Pharmaceutical container assembly including seal assembly for low-temperature storage

Abstract

A pharmaceutical container assembly includes a pharmaceutical container and a seal assembly. In the sealed state, the insert portion of the seal assembly is inserted into the opening of the pharmaceutical container to define the seal. In the sealed state, the top of the seal assembly extends over the upper surface of the flange of the pharmaceutical container and covers the opening. In the unsealed state, when the insert portion is not inserted into the opening, the outer diameter of a portion of the insert portion is greater than 3% and less than 15% than the diameter of the corresponding portion of the opening.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under Section 119 of U.S. Patent Act to U.S. Provisional Application No. 63 / 504,835, filed on 30 May 2023, the contents of which this Provisional Application is relied upon and incorporated herein by reference in its entirety.

[0002] This specification generally relates to containers, such as glass containers, for storing pharmaceutical compositions, and more specifically to pharmaceutical container assemblies, which include a seal assembly that works with the glass container to maintain the integrity of the container closure at relatively low storage temperatures. [Background technology]

[0003] Pharmaceutical containers, such as vials, are typically sealed via stoppers or other closures to maintain the integrity of the contained material. Closures are typically made of synthetic rubber and other elastomers. Such materials beneficially possess moderate and / or high leak resistance and elasticity to facilitate insertion into the container for sealing the interior. However, the elasticity of commonly used closure materials can decrease at low temperatures. For example, synthetic rubber currently used as material closures may have a transition temperature between -70°C and -10°C. Below this transition temperature, closures made of such synthetic rubber may behave as solids and may be unable to expand elastically to compensate for the relatively large difference between the thermal expansion coefficient of glass and that of the pressure-fit cap used to secure the closure to the container. Considering this, existing seal assemblies for pharmaceutical containers may fail at temperatures below -20°C.

[0004] Some biomaterials (e.g., blood, serum, proteins, stem cells, and other perishable biological fluids) require storage at temperatures below the glass transition temperature of conventional elastomers to remain useful. For example, certain RNA-based vaccines may require storage at dry ice temperatures (e.g., around -80°C) or liquid nitrogen temperatures (e.g., around -180°C) to maintain their activity. Such low temperatures can cause dimensional changes in closure components (e.g., glass or plastic containers, stoppers, aluminum caps), leading to issues with seal integrity and potential contamination of the materials stored in the closure components. [Overview of the Initiative]

[0005] In one embodiment, a pharmaceutical container assembly includes a pharmaceutical container and a seal assembly. The pharmaceutical container includes a shoulder portion, a neck portion extending from the shoulder portion, and a flange extending from the neck portion. The flange includes a back surface extending from the neck portion, an outer surface extending from the back surface, and an upper surface opposite to the back surface, the upper surface extending between the outer surface and an inner surface defining an opening in the pharmaceutical container, and a seal assembly. The seal assembly includes a stopper including an upper portion and an insertion portion, the upper portion having an upper surface, and the insertion portion having an outer surface. The insertion portion extends from the upper portion. When sealed, the insertion portion is inserted into the opening so as to define a seal between the insertion portion and the inner surface of the flange. When sealed, the upper portion extends over the upper surface of the flange and covers the opening. When the insertion portion is not inserted into the opening and is not sealed, the outer diameter of a portion of the insertion portion is 3% or more and 15% or less larger than the diameter of the corresponding portion of the opening.

[0006] In another embodiment, a method for sealing a pharmaceutical container includes inserting a pharmaceutical composition into the pharmaceutical container. The pharmaceutical container includes a shoulder, a neck extending from the shoulder, and a flange extending from the neck. The flange includes a back surface extending from the neck, an outer surface extending from the back surface, and an upper surface opposite to the back surface. The upper surface extends between the outer surface and an inner surface defining an opening in the pharmaceutical container. The method further includes inserting a stopper through the opening in the pharmaceutical container to form a pharmaceutical container assembly. The stopper includes an upper portion and an insertion portion extending from the upper portion. When sealed, the upper portion extends over the upper surface of the flange and covers the opening. The insertion portion extends into the opening and defines a seal between the insertion portion and the inner surface of the flange. The insertion portion includes an outer surface. Before inserting the stopper into the opening of the pharmaceutical container while it is not sealed, the outer diameter of a portion of the insertion part is 3% or more and 15% or less larger than the diameter of the corresponding portion of the opening.

[0007] These and additional features provided by the embodiments described herein will be better understood in conjunction with the drawings, taking into consideration the following detailed description.

[0008] The embodiments shown in the drawings are illustrative in nature and are not intended to limit the subject matter defined by the claims. The following detailed description of the exemplary embodiments can be understood in conjunction with the following drawings, and similar structures are indicated by similar reference numerals. [Brief explanation of the drawing]

[0009] [Figure 1] A schematic cross-sectional view of an unsealed pharmaceutical container assembly according to one or more embodiments shown and described herein is provided. [Figure 2] A schematic partial cross-sectional view of a sealed pharmaceutical container capped with a low residual seal force, according to one or more embodiments shown and described herein, is provided. [Figure 3] A schematic partial cross-sectional view of a sealed pharmaceutical container capped with maximum residual sealing force, according to one or more embodiments shown and described herein, is shown. [Figure 4] A schematic cross-sectional view of another capped pharmaceutical container assembly according to one or more embodiments shown and described herein is provided. [Figure 5] A schematic diagram of an enlarged cross-sectional view of the pharmaceutical container assembly of Figure 4, taken from frame 5 of Figure 4, according to one or more embodiments shown and described herein. [Figure 6] A schematic cross-sectional view of another sealed pharmaceutical container assembly according to one or more embodiments shown and described herein is provided. [Figure 7] A schematic diagram of an enlarged cross-sectional view of the pharmaceutical container assembly of Figure 6, taken from frame 7 of Figure 6, according to one or more embodiments shown and described herein. [Figure 8] A graph illustrating the relationship between the interference fit and the required stopper insertion force, according to one or more embodiments shown and described herein, is provided. [Figure 9] A graph illustrating the relationship between interference fit and oxygen concentration according to one or more embodiments shown and described herein is provided. [Modes for carrying out the invention]

[0010] Herein, we refer in detail to embodiments of pharmaceutical container assemblies that include a seal assembly that maintains container closure integrity at relatively low storage temperatures (e.g., below -80°C, below -100°C, below -125°C, below -150°C, below -175°C, below -180°C). In embodiments, the structures of pharmaceutical container assemblies described herein may differ in one or more respects from existing pharmaceutical container assembly structures in order to facilitate the maintenance of a seal at the interface between the pharmaceutical container and the seal assembly inserted into the pharmaceutical container. For example, an embodiment of a pharmaceutical container described herein may be a vial including a shoulder, a neck, and a flange including an upper surface against which a stopper of the seal assembly is pressed by the cap (but other container shapes are within the scope of this disclosure). Various properties of the pharmaceutical container and seal assembly cooperating to define the sealing surface may be adapted to facilitate the maintenance of a seal when the pharmaceutical container assembly is cooled to such low storage temperatures. For example, in the embodiment, when the seal assembly is not inserted into the pharmaceutical container and is not sealed, the outer diameter of a portion of the insertion part of the seal assembly is 3% to 15% larger than the diameter of the corresponding portion of the pharmaceutical container. In the embodiment, various other features of the seal assembly (e.g., the outer diameter of the upper part of the stopper, the geometric shape of the outer surface of the insertion part, etc.) may be adjusted to increase the seal integrity.

[0011] As used herein, the term “container seal integrity” refers to the maintenance of a seal at the interface between the pharmaceutical container and the seal assembly (e.g., between the inner surface of the flange of the pharmaceutical container and the outer surface of the stopper insertion portion) without gaps exceeding a threshold size, in order to maintain the probability of contaminant ingress or reduce the possibility of gas permeability below a predetermined threshold, based on the material stored in the pharmaceutical container. For example, in embodiments, USP <1207> (2016), in particular, the helium leak rate during the helium leak test described in (<1207.1>, <1207.2>, and <1207.3> is 1.4 × 10⁻⁶ -6 cm 3 If maintained at or below / s, container closure integrity is maintained.

[0012] In embodiments of the pharmaceutical containers described herein, the concentrations of the components (e.g., SiO2, Al2O3, B2O3, etc.) of the glass composition from which the pharmaceutical containers are formed are specified in mole percent (mol%) on an oxide basis, unless otherwise specified.

[0013] When used to describe the concentration and / or absence of a particular component in a glass composition, the term "substantially free of" means that the component is not intentionally added to the glass composition. However, the glass composition may contain trace amounts of a component in an amount less than 0.05 mol% as a contaminant or tramp.

[0014] As used herein, the term "CTE" refers to the coefficient of thermal expansion over a temperature range of about -200 °C to about 300 °C, unless otherwise specified.

[0015] As used herein, the term "about" means that the quantity, size, formulation, parameter, and other quantities and characteristics are not and need not be exact, and reflect allowable errors, conversion factors, rounding, measurement errors, and other factors known to those of skill in the art, and may be approximate and / or larger or smaller as desired. When the term "about" is used in describing a value or endpoint of a range, the specific value or endpoint being referred to is included. Whether or not the numerical values or endpoints of a range in this specification are recited with "about", two embodiments are described, one modified by "about" and one not modified by "about". It will be further understood that each endpoint of a range is significant, whether related to or independent of the other endpoint.

[0016] Directional terms used herein (e.g., up, down, right, left, front, back, top, bottom, above, below) are for reference only as drawn in the figures and are not intended to imply absolute orientation.

[0017] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a" component includes aspects having two or more such components unless the context clearly indicates otherwise.

[0018] Referring now to FIGS. 1 - 3, one embodiment of a pharmaceutical container assembly 100 for storing a pharmaceutical formulation is schematically depicted in cross - section. The pharmaceutical container assembly 100 includes a pharmaceutical container 102 and a seal assembly 104. The pharmaceutical container assembly 100 is depicted unsealed in FIG. 1 where the seal assembly 104 is not inserted into the pharmaceutical container 102, and is partially depicted sealed in FIGS. 2 and 3 where the seal assembly 104 is inserted into the pharmaceutical container 102. More specifically, as will be discussed in more detail herein, the pharmaceutical container assembly 100 is depicted sealed in FIG. 2 and capped with a low residual seal force (RSF), e.g., 2 pounds force (lbf) or more and 10 lbf or less, more specifically 5 lbf, and in FIG. 3 is depicted sealed and capped with a maximum RSF, e.g., 10 lbf or more and 20 lbf or less, more specifically 15 lbf.

[0019] Referring again to FIG. 1, the pharmaceutical container 102 generally includes a body 112. The body 112 has a wall thickness T that extends between an inner surface 114 and an outer surface 116 of the pharmaceutical container 102, includes a central axis A, and generally surrounds an internal volume 118. The wall thickness T of the pharmaceutical container 102 can vary depending on the implementation. In an embodiment, the wall thickness T of the pharmaceutical container 102 can be 6 millimeters (mm) or less, e.g., 4 mm or less, 2 mm or less, 1.5 mm or less, or 1 mm or less. In some embodiments, the wall thickness T W has, includes a central axis A, and generally surrounds an internal volume 118. The wall thickness T of the pharmaceutical container 102 W can vary depending on the implementation. In an embodiment, the wall thickness T of the pharmaceutical container 102 W is from 6 millimeters (mm) or less, e.g., 4 mm or less, 2 mm or less, 1.5 mm or less, or 1 mm or less. In some embodiments, the wall thickness T wThis can be 0.1 mm or more and 6 mm or less, 0.3 mm or more and 4 mm or less, 0.5 mm or more and 4 mm or less, 0.5 mm or more and 2 mm or less, or 0.5 mm or more and 1.5 mm or less. In the embodiment, the wall thickness T W It can be 0.9 mm or more and 1.8 mm or less. Wall thickness T W This can change depending on the axial position within the pharmaceutical container 102.

[0020] In the embodiment of the pharmaceutical container 102 shown in Figure 1, the body 112 generally includes a wall portion 120 and a base portion 122. The wall portion 120 transitions to the base portion 122 through a heel portion 124. In the depicted embodiment, the wall portion 120 of the pharmaceutical container 102 defines a flange 126, a neck portion 128 extending from the flange 126, a barrel 115, and a shoulder portion 130 extending between the neck portion 128 and the barrel 115. The base portion 122 is connected to the barrel 115 via the heel portion 124. In the embodiment, the pharmaceutical container 102 is symmetrical about a central axis A, and each of the barrel 115, neck portion 128, and flange 126 is substantially cylindrical in shape.

[0021] As shown in Figure 1, the flange 126 comprises a back surface 132, an outer surface 134 extending from the back surface 132, and an upper surface 136 opposite to the back surface 132. The inner surface 114 of the body 112 extends along the barrel 115, the flange 126, and the neck portion 128, respectively, defining an opening 105 on the upper surface 136 of the flange 126.

[0022] More specifically, in the embodiments of the pharmaceutical container 102 depicted in Figures 1 to 3, the rim 138 is formed on the inner surface 114 of the body 112 at the flange 126. As shown in Figure 1, the rim 138 is depicted on both sides of the inner surface 114 of the body 112 at the flange 126. It should be understood that the rim 138 may be formed to extend along the entire circumference of the inner surface 114 of the body 112, or in other embodiments, to form a plurality of individual rim portions that are spaced apart from each other and formed at intervals along the circumference of the inner surface 114 of the body 112. The rim 138 prevents blowback of the seal assembly 104 during insertion of the pharmaceutical container 102 into the opening 105. The inner surface 114 of the body 112 extending from the rim 138 along the flange 126 and neck 128 extends parallel to the central axis A. The inner surface 114 of the body 112 directly below the rim 138 defines a flange seal position 140 having an inner diameter D1. As described in more detail herein, the seal assembly 104 contacts the flange seal position 140 when inserted into the pharmaceutical container 102, defining a seal between the seal assembly 104 and the pharmaceutical container 102. However, in embodiments where the rim 138 is not provided, it should be understood that the flange seal position 140 may be located at any point on the inner surface 114 of the body 112 along the flange 126 or neck 128 that contacts the seal assembly 104 when sealed.

[0023] In this embodiment, the pharmaceutical container 102 is a USP <660> It may be formed from Type I, Type II, or Type III glass as defined in the USP <660> This includes borosilicate glass compositions such as a type 1B borosilicate glass composition. Alternatively, the pharmaceutical container 102 may be formed from an alkaline aluminosilicate glass composition, such as that disclosed in U.S. Patent No. 8,551,898, which is incorporated herein by reference in its entirety, or from an alkaline earth aluminosilicate glass, such as that described in U.S. Patent No. 9,145,329, which is incorporated herein by reference in its entirety. In embodiments, the pharmaceutical container 102 may be composed of a soda-lime glass composition. In embodiments, the pharmaceutical container 102 may be 0 × 10-7 above / K and 100×10 -7 below / K (for example, 30×10 -7 above / K and 70×10 -7 below / K), and is composed of a composition having a coefficient of thermal expansion.

[0024] The pharmaceutical container 102 is depicted in FIG. 1 as having a specific form factor (i.e., a vial), but as will be discussed in more detail herein, the pharmaceutical container 102 can have other form factors including, but not limited to, Vacutainers®, cartridges, syringes, ampoules, bottles, flasks, vials, tubes, beakers, etc. Further, it should be understood that the pharmaceutical containers described herein can be used for a variety of applications including, but not limited to, pharmaceutical packages, beverage containers, etc.

[0025] Although referred to herein as the pharmaceutical container 102, it should be understood that the pharmaceutical container 102 can be formed of materials other than glass such as, for example, polymers, metals, ceramics, etc. Further, the coefficient of thermal expansion of these materials can be from 0×10 -7 above / K and 8,000×10 -7 below / K.

[0026] 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 an embodiment, the stopper 106 is composed of a polymer-based material (e.g., butyl synthetic rubber 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.

[0027] The insertion portion 144 extends from the upper portion 142 in the direction opposite to the upper surface 146 of the upper portion 142. The insertion portion 144 comprises an upper end 152 of 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 in which the pharmaceutical container 102 includes a rim 138, a groove 162 may be formed in the upper outer surface portion 158 of the insertion portion 144 at the upper end 152 of the insertion portion 144, as described herein. In one embodiment, the grooves 162 may form a plurality of individual groove portions that are spaced apart from each other and spaced apart along the circumference of the upper outer surface portion 158 of the insertion portion 144. In another embodiment, the grooves 162 surround the entire circumference of the insertion portion 144.

[0028] In the embodiment, the insertion portion 144 includes a projection 164 formed on the upper outer surface portion 158 of the insertion portion 144 at a position where the upper outer surface portion 158 faces the lower outer surface portion 160. In embodiments where a groove 162 is provided, the projection 164 may be formed directly below the groove 162 on the opposite side of the upper portion 142 of the stopper 106. However, it should be understood that the projection 164 may be provided at any position on the outer surface 156 of the insertion portion 144, such as on the lower outer surface portion 160. The projection 164 defines the insertion seal position 166 and has an outer diameter D3. The outer diameter D3 of the insertion seal position is greater than the outer diameter of the insertion portion at any other point along the outer surface of the insertion portion.

[0029] As shown in Figure 1, when the insertion portion 144 is not inserted into the opening 105 of the pharmaceutical container 102 and is not sealed, the outer diameter D3 of the insertion portion 144 defined by the protrusion 164 at the insertion seal position 166 is 3% or more and 15% or less larger than the inner diameter D1 of the inner surface 114 of the main body 112 at the flange seal position 140. In the embodiment, the outer diameter D3 of the insertion portion 119 defined by the protrusion 164 at the insertion seal position 166 is 5.8% or more and 13.5% or less larger than the inner diameter D1 of the inner surface 114 of the main body 112 at the flange seal position 140. In the embodiment, the outer diameter D3 of the insertion portion 144 defined by the protrusion 164 at the insertion seal position 166 is 7% or more and 13% or less larger than the inner diameter D1 of the inner surface 114 of the main body 112 at the flange seal position 140. In this embodiment, the outer diameter D3 of the insertion portion 144 defined by the projection 164 at the insertion seal position 166 is 9% or more and 11% or less larger than the inner diameter D1 of the inner surface 114 of the body 112 at the flange seal position 140. The percentage difference between the outer diameter D3 of the insertion portion 144 defined by the projection 164 at the insertion seal position 166 and the inner diameter D1 of the inner surface 114 of the body 112 at the flange seal position 140 may be referred to herein as an interference fit. Therefore, the larger the percentage difference between the outer diameter D3 of the insertion portion 144 and the inner diameter D1 of the inner surface 114 of the body 112, the greater the interference fit. Thus, an interference fit refers to the compressive force on the insertion portion 144 of the stopper 106 caused by the pharmaceutical container 102 when the insertion portion 144 of the stopper 106 is inserted into the opening 105 of the pharmaceutical container 102.

[0030] In the embodiment, the lower outer surface portion 160 of the insertion portion 144 tapers from the upper outer surface portion 158 toward the lower end portion 154 of the insertion portion 144. In the embodiment in which the groove 162 and / or projection 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 may also taper from the upper end portion 152 toward the lower outer surface portion 160, and the lower outer surface portion 160 may continue to taper toward the lower end portion 154 of the insertion portion 144.

[0031] The insertion portion 144 has a lower surface 168 at its lower end 154. In this embodiment, a notch 170 is formed in the lower surface 168 and extends toward the lower surface 148 of the upper portion 142. The notch 170 may have any preferred shape, such as a concave shape. However, it should be understood that the notch 170 may have any other preferred shape, such as a tubular or rectangular shape.

[0032] Referring again to Figure 1, the metal-containing cap 108 of the seal assembly 104 comprises 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, when the seal assembly 104 is separated from the pharmaceutical container 102, the inner diameter D4 of the side portion 174 of the metal-containing cap 108 is larger than the outer diameter D2 of the upper portion 142 of the stopper 106, and as a result, a gap 176 is defined between the side portion 174 and the upper portion 142. As referred to herein, the gap 176 means that 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. As described in more detail herein, the side portion 174 of the metal-containing cap 108, in particular the lower end portion 178 of the side portion 174, is deformable by engaging with the back surface 132 of the flange 126, i.e., by pressing it against the seal assembly 104 to seal the pharmaceutical container 102.

[0033] In the embodiment, in order to maintain the seal, the metal-containing cap 108 and stopper 106 may be configured such that the contraction of the metal-containing cap 108 is greater than the combined contraction of the pharmaceutical container 102 and stopper 106. To facilitate satisfying such a relationship, in the embodiment, the metal-containing cap 108 is approximately 240 × 10 -7 It is made of aluminum which may have a CTE of / K. In other embodiments, the metal-containing cap is made of a metal alloy containing at least one of Zn, Mg, and Cu. A typical rubber (e.g., butyl 325, butyl 035, etc.) on which the stopper 106 is made is 1,400 × 10 -7It may have a CTE of 1 / K or higher. That is, purely from the standpoint of CTE difference, the metal-containing cap 108 tends not to shrink as much as the stopper 106, resulting in a decrease in sealing force at lower storage temperatures. In addition to the CTE mismatch described above, the stopper 106 may constitute a larger volume percentage of the seal assembly 104 than the metal-containing cap 108, further compounding the tendency for the stopper 106 to undergo greater thermal shrinkage.

[0034] Referring to Figure 2, the pharmaceutical container assembly 100 is depicted in a sealed and capped state. Specifically, the seal assembly 104 is coupled to the pharmaceutical container 102 at its opening 105. When sealed, the insertion portion 144 is inserted into the opening 105 of the pharmaceutical container 102 until its upper portion 142 contacts the upper surface 136 of the flange 126 of the pharmaceutical container 102. When sealed, the lower surface 148 of the upper portion 142 of the stopper 106 abuts against the upper surface 136 of the flange 126 of the pharmaceutical container 102. In addition, the edge 138 formed on the inner surface 114 of the pharmaceutical container 102 is received in a groove 162 formed on the upper outer surface portion 158 of the insertion portion 144. Thus, when sealed, the flange seal position 140 and the insertion seal position 166 are aligned along the X-axis of the coordinate axes depicted in the figure, abutting against each other to define a seal. The inner surface 114 of the pharmaceutical container 102 compresses the insertion portion 144 of the stopper 106 at the flange seal position 140 and the insertion seal position 166, according to a specific tight fit.

[0035] Subsequently, the upper portion 142 is pressed against the upper surface 136 of the flange 126 via the pressure contact of the metal-containing cap 108, tightening the seal assembly 104 against the pharmaceutical container 102. During pressure contact, a compressive force is applied to the metal-containing cap 108, and the pharmaceutical container 102 is capped by deforming the side portion 174 of the metal-containing cap 108 around the back surface 132 of the flange 126 via any preferred pressure contact method (e.g., a pneumatic pressure contact device). Upon pressure contact, the side portion 174 of the metal-containing cap 108 defines the lower portion 180 at the lower end 178 of the side portion 174 that contacts the back surface 132 of the flange 126, keeping the stopper 106 compressed.

[0036] The compression of the stopper 106 generates an RSF within the flange 126 that maintains the compression against the stopper 106 after the metal-containing cap 108 has been pressed into place. Various embodiments of the pharmaceutical container 102 and seal assembly 104 are designed to ensure the maintenance of container closure integrity of the pharmaceutical container 102 at low storage temperatures below -80°C, as described herein.

[0037] As shown in Figure 2, the pharmaceutical container assembly 100 is depicted in a sealed state and capped with a low RSF, such as 5 lbf. However, as shown in Figure 2, 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. Therefore, the outer surface 150 of the upper portion 142 of the stopper 106 does not contact the side portion 174 of the metal-containing cap 108.

[0038] Similarly, as shown in Figure 3, the pharmaceutical container assembly 100 is depicted in a sealed state and capped with a maximum RSF, such as 15 lbf. However, as shown in Figure 3, 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 despite the compression of the stopper 106. Therefore, the outer surface 150 of the upper portion 142 of the stopper 106 does not contact the side portion 174 of the metal-containing cap 108. It should be understood that if the gap 176 were not provided between the upper portion 142 of the stopper 106 and the side portion 174 of the metal-containing cap 108, a failure mode could occur in which the seal formed between the seal assembly 104 and the pharmaceutical container 102 would be compromised.

[0039] When the sealed and capped pharmaceutical container assembly 100 is cooled to a relatively low storage temperature below -80°C (e.g., below -80°C, below -100°C, below -125°C, below -150°C, below -175°C, below -180°C), each component of the pharmaceutical container assembly 100 may undergo volume contraction depending on the thermal properties of that component. If the combination of stoppers 106 contracts by a greater amount than the amount of contraction of the flange 126, the compression on the stoppers 106 provided by the flange 126 is reduced, and the probability of the seals formed at the flange seal position 140 and the insertion seal position 166 being broken may increase. However, the increased interference fit, i.e., the outer diameter D3 of the insertion portion 144 being larger than the inner diameter D1 of the flange 126 when it is unsealed (Figure 1), allows for greater contraction while reducing the likelihood of seal failure.

[0040] Although not illustrated herein, it should be understood that alternatives to the pharmaceutical container assembly 100 described herein with respect to Figures 1-3 may be used while still maintaining container closure integrity at storage temperatures below -80°C. For example, another embodiment of the pharmaceutical container assembly 200 is depicted in Figures 4 and 5. It should be understood that the pharmaceutical container assembly 200 is similar to the pharmaceutical container assembly 100; therefore, the same reference numerals are used to refer to similar parts.

[0041] As shown in Figures 4 and 5, the pharmaceutical container assembly 200 comprises a pharmaceutical container 202 and a seal assembly 204. Similar to the pharmaceutical container 102 depicted in Figures 1 to 3, the pharmaceutical container 202 comprises a body 212 including a flange 226 and a neck 128 having an inner surface 214 extending along the body 212. However, the pharmaceutical container 202 does not include a rim 138 formed on the inner surface 214 of the pharmaceutical container 202 at the flange 226, as shown in the pharmaceutical container 102 depicted in Figures 1 to 3. Instead, the inner surface 214 of the pharmaceutical container 202 along the flange 226 and the neck 128 extends parallel to the central axis A from the upper surface 236 of the flange 226. Therefore, as more specifically shown in Figure 5, no rim is formed at the junction between the upper surface 236 of the flange 226 and the inner surface 214 of the pharmaceutical container 202 at the flange 226. Therefore, the inner diameter D5 of the flange 226 defining the opening 105 is consistent, i.e., does not change, along the flange 226 and neck 128 of the pharmaceutical 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, and this angle is 3 degrees or less relative to the upper surface 236 of the flange 226. The inner surface 214 of the pharmaceutical container 202 in the flange 226 defines the flange seal position 240.

[0042] The seal assembly 204 comprises a stopper 206 including an upper portion 142 and an insertion portion 244 extending from the upper portion 142. As shown in Figure 5, similar to the insertion portion 144 of the stopper 106 depicted in Figures 1 to 3, the insertion portion 244 comprises an outer surface 256 including an upper outer surface portion 258 and a lower outer surface portion 260 extending from the upper outer surface portion 258 in the direction opposite to the upper portion 142 of the stopper 106. However, instead of the upper outer surface portion 258 including grooves 162 and projections 164 as provided in the insertion portion 144 of the stopper 106 depicted in Figures 1 to 3, the upper outer surface portion 258 is planar such that the upper outer surface portion 258 extends parallel to the central axis A of the pharmaceutical container 202. Therefore, the outer diameter D6 of the insertion portion 244 is consistent, i.e., does not change, along the upper outer surface portion 258. The upper outer surface portion 258 of the insertion portion 244 defines the insertion seal position 266.

[0043] Similar to the pharmaceutical container assembly 100 depicted in Figures 1 to 3, when the insertion portion 244 is not inserted into the opening 105 of the pharmaceutical container 202 and is not sealed, the outer diameter D6 of the insertion portion 244 at the insertion seal position 266 is 3% or more and 15% or less larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. In the embodiment, the outer diameter D6 of the insertion portion 244 at the insertion seal position 266 is 5.8% or more and 13.5% or less larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. In the embodiment, the outer diameter D6 of the insertion portion 244 at the insertion seal position 266 is 7% or more and 13% or less larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. In this embodiment, the outer diameter D6 of the insertion portion 244 at the insertion seal position 266 is 9% or more and 11% or less larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. Although the outer diameter D6 of the insertion portion 244 is depicted as being equal to the inner diameter D5 of the inner surface 214 in Figure 4, it should be understood that the outer diameter D6 is larger than the inner diameter D5 when the seal assembly 204 is not inserted into the opening 105 of the pharmaceutical container 202.

[0044] Therefore, as shown in Figure 5, when the insertion portion 244 of the stopper 206 is inserted into the opening 105 of the pharmaceutical container 202 and is in a sealed state, the upper outer surface portion 258 of the insertion portion 244 is compressed against the inner surface 214 of the pharmaceutical container 202 at the flange 226 and is coplane with the inner surface 214. Thus, the flange seal position 240 and the insertion seal position 266 abut against each other, defining the seal between the seal assembly 204 and the pharmaceutical container 202.

[0045] Referring to Figures 6 and 7, another embodiment of the pharmaceutical container assembly 300 is depicted. It should be understood that the pharmaceutical container assembly 300 is similar to pharmaceutical container assemblies 100 and 200. Therefore, the same reference numerals are used to refer to similar parts.

[0046] The pharmaceutical container assembly 300 comprises a pharmaceutical container 202 and a seal assembly 304. The seal assembly 304 comprises a stopper 306 including an upper portion 142 and an insertion portion 344 extending from the upper portion 142. As shown in Figure 7, similar to the insertion portion 244 of the stopper 206 depicted in Figures 4 and 5, the insertion portion 344 comprises an outer surface 356 including an upper outer surface portion 358 and a lower outer surface portion 360 extending from the upper outer surface portion 358 in the direction opposite to the upper portion 142 of the stopper 306. However, the insertion portion 344 includes one or more ribs 361 surrounding the upper outer surface portion 358 of the insertion portion 344, the ribs 361 defining an insertion seal position 366 having an outer diameter D7. The insertion portion 344 includes any preferred number of ribs 361, such as one, two, three, or more than three ribs 361. As shown in Figure 7, the insertion portion 344 includes three ribs 361 surrounding the insertion portion 344. In one embodiment, the ribs 361 are equally spaced apart vertically, extending along the upper outer surface portion 358. Each rib 361 extends the same distance from the upper outer surface portion 358. In another embodiment, the ribs 361 are spaced apart vertically at different intervals, such that the distance between each rib 261 is different. Each rib 361 extends the same distance from the upper outer surface portion 358. Thus, the ribs 361 define the insertion seal position 366.

[0047] Similar to the pharmaceutical container assemblies 100 and 200 depicted in Figures 1 to 5, when the insertion portion 344 is not inserted into the opening 105 of the pharmaceutical container 302 and is not sealed, the outer diameter D7 of the insertion portion 344 at the insertion seal position 366 is 3% or more and 15% or less larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. In the embodiment, the outer diameter D7 of the insertion portion 344 at the insertion seal position 366 is 5.8% or more and 13.5% or less larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. In the embodiment, the outer diameter D7 of the insertion portion 344 at the insertion seal position 366 is 7% or more and 13% or less larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. In this embodiment, the outer diameter D7 of the insertion portion 344 at the insertion seal position 366 is 9% to 11% larger than the inner diameter D5 of the inner surface 214 of the pharmaceutical container 202 at the flange seal position 240. 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 Figure 6, it should be understood that the outer diameter D7 is larger than the inner diameter D5 when the seal assembly 304 is not inserted into the opening 105 of the pharmaceutical container 202.

[0048] Therefore, as shown in Figure 7, when the insertion portion 344 of the stopper 306 is inserted into the opening 105 of the pharmaceutical container 202, the rib 361 extending from the upper outer surface portion 358 of the insertion portion 344 is compressed against the inner surface 214 of the pharmaceutical container 202 at the flange 226. Thus, the flange seal position 240 and the insertion seal position 366 abut against each other, defining the seal between the seal assembly 304 and the pharmaceutical container 202. It should be understood that the amount of friction between the stopper 306 of the seal assembly 304 and the pharmaceutical container 202 is reduced by the provision of the rib 361. However, the interference fit between the stopper 306 of the seal assembly 304 and the pharmaceutical container 202 is not affected.

[0049] Referring here to Figure 8, a chart illustrating the relationship between stopper insertion force and interference fit is shown. As referred to herein, stopper insertion force is the force required to insert a stopper into the opening of a pharmaceutical container in a particular interference fit. Thus, as shown in Figure 8, multiple measurements are taken at specific interference fits, e.g., about 3%, about 6%, about 10%, and about 14%. As shown, the stopper insertion force at about 3% is about 2 lbf, the stopper insertion force at about 6% is about 6 lbf, the stopper insertion force at about 10% is about 8 lbf, and the stopper insertion force at about 14% is about 16 lbf. In this case, a linear fitting line is fitted to the measured data points to show the required stopper insertion force for each interference fit. Therefore, it should be understood that as the tight fit increases, for example, the larger the outer diameter of the insertion portion of the stopper relative to the inner diameter of the opening of the pharmaceutical container, the greater the stopper insertion force required to insert the stopper into the opening of the pharmaceutical container.

[0050] As discussed herein, there is an optimal range for interference fit. For example, an interference fit of 3% or more and 15% or less is preferred. An interference fit of less than 3% may result in problems caused by the stopper contracting at a faster rate than the pharmaceutical container at relatively low temperatures. In addition, an interference fit of more than 15% may result in problems caused by the outer surface of the upper portion of the stopper enclosing the side portion of the metal-containing cap during capping.

[0051] Referring to Figure 9, a chart illustrating the relationship between oxygen concentration and tight fit is shown. Specifically, several samples, such as pharmaceutical container assemblies, were tested to determine the container closure integrity pass rates at various stages of sealing, before and after capping with metal-containing caps, and at various tight fits at -80°C. For example, as shown in Figure 9, uncapped samples with 5.5%, 10%, and 13.5% tight fits exhibited an oxygen concentration of approximately 0%. However, capped samples with 5.5%, 10%, and 13.5% tight fits exhibited an oxygen concentration of approximately 21%. Although not depicted in Figure 9, an uncapped sample with a 10% tight fit, i.e., a residual seal force of 0 lbf, was found to be USP <1207> It should be understood that this resulted in a 60% container closure integrity. However, capped samples with tight fit between 5.8% and 13.5% were found to be unrelated to residual sealing force, USP <1207> It demonstrated 100% container closure integrity.

[0052] From the above, it should be understood that what is defined herein is a pharmaceutical container assembly, including a pharmaceutical container and a seal assembly. In the sealed state, the insert portion of the seal assembly is inserted into the opening of the pharmaceutical container to define the seal. In the sealed state, the top of the seal assembly extends over the upper surface of the flange of the pharmaceutical container and covers the opening. In the unsealed state, when the insert portion is not inserted into the opening, the outer diameter of a portion of the insert portion is greater than 3% and less than 15% than the diameter of the corresponding portion of the opening.

[0053] Further embodiments of the embodiments described herein are provided by the subject matter of the following clauses.

[0054] Clause 1. A pharmaceutical container assembly comprising a pharmaceutical container having a shoulder portion, a neck portion extending from the shoulder portion, and a flange extending from the neck portion, wherein the flange comprises a back surface extending from the neck portion, an outer surface extending from the back surface, and an upper surface opposite to the back surface, wherein the upper surface extends between the outer surface and an inner surface defining the opening of the pharmaceutical container, and a seal assembly comprising a stopper having an upper portion and an insertion portion, wherein the upper portion has an upper surface, and the insertion portion has an outer surface, A pharmaceutical container assembly comprising a pipe assembly, wherein the insertion portion extends from the upper portion, and in a sealed state, the insertion portion is inserted into the opening so as to define a seal between the insertion portion and the inner surface of the flange, and in a sealed state, the upper portion extends onto the upper surface of the flange and covers the opening, and in an unsealed state where the insertion portion is not inserted into the opening, the outer diameter of a portion of the insertion portion is 3% or more and 15% or less than the diameter of the corresponding portion of the opening.

[0055] Clause 2. The pharmaceutical container assembly according to Clause 1, further comprising a metal-containing cap that engages with the stopper and secures 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 abutting against the upper surface of the upper portion of the stopper, and the side portion of the metal-containing cap defining the inner diameter of the metal-containing cap, the inner diameter of the metal-containing cap being greater than the outer diameter of the upper portion of the stopper such that a gap is provided between the outer surface of the upper portion and the side portion of the metal-containing cap.

[0056] The pharmaceutical container assembly according to Clause 3.5, wherein when a compressive force of 15 lbf or more is applied, the side portion of the metal-containing cap remains separated from the outer surface of the upper portion of the stopper.

[0057] Clause 4. The pharmaceutical container assembly according to Clause 2 or 3, wherein the inner diameter of the side portion of the metal-containing cap is 1% or more and 20% or less larger than the outer diameter of the upper portion of the stopper.

[0058] Clause 5. The pharmaceutical container assembly according to Clause 4, wherein the inner diameter of the side portion of the metal-containing cap is 3% or more and 10% or less larger than the outer diameter of the upper portion of the stopper.

[0059] Clause 6. The pharmaceutical container assembly according to any one of Clauses 1 to 5, wherein the upper portion of the stopper comprises 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 toward the upper surface of the upper portion.

[0060] Clause 7. The pharmaceutical container assembly according to Clause 6, wherein a notch is formed on the lower surface of the insertion portion and extends toward the lower surface of the upper portion.

[0061] Clause 8. The pharmaceutical container assembly according to Clause 6 or 7, wherein a groove is formed at the upper end of the insertion portion.

[0062] Clause 9. The pharmaceutical container assembly according to Clause 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.

[0063] Clause 10. The pharmaceutical container assembly according to Clause 9, wherein the outer surface of the insertion portion includes a lower outer surface portion that is tapered toward the lower end of the insertion portion, adjacent to the groove.

[0064] Clause 11. The groove surrounds the insertion portion of the pharmaceutical container assembly as described in any one of Clauses 8 to 10.

[0065] Clause 12. The pharmaceutical container assembly described in any one of Clauses 7 to 11, wherein the notch is concave.

[0066] Clause 13. The pharmaceutical container assembly according to any one of Clauses 1 to 12, wherein the upper portion comprises a lower surface opposite to the upper surface of the upper portion, the insertion portion extends from the lower surface of the upper portion toward the upper surface of the upper portion, and a plurality of ribs are formed on the outer surface of the insertion portion.

[0067] Clause 14. The pharmaceutical container assembly according to Clause 13, wherein the plurality of ribs are spaced equally apart from one another.

[0068] Clause 15. The plurality of ribs include three ribs, as described in Clause 13 or 14.

[0069] Clause 16. A pharmaceutical container assembly according to 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 the central axis of the pharmaceutical container, and the outer surface of the insertion portion includes an upper outer surface portion that extends parallel to the inner surface of the flange and abuts against the inner surface of the flange when in the sealed state.

[0070] Clause 17. The pharmaceutical container assembly according to Clause 16, wherein the inner surface of the flange extends substantially perpendicularly from the upper surface of the flange.

[0071] Clause 18. The pharmaceutical container assembly according to Clause 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 is tapered from the upper outer surface portion.

[0072] Clause 19. The pharmaceutical container assembly according to Clause 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.

[0073] Clause 20. In the sealed state, the pharmaceutical container assembly is subject to USP <1207> A pharmaceutical container assembly as described in any one of Clauses 1 to 19, having a container closure integrity pass rate of at least 60%.

[0074] Clause 21. A method for sealing a pharmaceutical container, the method comprising inserting a pharmaceutical composition into the pharmaceutical container, the pharmaceutical container comprising a shoulder portion, a neck portion extending from the shoulder portion, and a flange extending from the neck portion, the flange comprising a back surface extending from the neck portion, an outer surface extending from the back surface, and an upper surface opposite to the back surface, the upper surface extending between the outer surface and an inner surface defining an opening of the pharmaceutical container, and inserting a stopper through the opening of the pharmaceutical container to form a pharmaceutical container assembly. The method includes forming the stopper comprising an upper portion and an insertion portion extending from the upper portion, wherein the upper portion, when sealed, extends onto the upper surface of the flange and covers the opening, and the insertion portion extends into the opening to define a seal between the insertion portion and the inner surface of the flange, and the insertion portion has an outer surface, wherein, when unsealed, before inserting the stopper into the opening of the pharmaceutical container, the outer diameter of a portion of the insertion portion is 3% or more and 15% or less than the diameter of the corresponding portion of the opening.

[0075] Clause 22. The method according to Clause 21, further comprising pressing a metal-containing cap onto 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 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, the inner diameter of the metal-containing cap is greater than the outer diameter of the upper portion of the stopper such that a gap is provided between the outer surface of the upper portion of the stopper and the side portion of the metal-containing cap.

[0076] The method according to Clause 22, wherein when a compressive force of 5 pounds (lbf) or more and 15 lbf or less is applied, the metal-containing cap remains separated from the outer surface of the upper portion of the stopper.

[0077] Clause 24. The method according to Clause 22 or 23, wherein the inner diameter of the side portion of the metal-containing cap is 1% or more and 20% or less greater than the outer diameter of the upper portion of the stopper.

[0078] Clause 25. The method according to Clause 24, wherein the inner diameter of the side portion of the metal-containing cap is 3% or more and 10% or less greater than the outer diameter of the upper portion of the stopper.

[0079] Clause 26. The method according to any one of Clauses 22 to 25, 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 pharmaceutical container, the insertion portion of the stopper extends from the lower surface of the upper portion toward the upper surface of the upper portion, and the outer surface of the insertion portion includes an upper outer surface portion that extends parallel to the inner surface of the flange and abuts against the inner surface of the flange when it is sealed.

[0080] Clause 27. The method according to Clause 26, wherein the inner surface of the flange extends substantially perpendicularly from the upper surface of the flange.

[0081] Clause 28. The method according to Clause 26 or 27, wherein the insertion portion comprises a plurality of ribs formed on the outer surface of the insertion portion, the plurality of ribs abutting against the inner surface of the flange when in the sealed state.

[0082] Clause 29. The method according to Clause 28, wherein the plurality of ribs surround the outer surface of the insertion portion.

[0083] Clause 30. The method according to Clause 28 or 29, wherein the plurality of ribs are spaced equally apart from one another.

[0084] Clause 31. The distances between each of the plurality of ribs are not equal, as described in Clause 28 or 29.

[0085] Clause 32. The plurality of ribs, including three ribs, as described in any one of Clauses 28 to 31.

[0086] Clause 33. In the sealed state, the pharmaceutical container assembly is subject to USP <1207> The method according to any one of the clauses 21 to 32, having a container closure integrity pass rate of at least 60%.

[0087] It will be apparent to those skilled in the art that various modifications and changes can be made to the embodiments described herein without departing from the scope of the claimed subject matter. Therefore, this specification is intended to encompass various modifications and changes to the embodiments described herein, insofar as such modifications and changes fall within the scope of the appended claims and their equivalents.

Claims

1. A pharmaceutical container assembly, A pharmaceutical container, Shoulder area, The neck portion extends from the aforementioned shoulder portion, It comprises a flange extending from the neck portion, and the flange is The back surface extending from the aforementioned neck portion, The outer surface extending from the aforementioned back surface, A pharmaceutical container comprising: an upper surface opposite to the aforementioned back surface, the upper surface extending between the outer surface and the inner surface defining the opening of the pharmaceutical container; A seal assembly, A seal assembly comprising a stopper having an upper portion and an insertion portion, wherein the upper portion has an upper surface and the insertion portion has an outer surface, The aforementioned insertion portion extends from the aforementioned upper portion, In the sealed state, the insertion portion is inserted into the opening such that it defines a seal between the insertion portion and the inner surface of the flange. In the sealed state, the upper portion extends onto the upper surface of the flange and covers the opening. A pharmaceutical container assembly in which, when the insertion portion is not inserted into the opening and is not sealed, the outer diameter of a portion of the insertion portion is 3% or more and 15% or less larger than the diameter of the corresponding portion of the opening.

2. The system further comprises a metal-containing cap that engages with the stopper and fixes the stopper to the flange when in the sealed state, The aforementioned metal-containing cap comprises an upper portion and a side portion, The upper portion of the metal-containing cap abuts against the upper surface of the upper part of the stopper, The side portion of the metal-containing cap defines the inner diameter of the metal-containing cap, The pharmaceutical container assembly according to claim 1, wherein the inner diameter of the metal-containing cap is larger than the outer diameter of the upper portion of the stopper such that a gap is provided between the outer surface of the upper portion and the side portion of the metal-containing cap.

3. The pharmaceutical container assembly according to claim 2, wherein when a compressive force of 5 pounds (lbf) or more and 15 lbf or less is applied, the side portion of the metal-containing cap remains separated from the outer surface of the upper portion of the stopper.

4. The pharmaceutical container assembly according to claim 2, wherein the inner diameter of the side portion of the metal-containing cap is 1% or more and 20% or less larger than the outer diameter of the upper portion of the stopper.

5. The pharmaceutical container assembly according to claim 4, wherein the inner diameter of the side portion of the metal-containing cap is 3% or more and 10% or less larger than the outer diameter of the upper portion of the stopper.

6. The upper portion of the stopper comprises a lower surface opposite to the upper surface of the upper part, and an outer surface extending between the upper surface and the lower surface. The pharmaceutical container assembly according to claim 1, wherein 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 pharmaceutical container assembly according to claim 6, wherein a notch is formed on the lower surface of the insertion portion and extends toward the lower surface of the upper portion.

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

9. The pharmaceutical container assembly according to claim 8, wherein the outer diameter of the insertion portion at the lower end of the groove is larger than the outer diameter of the insertion portion at the lower end of the insertion portion.

10. The pharmaceutical container assembly according to claim 9, wherein the outer surface of the insertion portion includes a lower outer surface portion that is tapered toward the lower end of the insertion portion and is close to the groove.

11. The groove surrounds the insertion portion, as described in claim 8, for the pharmaceutical container assembly.

12. The pharmaceutical container assembly according to claim 7, wherein the notch is concave.

13. The aforementioned upper portion comprises a lower surface opposite to the upper surface of the upper portion, The insertion portion extends from the lower surface of the upper part toward the upper surface of the upper part, The pharmaceutical container assembly according to claim 1, wherein a plurality of ribs are formed on the outer surface of the insertion portion.

14. The pharmaceutical container assembly according to claim 13, wherein the plurality of ribs are spaced equally apart from one another.

15. The pharmaceutical container assembly according to claim 13, wherein the plurality of ribs include three ribs.

16. 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 pharmaceutical container. The pharmaceutical container assembly according to claim 1, wherein the outer surface of the insertion portion includes an upper outer surface portion that extends parallel to the inner surface of the flange and abuts against the inner surface of the flange when in the sealed state.

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

18. The pharmaceutical container assembly according to 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 is tapered from the upper outer surface portion.

19. The pharmaceutical container assembly according to 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 larger than the outer diameter of the insertion portion at the lower end of the insertion portion.

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

21. A method for sealing a pharmaceutical container, wherein the method is Inserting a pharmaceutical composition into the pharmaceutical container, wherein the pharmaceutical container comprises a shoulder portion, a neck portion extending from the shoulder portion, and a flange extending from the neck portion, the flange being The back surface extending from the aforementioned neck portion, The outer surface extending from the aforementioned back surface, The upper surface opposite to the aforementioned back surface, the upper surface having an upper surface that extends between the aforementioned outer surface and the inner surface defining the opening of the pharmaceutical container, for insertion, The process involves inserting a stopper through the opening of the pharmaceutical container to form a pharmaceutical container assembly, wherein the stopper comprises an upper portion and an insertion portion extending from the upper portion, the upper portion extending onto the upper surface of the flange and covering the opening when sealed, the insertion portion extending into the opening to define a seal between the insertion portion and the inner surface of the flange, and the insertion portion having an outer surface, In an unsealed state, before inserting the stopper into the opening of the pharmaceutical container, the outer diameter of a portion of the insertion part is 3% or more and 15% or less than the diameter of the corresponding portion of the opening.

22. The method further includes pressing a metal-containing cap onto the stopper and against the flange, thereby compressing the stopper against its upper surface. The aforementioned metal-containing cap comprises an upper portion and a side portion, The upper portion of the metal-containing 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, The method according to claim 21, wherein the inner diameter of the metal-containing cap is larger than the outer diameter of the upper portion of the stopper such that a gap is provided between the outer surface of the upper portion of the stopper and the side portion of the metal-containing cap.

23. The method according to claim 22, wherein when a compressive force of 5 pounds (lbf) or more and 15 lbf or less is applied, the metal-containing cap remains separated from the outer surface of the upper part of the stopper.

24. The method according to claim 22, wherein the inner diameter of the side portion of the metal-containing cap is 1% or more and 20% or less larger than the outer diameter of the upper portion of the stopper.

25. The method according to claim 24, wherein the inner diameter of the side portion of the metal-containing cap is 3% or more and 10% or less larger than the outer diameter of the upper portion of the stopper.

26. 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 pharmaceutical container. The insertion portion of the stopper extends from the lower surface of the upper portion toward the upper surface of the upper part, The method according to claim 22, wherein the outer surface of the insertion portion includes an upper outer surface portion that extends parallel to the inner surface of the flange and abuts against the inner surface of the flange when in the sealed state.

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

28. The method according to claim 26, wherein the insertion portion comprises a plurality of ribs formed on the outer surface of the insertion portion, and the plurality of ribs abut against the inner surface of the flange when in the sealed state.

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

30. The method according to claim 28, wherein the plurality of ribs are spaced equally apart from one another.

31. The method according to claim 28, wherein the distances between each of the plurality of ribs are not equal.

32. The method according to claim 28, wherein the plurality of ribs include three ribs.

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

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