366 interface with one another to define a seal between the sealing assembly 304 and the drug container 202. It should be appreciated that by providing the rib 361, the amount of friction between the stopper 306 of the sealing assembly 304 and the drug container 202 is reduced. However, the interference fit between the stopper 306 of the sealing assembly 304 and the drug container 202 is not affected.

[0058] Referring now to FIG. 4, Figure 8 a graph depicting a relationship between stopper insertion force versus interference fit is depicted. As referred to herein, stopper insertion force is the force required to insert a stopper into an opening of a drug container at a particular interference fit. Thus, as Figure 8 shown in FIG. 4, multiple measurements were taken at particular interference fits, such as about 3%, about 6%, about 10%, and about 14%. As shown, the stopper insertion force at about 3% was about 2 lbf, the stopper insertion force at about 6% was about 6 lbf, the stopper insertion force at about 10% was about 8 lbf, and the stopper insertion force at about 14% was about 16 lbf. A linear fit line was then fit to the measured data points to indicate the stopper insertion force required at each interference fit. Thus, it should be appreciated that as the interference fit increases, e.g., the stopper includes an insertion portion having a greater outer diameter relative to the inner diameter of the opening of the drug container, the stopper insertion force required to insert the stopper into the opening of the drug container is greater.

[0059] As discussed herein, there is an optimal range of interference fit. For example, an interference fit equal to or greater than 3% and less than or equal to 15% is preferred. An interference fit less than 3% can result in a failure due to the stopper shrinking at a faster rate than the drug container at relatively low temperatures. Additionally, an interference fit greater than 15% can result in a failure due to the outer surface of the upper portion of the stopper containing the side portion of the metal-containing cap during capping.

[0060] Referring now to FIG. 5, Figure 9 a graph depicting a relationship between oxygen concentration versus interference fit is depicted. Specifically, a plurality of samples, e.g., drug container assemblies, were tested to identify container closure integrity pass rates at various interference fits at various sealing stages, e.g., before and after capping with a metal-containing cap and at -80°C. For example, as Figure 9As shown in Table 1, uncapped samples with interference fits of 5.5%, 10%, and 13.5% primarily exhibited oxygen concentrations of about 0%. However, capped samples with interference fits of 5.5%, 10%, and 13.5% primarily exhibited oxygen concentrations of about 21%. Although Figure 9 While not depicted in Table 1, it should be appreciated that, in accordance with USP <1207>, uncapped samples with interference fits of 10%, i.e., residual seal forces of 0 lbf, exhibited container closure integrity of 60%. However, in accordance with USP <1207>, capped samples with interference fits between 5.8% and 13.5% exhibited container closure integrity of 100%, regardless of residual seal force.

[0061] From the foregoing, it should be appreciated that a pharmaceutical container assembly is defined herein that includes a pharmaceutical container and a sealing assembly. In a sealed condition, an insertion portion of the sealing assembly is inserted into an opening of the pharmaceutical container to define a seal. In the sealed condition, an upper portion of the sealing assembly extends above an upper surface of a flange of the pharmaceutical container and covers the opening. In an unsealed condition in which the insertion portion is not inserted into the opening, an outer diameter of a portion of the insertion portion is greater than a diameter of a corresponding portion of the opening by an amount equal to or greater than 3% and less than or equal to 15%.

[0062] Other aspects of the embodiments described herein are provided by the subject matter of the following clauses:

[0063] Clause 1. A pharmaceutical container assembly comprising: a pharmaceutical container comprising a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange comprising a lower side surface extending from the neck, an outer surface extending from the lower side surface, an upper surface opposite the lower side surface, the upper surface extending between the outer surface and an inner surface defining an opening in the pharmaceutical container; and a sealing assembly comprising a stopper, the stopper comprising an upper portion and an insertion portion, the upper portion comprising an upper surface, the insertion portion comprising an outer surface, wherein: the insertion portion extends from the upper portion; in a sealed condition, the insertion portion is inserted into the opening to define a seal between the insertion portion and the inner surface of the flange; in the sealed condition, the upper portion extends above the upper surface of the flange and covers the opening; and in an unsealed condition in which the insertion portion is not inserted into the opening, an outer diameter of a portion of the insertion portion is greater than a diameter of a corresponding portion of the opening by an amount equal to or greater than 3% and less than or equal to 15%.

[0064] Clause 2. The pharmaceutical container assembly of Clause 1, further comprising: a metal-containing cap engaged with the stopper and securing the stopper to the flange when in the sealed state, wherein: the metal-containing cap comprises an upper portion and a side portion; the upper portion of the metal-containing cap abuts the upper surface of the upper portion of the stopper; the side portion of the metal-containing cap defines an inner diameter of the metal-containing cap; and the inner diameter of the metal-containing cap is greater than an outer diameter of the upper portion of the stopper, such that a gap is disposed between an outer surface of the upper portion and the side portion of the metal-containing cap.

[0065] Clause 3. The pharmaceutical container assembly of Clause 2, wherein, upon application of a compression force equal to or greater than 5 pounds force (lbf) and less than or equal to 15 lbf, the side portion of the metal-containing cap remains spaced apart from the outer surface of the upper portion of the stopper.

[0066] Clause 4. The pharmaceutical container assembly of Clause 2 or Clause 3, wherein the inner diameter of the side portion of the metal-containing cap is greater than the outer diameter of the upper portion of the stopper by an amount equal to or greater than 1% and less than or equal to 20%.

[0067] Clause 5. The pharmaceutical container assembly of Clause 4, wherein the inner diameter of the side portion of the metal-containing cap is greater than the outer diameter of the upper portion of the stopper by an amount equal to or greater than 3% and less than or equal to 10%.

[0068] Clause 6. The pharmaceutical container assembly of any of Clauses 1-5, wherein: the upper portion of the stopper comprises a lower surface opposite the upper surface of the upper portion, and an outer surface extending between the upper surface and the lower surface; and the insertion portion extends from the lower surface of the upper portion in a direction away from the upper surface of the upper portion.

[0069] Clause 7. The pharmaceutical container assembly of Clause 6, wherein a cutout is formed in a lower surface of the insertion portion and extends in a direction toward the lower surface of the upper portion.

[0070] Clause 8. The pharmaceutical container assembly of Clause 6 or Clause 7, wherein a groove is formed at an upper terminal end of the insertion portion.

[0071] Clause 9. The pharmaceutical container assembly of Clause 8, wherein the outer diameter of the insertion portion at a lower terminal end of the groove is greater than the outer diameter of the insertion portion at a lower terminal end of the insertion portion.

[0072] Clause 10. The drug container assembly of clause 9, wherein the outer surface of the insertion portion includes a lower outer surface portion proximate the groove tapering toward the lower end of the insertion portion.

[0073] Clause 11. The drug container assembly of any one of clauses 8 to 10, wherein the groove encircles the insertion portion.

[0074] Clause 12. The drug container assembly of any one of clauses 7 to 11, wherein the cutout has a concave shape.

[0075] Clause 13. The drug container assembly of any one of clauses 1 to 12, wherein: the upper portion includes a lower surface opposite the upper surface of the upper portion; the insertion portion extends from the lower surface of the upper portion in a direction away from the upper surface of the upper portion; and a plurality of fins are formed on the outer surface of the insertion portion.

[0076] Clause 14. The drug container assembly of clause 13, wherein the plurality of fins are equally spaced apart from one another.

[0077] Clause 15. The drug container assembly of clause 13 or clause 14, wherein the plurality of fins includes three fins.

[0078] Clause 16. The drug container assembly of any one of clauses 1 to 15, wherein: the inner surface of the flange extending from the upper surface of the flange is planar and extends parallel to a central axis of the drug container; and an outer surface of the insertion portion includes an upper outer surface portion that, when in the sealed state, extends parallel to the inner surface of the flange abutting against the inner surface of the flange.

[0079] Clause 17. The drug container assembly of clause 16, wherein the inner surface of the flange extends substantially perpendicularly from the upper surface of the flange.

[0080] Clause 18. The drug container assembly of clause 17, wherein the upper outer surface portion of the insertion portion extends from a lower surface of the upper portion to a lower outer surface portion of the insertion portion tapering from the upper outer surface portion.

[0081] Clause 19. The drug container assembly of clause 18, wherein an outer diameter of the insertion portion at an upper end of the lower outer surface portion of the insertion portion is greater than an outer diameter of the insertion portion at a lower end of the insertion portion.

[0082] Clause 20. The pharmaceutical container assembly of any one of Clauses 1 to 19, wherein in the sealed state, the pharmaceutical container assembly has a container closure integrity pass rate of at least 60% according to USP <1207>.

[0083] Clause 21. A method of sealing a pharmaceutical container, the method comprising: inserting a pharmaceutical composition into the pharmaceutical container, the pharmaceutical container comprising a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange comprising a lower side surface extending from the neck, an outer surface extending from the lower side surface, and an upper surface opposite the lower side surface, the upper surface extending between the outer surface and an inner surface defining an opening in the pharmaceutical container; and inserting a stopper through the opening in the pharmaceutical container to form a pharmaceutical container assembly, the stopper comprising an upper portion and an insertion portion extending from the upper portion, the upper portion extending above the upper surface of the flange and covering the opening when in a sealed state, the insertion portion extending within the opening to define a seal between the insertion portion and the inner surface of the flange, the insertion portion comprising an outer surface, wherein prior to inserting the stopper into the opening of the pharmaceutical container, in a non-sealed state, an outer diameter of a portion of the insertion portion is greater than a diameter of a corresponding portion of the opening by an amount equal to or greater than 3% and less than or equal to 15%.

[0084] Clause 22. The method of Clause 21, further comprising: crimping a metal-containing cap over the stopper and against the flange to compress the stopper against the upper surface, wherein: the metal-containing cap comprises an upper portion and a side portion; the upper portion of the metal-containing cap abuts an upper surface of the upper portion; the side portion of the metal-containing cap defines an inner diameter of the metal- containing cap; and the inner diameter of the metal-containing cap is greater than an outer diameter of the upper portion of the stopper such that a gap is disposed between an outer surface of the upper portion of the stopper and the side portion of the metal-containing cap.

[0085] Clause 23. The method of Clause 22, wherein, upon application of a compression force equal to or greater than 5 pounds force (lbf) and less than or equal to 15 lbf, the metal- containing cap remains spaced apart from the outer surface of the upper portion of the stopper.

[0086] Clause 24. The method of Clause 22 or Clause 23, wherein the inner diameter of the side portion of the metal-containing cap is greater than the outer diameter of the upper portion of the stopper by an amount equal to or greater than 1% and less than or equal to 20%.

[0087] Clause 25. The method of clause 24, wherein the inner diameter of the side portion of the metal-containing cap is greater than the outer diameter of the upper portion of the stopper by an amount equal to or greater than 3% and less than or equal to 10%.

[0088] Clause 26. The method of any one of clauses 22-25, wherein: the inner surface of the flange extending from the upper surface of the flange is planar and extends parallel to a central axis of the pharmaceutical container; the insertion portion of the stopper extends from a lower surface of the upper portion in a direction away from the upper surface of the upper portion; and the outer surface of the insertion portion includes an upper outer surface portion that, when in the sealed state, extends parallel to and abuts the inner surface of the flange.

[0089] Clause 27. The method of clause 26, wherein the inner surface of the flange extends substantially perpendicularly from the upper surface of the flange.

[0090] Clause 28. The method of clause 26 or clause 27, wherein the insertion portion includes a plurality of fins formed on the outer surface of the insertion portion that, when in the sealed state, abut the inner surface of the flange.

[0091] Clause 29. The method of clause 28, wherein the plurality of fins encircle the outer surface of the insertion portion.

[0092] Clause 30. The method of clause 28 or clause 29, wherein the plurality of fins are equally spaced apart from one another.

[0093] Clause 31. The method of clause 28 or clause 29, wherein a distance between each fin of the plurality of fins is not equal.

[0094] Clause 32. The method of any one of clauses 28-31, wherein the plurality of fins includes three fins.

[0095] Clause 33. The method of any one of clauses 21-32, wherein, in the sealed state, the pharmaceutical container assembly has a container closure integrity pass rate of at least 60% according to USP <1207>.

[0096] 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 came within the scope of the appended claims and their equivalents.

Claims

1. A drug container assembly, comprising: Drug containers, comprising: Shoulders; The neck, which extends from the shoulder; and A flange extending from the neck, the flange comprising: The lower surface, which extends from the neck; The outer surface, which extends from the lower surface; An upper surface, opposite the lower surface, extending between the outer surface and the inner surface defining an opening in the drug container; and Sealing assembly, comprising: A stopper comprising an upper portion and an insertion portion, the upper portion including an upper surface and the insertion portion including an outer surface, wherein: The insertion portion extends from the upper portion; In the sealed state, the insertion portion is inserted into the opening to define a seal between the insertion portion and the inner surface of the flange; In the sealed state, the upper portion extends above the upper surface of the flange and covers the opening; and In the unsealed state where the insertion portion is not inserted into the opening, the outer diameter of a portion of the insertion portion is larger than the diameter of the corresponding portion of the opening by an amount equal to or greater than 3% and less than or equal to 15%.

2. The drug container assembly according to claim 1, further comprising: Includes a metal cap that engages with the stopper and, when in the sealed state, secures the stopper to the flange, wherein: The metal-containing cap includes an upper portion and a side portion; The upper portion of the metal cap abuts against the upper surface of the upper portion of the plug; The side portion of the metal-containing cap defines the inner diameter of the metal-containing cap; and The inner diameter of the metal cap is larger than the outer diameter of the upper portion of the plug, such that a gap is provided between the outer surface of the upper portion and the side portion of the metal cap.

3. The drug container assembly according to claim 2, wherein, After a compressive force equal to or greater than 5 pounds (lbf) and less than or equal to 15 lbf is applied, the side portion of the metal cap remains spaced apart from the outer surface of the upper portion of the plug.

4. The drug container assembly of claim 2, wherein the inner diameter of the side portion containing the metal cap is larger than the outer diameter of the upper portion of the stopper by an amount equal to or greater than 1% and less than or equal to 20%.

5. The drug container assembly of claim 4, wherein the inner diameter of the side portion containing the metal cap is larger than the outer diameter of the upper portion of the stopper by an amount equal to or greater than 3% and less than or equal to 10%.

6. The drug container assembly according to claim 1, wherein: The upper portion of the plug includes a lower surface opposite to the upper surface of the upper portion, and an outer surface extending between the upper surface and the lower surface; and The insertion portion extends from the lower surface of the upper portion in a direction away from the upper surface of the upper portion.

7. The drug container assembly of claim 6, wherein a cut is formed in the lower surface of the insertion portion and extends in a direction toward the lower surface of the upper portion.

8. The drug container assembly of claim 6, wherein a groove is formed at the upper end of the insertion portion.

9. The drug container assembly of claim 8, wherein the outer diameter of the insertion portion at the lower end of the groove is greater than the outer diameter of the insertion portion at the lower end of the insertion portion.

10. The drug container assembly of claim 9, wherein the outer surface of the insertion portion includes a lower outer surface portion that tapers toward the lower end of the insertion portion near the groove.

11. The drug container assembly of claim 8, wherein the groove surrounds the insertion portion.

12. The drug container assembly of claim 7, wherein the cut is concave.

13. The drug container assembly according to claim 1, wherein: The upper portion includes a lower surface opposite to the upper surface of the upper portion; The insertion portion extends from the lower surface of the upper portion in a direction away from the upper surface of the upper portion; and Multiple ribs are formed on the outer surface of the insertion portion.

14. The drug container assembly of claim 13, wherein the plurality of ribs are spaced equidistant from each other.

15. The drug container assembly of claim 13, wherein the plurality of ribs comprises three ribs.

16. The drug container assembly according to claim 1, wherein: The inner surface of the flange, extending from the upper surface of the flange, is planar and extends parallel to the central axis of the drug container; and The outer surface of the insertion portion includes an upper outer surface portion, which, when in the sealed state, extends parallel to the inner surface of the flange and abuts against the inner surface of the flange.

17. The drug container assembly of claim 16, wherein the inner surface of the flange extends substantially perpendicularly from the upper surface of the flange.

18. The drug container assembly of claim 17, wherein the upper outer surface portion of the insertion portion extends from the lower surface of the upper portion to the lower outer surface portion of the insertion portion, which tapers from the upper outer surface portion.

19. The drug container assembly of claim 18, wherein the outer diameter of the insertion portion at the upper end of the lower outer surface portion of the insertion portion is greater than the outer diameter of the insertion portion at the lower end of the insertion portion.

20. The drug container assembly of claim 1, wherein in the sealed state, according to USP <1207> The drug container assembly has a container closure integrity pass rate of at least 60%.

21. A method for sealing a drug container, the method comprising: A pharmaceutical composition is inserted into the pharmaceutical container, the pharmaceutical container including a shoulder, a neck extending from the shoulder, and a flange extending from the neck, the flange including: The lower surface, which extends from the neck; The outer surface, which extends from the lower surface; and An upper surface, opposite the lower surface, extending between the outer surface and the inner surface defining an opening in the drug container; and A stopper is inserted through the opening in the drug container to form a drug container assembly. The stopper includes an upper portion and an insertion portion extending from the upper portion. When sealed, the upper portion extends above the upper surface of the flange and covers the opening. The insertion portion extends within the opening to define a seal between the insertion portion and the inner surface of the flange. The insertion portion includes an outer surface. Before the stopper is inserted into the opening of the drug container, in the unsealed state, the outer diameter of a portion of the insertion portion is larger than the diameter of the corresponding portion of the opening by an amount equal to or greater than 3% and less than or equal to 15%.

22. The method of claim 21, further comprising: The metal cap is pressed onto the stopper and against the flange to compress the stopper against the upper surface, wherein: The metal-containing cap includes an upper portion and a side portion; The upper portion containing the metal cap abuts against the upper surface of the upper portion; The side portion of the metal-containing cap defines the inner diameter of the metal-containing cap; and The inner diameter of the metal cap is larger than the outer diameter of the upper portion of the plug, such that a gap is formed between the outer surface of the upper portion of the plug and the side portion of the metal cap.

23. The method according to claim 22, wherein, After a compressive force equal to or greater than 5 pounds (lbf) and less than or equal to 15 lbf is applied, the metal cap remains spaced apart from the outer surface of the upper portion of the plug.

24. The method of claim 22, wherein the inner diameter of the side portion containing the metal cap is larger than the outer diameter of the upper portion of the plug by an amount equal to or greater than 1% and less than or equal to 20%.

25. The method of claim 24, wherein the inner diameter of the side portion containing the metal cap is larger than the outer diameter of the upper portion of the plug by an amount equal to or greater than 3% and less than or equal to 10%.

26. The method according to claim 22, wherein: The inner surface of the flange, extending from the upper surface of the flange, is planar and extends parallel to the central axis of the drug container; The insertion portion of the plug extends from the lower surface of the upper portion in a direction away from the upper surface of the upper portion; and The outer surface of the insertion portion includes an upper outer surface portion that, when in a sealed state, extends parallel to and engages with the inner surface of the flange.

27. The method of claim 26, wherein the inner surface of the flange extends substantially perpendicularly from the upper surface of the flange.

28. The method of claim 26, wherein the insertion portion includes a plurality of ribs formed on the outer surface of the insertion portion, the plurality of ribs abutting the inner surface of the flange when in the sealed state.

29. The method of claim 28, wherein the plurality of ribs surround the outer surface of the insertion portion.

30. The method of claim 28, wherein the plurality of ribs are spaced equidistant from each other.

31. The method of claim 28, wherein the distance between each of the plurality of ribs is not equal.

32. The method of claim 28, wherein the plurality of ribs comprises three ribs.

33. The method of claim 21, wherein in the sealed state, according to USP <1207> The drug container assembly has a container closure integrity pass rate of at least 60%.

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