Gas-permeable sealing member and assembly method for drug containers

Abstract

To provide drug delivery devices, sealing members for containers housed within such drug delivery devices, and related methods of assembly.SOLUTION: The drug delivery device may include a housing 29, a container 14 disposed in the housing 29 and having an interior volume, a drug 32 disposed in the interior volume, and a septum 40. The container 14 may have an opening which is formed in an end surface and which communicates with the interior volume. The septum 40 may include a proximal end inserted through the opening into the interior volume of the container. Additionally, the septum 40 may include a distal end having a flange disposed outwardly of the proximal end and contacting the end surface of the container 14. At least an end portion of the flange may be made of a material that is permeable to a gaseous sterilizing agent.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - Reference to Related Applications The benefit of priority of U.S. Provisional Patent Application No. 62 / 535,777, filed on July 21, 2017, is claimed, and the entire content thereof is hereby expressly incorporated by reference into this specification.

[0002] The present disclosure generally relates to drug containers, and more specifically, to the assembly and sterilization of such containers within syringes.

Background Art

[0003] Many drug containers or vials include an opening covered by a septum, sometimes also called a stopper. The septum seals the drug within the container and can typically be pierced by a needle or other sharp member to provide fluid communication with the drug. Conventional septa are typically constructed of materials having a very low gas permeability and / or moisture vapor transmission rate to prevent the ingress of contaminants and leakage of the drug composition. Nevertheless, there is a risk of contamination along the interface where the septum contacts the container.

[0004] Some drug containers are filled under sterile or aseptic conditions, sealed with a septum, and then stored in medical-grade packaging until used by the patient or healthcare provider. Under these circumstances, the risk of contamination at the interface between the septum and the container is low. In other circumstances, drug containers may be exposed to non-sterile or non-aseptic conditions during the filling process, creating a risk of contamination at the interface between the septum and the container after the filling process. One such situation is when a manufacturer attaches a pre-filled drug container to a drug delivery device, such as a wearable injector or pen-type injector, for the purpose of creating a pre-filled and pre-loaded drug delivery device. Contamination can occur, for example, during transport of the pre-filled drug container between the filling facility and the attachment facility, and / or within the area of ​​the attachment facility that is not operating under sterile or aseptic conditions. To address this contamination risk, manufacturers often sterilize the drug delivery device near the end of the assembly process.

[0005] However, at this stage, the available sterilization methods may be limited. This is because certain sterilization methods may have adverse effects on the drug in the container and / or the materials used to construct the container. Radiation sterilization (e.g., gamma ray sterilization or electron beam sterilization) can cause oxidation of the drug and / or discoloration of the glass of the container. Gas sterilization methods such as ethylene oxide (EtO) and steam treatment may not cause damage to the drug or container material, but they are often ineffective in killing bacteria or spores inoculated at the interface between the conventional septum and the container. Conventional septums have very low gas permeability, preventing gaseous disinfectants from reaching the interface between the septum and the container. Even prolonged ethylene oxide treatment (e.g., up to 30 hours) has been found ineffective in sterilizing the interface between the conventional septum and the container. Furthermore, prolonged ethylene oxide treatment presents significant manufacturing challenges, as it requires extended aeration cycles (e.g., 30–60 days) to extract residual ethylene oxide from other components of the container and drug delivery device. [Overview of the Initiative] [Means for solving the problem]

[0006] This disclosure describes septums, container assemblies, drug delivery devices and associated assembly methods that embody advantageous alternatives to existing types of such devices and methods and can address one or more of the problems or needs referred to herein, as well as provide other benefits and advantages.

[0007] One aspect of the present disclosure provides a drug delivery device comprising a housing, a container, a drug, and a septum. The container is located within the housing and may have an internal volume and an end surface. An opening is formed on the end surface and may communicate with the internal volume. The drug may be located within the internal volume of the container. The septum may include a proximal end and an anterior end. The proximal end of the septum may be inserted into the internal volume of the container through the opening. The anterior end of the septum may include a flange, which is located outside the proximal end and in contact with the end surface of the container. At least the end portion of the flange may be made of a first material, which is permeable to gaseous sterilizers. Furthermore, at least a portion of the anterior end of the septum may be made of a second material.

[0008] Another aspect of the present disclosure provides a method for assembling a drug delivery device, comprising: (a) a container having a volume and an end surface, the opening of which is formed on the end surface and communicates with the volume; and a septum comprising a proximal end and a tip, the proximal end being inserted into the volume of the container through the opening, the tip comprising a flange, the flange positioned outside the proximal end and in contact with the end surface of the container, and at least the end portion of the flange being made of a first material, the first material being permeable to a gaseous sterilizer; and (b) sterilizing the container assembly with a gaseous sterilizer so that the gaseous sterilizer diffuses through the first material to sterilize the end surface of the container; (c) filling the volume of the container with a drug; and (d) attaching the container assembly to a drug delivery device.

[0009] A further aspect of the present disclosure provides a container assembly comprising a container and a septum. The container may have an internal volume and an end surface. An opening may be formed on the end surface and communicate with the internal volume. The septum may include a base portion and a tip portion. The base portion of the septum may be insertable into the internal volume of the container through the opening. The tip portion of the assembly may include a flange positioned outside the base portion. At least the end portion of the flange may be made of a first material, which is permeable to gaseous sterilizers. At least a portion of the tip portion of the septum may be made of a second material.

[0010] Further embodiments of the present disclosure provide a container assembly comprising a container, a septum, and an annular sealing member. The container may have an internal volume and an end surface. An opening may be formed on the end surface and communicate with the internal volume. The septum may include a base end and a tip end. The base end of the septum may be insertable into the internal volume of the container through the opening. The tip end of the septum may include a flange positioned outside the base end. An annular sealing member may be positioned between the flange and the end surface of the container. The annular sealing member may be made of a first material, which is permeable to a gaseous sterilizer.

[0011] Another aspect of the present disclosure provides a septum for a drug container. The septum may include a longitudinal axis, a proximal end insertable into a drug container, and a tip portion including a flange positioned radially outward from the proximal end. The flange may include an outer peripheral surface and a proximal-side opposing surface. At least the tip portion of the flange may be made of a first material. The first material is permeable to a gaseous disinfectant so as to allow the disinfectant to diffuse through the first material between the outer peripheral surface of the flange and the proximal-side opposing surface of the flange. At least a portion of the tip portion of the septum may be made of a second material.

[0012] A further aspect of the present disclosure provides a drug delivery device comprising a housing, a container, a drug, and a septum. The container is housed within the housing and may have an internal volume and an end surface. An opening is formed on the end surface and may communicate with the internal volume. The drug may be housed within the internal volume of the container. The septum may include a proximal end and a tip. The proximal end of the septum may be inserted into the internal volume of the container through the opening. The tip of the septum may include a flange, which is housed outside the proximal end and in contact with the end surface of the container. Furthermore, the entire septum may be made of a material permeable to gaseous sterilizers.

[0013] This disclosure is intended to be understood in more detail from the following statement, which should be read in conjunction with the accompanying drawings. Some of the drawings have been simplified by omitting selected elements in order to more clearly illustrate other elements. Such omissions of elements in some drawings do not necessarily indicate the presence or absence of a particular element in any of the exemplary embodiments, unless explicitly stated in the corresponding written description. Also, none of the drawings necessarily adhere to a uniform scale. [Brief explanation of the drawing]

[0014] [Figure 1] A schematic cross-sectional view of one embodiment of a drug delivery device based on the principles of this disclosure is shown. [Figure 2A] Figure 1 shows an exploded view of the container assembly, with the container and stopper shown in a cross-sectional view. [Figure 2B] Figure 2A shows an assembly diagram of the container assembly, with the container, stopper, and fasteners shown in cross-sectional view. [Figure 3A] Figures 1 to 2B show a top perspective view of the septum. [Figure 3B] Figure 3A is a bottom perspective view of the septum. [Figure 4] This is a cross-sectional view of one embodiment of a septum constructed in accordance with the principles of this disclosure. [Figure 5] This is a cross-sectional view of another embodiment of a septum constructed in accordance with the principles of this disclosure. [Figure 6] This is a cross-sectional view of yet another embodiment of a septum constructed in accordance with the principles of this disclosure. [Figure 7] This is a cross-sectional view of yet another embodiment of a septum constructed in accordance with the principles of this disclosure. [Figure 8] This is a partial cross-sectional view of an embodiment of the septum shown in Figure 5, which is coated with a resin film. [Figure 9A] An exploded view of another embodiment of the container assembly is shown, with the container, stopper, and annular sealing member shown in cross-sectional view. [Figure 9B] Figure 9A shows an assembly diagram of the container assembly, with the container, stopper, annular sealing member, and fasteners shown in cross-sectional view. [Figure 10] Figures 9A and 9B show upper perspective views of the annular sealing member. [Modes for carrying out the invention]

[0015] The present disclosure generally relates to protecting drugs stored in containers (e.g., vials or ampoules) from microorganisms and other contaminants. The hermetic closure of the openings of such containers is often achieved by a septum or in part by what is called a stopper. A septum may include a proximal end portion, i.e., a lower end portion, inserted into the container through the opening, and an expanded distal end portion, i.e., an upper end portion, that abuts the end surface or edge of the container. By the engagement of the expanded distal end portion of the septum with the end surface of the container, the intrusion of contaminants can be prevented. The septum disclosed herein, in addition to providing a contaminant barrier, advantageously facilitates the sterilization of the interface between the septum and the container during manufacturing. This aspect of the septum disclosed herein is facilitated by constructing the septum, at least in part, of a material that permits the passage of gaseous sterilants such as, for example, ethylene oxide (EtO) and / or vapor. This permeability may enable the gaseous sterilant to diffuse through the septum to sterilize the interface between the septum and the container. Other portions of the septum may be constructed of a different material with lower or even impermeable permeability to the gaseous sterilant, thereby resulting in a composite septum made of at least two different materials. Also, as described below, embodiments of the septum according to the present disclosure advantageously enable a drug container, which may or may not be of a pre-filled type, to be attached or assembled to a drug delivery device under non-sterile or non-aseptic conditions and then subjected to a gaseous sterilization treatment without harming the drug stored in the container. Further disclosed is a sealing member, such as a gasket, disposed between the septum and the end surface of the container, separate from the septum. The sealing member may be constructed of a material that permits the passage of gaseous sterilants to provide a diffusion path for the gaseous sterilant to remove or reduce contaminants present on the end surface of the container.

[0016] Here, each of the aforementioned components and the method of assembling a drug delivery device including these components will be described in more detail.

[0017] Before describing various embodiments of septums constructed in accordance with the principles of this disclosure, a general overview of drug delivery devices that may incorporate the septum embodiments described below is provided with reference to Figure 1.

[0018] Figure 1 shows one embodiment of a drug delivery device 10 that can operate to deliver drugs to a patient subcutaneously or percutaneously. In the illustrated embodiment, the drug delivery device 10 is configured as a wearable drug delivery device, such as an on-body injector or portable infusion pump, that is detachably attached to the patient's tissue 11 (e.g., the patient's skin). In other embodiments (not shown), the drug delivery device 10 may be configured as a pen-type injector, such as an auto-injector or injection pen, that is temporarily held in the patient's tissue 11 throughout the course of injection. The drug delivery device 10 may be configured to automatically deliver a constant or patient / operator-configurable dose of drug over a controlled or selected time. Furthermore, the drug delivery device 10 may be for patient self-administration or may be operated by a formally trained healthcare professional or other caregiver performing the infusion.

[0019] Generally, the drug delivery device 10 may include an insertion mechanism 12, a container 14, a fluid path assembly 22, a drive mechanism 24, and a controller 26, each of which may be located within the internal space of a main housing 29. An actuator 28 (e.g., a button, touchscreen, microphone, etc., that a user can press) may protrude from or be located on the external surface of the housing 29 and may be configured to initiate the operation of the drug delivery device 10 by mechanical and / or electrical means (shown as dashed lines in Figure 1) to activate the insertion mechanism 12, the fluid path assembly 22, the drive mechanism 24, the controller 26, and / or other mechanisms and / or electronic equipment. In embodiments where the actuator 28 is a button pressed by a user or patient or otherwise physically operated, the actuator 28 may be configured to actuate the driving force necessary to activate the insertion mechanism 12, the fluid path assembly 22, the drive assembly 24, the controller 26, and / or other mechanisms. In such embodiments, the actuator 28 may be physically connected to the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms, either directly or indirectly via a mechanical linkage mechanism, to supply the driving force necessary to activate the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms by pushing the actuator 28 by hand or interacting with it in other ways. For example, in some embodiments, pushing the actuator 28 by hand may move the fluid path assembly 22 toward the fixed container 14, or move the container 14 toward the fixed fluid path assembly 22, thereby allowing the container access needle to penetrate the sealing member and be placed into the reservoir or internal volume of the container 14. Additionally or alternatively, the actuator 28 may act as an input device that transmits electrical and / or mechanical signals to the controller 26, which may further execute programmable instructions to control the operation of the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms.In such an embodiment, the controller 26 may include a processor (e.g., a microprocessor) and a non - temporary memory for storing program - able instructions executed by the processor. Further, in such an embodiment, the drug delivery device 10 may include a prime mover (e.g., an electric motor, a pneumatic or hydraulic pump, and / or a pressurized gas or liquid source) separate from the actuator 28 that applies a motive force necessary to activate the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms in response to an electrical control signal received from the controller 26.

[0020] Referring further to FIG. 1, the housing 29 may include a bottom wall 25 configured to be removably attached (e.g., adhered by an adhesive) to the patient's tissue 11, and a top wall 27 including one or more visual indicators 42 (e.g., lighting, a graphical display, etc.) and / or a window 35 for observing the container 14 and the drug 32 contained therein. The one or more visual indicators 42 may be used to convey information to the user regarding the operating state of the drug delivery device 10 and / or the state of the drug 32. An opening 31 may be formed in the bottom wall 25, and optionally, a pierce - able sterilization barrier 33 may extend across the opening 31 to seal the interior of the housing 29 prior to use. In some embodiments, the pierce - able sterilization barrier 33 may be omitted, and instead, a removable sealing member (not shown) may cover and hermetically seal the opening 31 prior to use.

[0021] More specifically, with respect to the window 35, this element may be constructed from a transparent or translucent material and may be roughly aligned with the container 14 to allow the patient or user of the drug delivery device 10 to verify the drug 32 in the container 14 and / or confirm the completion of administration. Suitable materials for constructing the window 35 include, but are not limited to, glass and plastic. Because the window 35 is located on the outside of the drug delivery device 10, it may expose the drug 32 to ambient light such as sunlight. Some drugs may be sensitive to certain wavelengths of light and may undergo undesirable molecular changes when exposed to light. For example, some drugs may be sensitive to wavelengths of light in the ultraviolet (UV), visible, and / or infrared regions. To protect drugs that are primarily sensitive to UV and / or infrared light, the window 35 may be given a darker tint, and / or the window 35 may be sized to cover a relatively small surface area of ​​the housing 29. For drugs that are primarily sensitive to visible light, it may not be necessary to add a dark tint to the window 35 and / or reduce the size of the window 35. Instead, the window 35 may be constructed with a polarizing filter. In some embodiments, the polarizing filter may be a film or other coating applied to the window 35. In other embodiments, the polarizing filter may be directly incorporated into the material of the window 35. The polarizing filter may allow observation and confirmation of the drug 32 in the container 14 while blocking approximately (e.g., ±10%) less than 50% of visible light. In some embodiments, the portion of visible light blocked by the window 35 may range from approximately (e.g., ±10%) 0 to 50%, or 10 to 50%, or 20 to 50%, or 25 to 50%, or 0 to 40%, or 0 to 30%, or 0 to 25%, depending, among other considerations, the photosensitivity of the drug 32 and / or the typical visual acuity of the patient population for the drug 32. By adding a polarizing filter to the window 35 instead of adding a dark tint to the window 35 and / or reducing the size of the window 35, the drug 35 is advantageously protected from visible light without substantially impairing the ability of the patient or user of the drug delivery device 10 to see the drug 32 before and / or during injection.

[0022] After the bottom wall 25 of the housing 29 is attached to the patient's tissue 13, the insertion mechanism 12 can be activated to move the delivery member from a retracted position within the housing 29 to an extended position extending outside the housing 29. In this embodiment, this includes the insertion mechanism 12 inserting the trocar 21 and the hollow cannula 23 surrounding the trocar 21 into the patient's tissue 11 through a perforable sterile barrier 33, as shown in Figure 1. Immediately thereafter or shortly thereafter, the insertion mechanism 12 may automatically retract the trocar 21, leaving the tip-side open end of the cannula 23 inside the patient for subcutaneous delivery of the drug 32. The trocar 21 is solid and may have a sharp end for puncturing the patient's skin 11. Furthermore, the trocar 21 may be made of a material that is more rigid than the cannula 23. In some embodiments, the trocar 21 may be made of metal, and the cannula 23 may be made of plastic or another polymer. The relative flexibility of the cannula 23 may allow it to be subcutaneously positioned within the patient's tissue 11 for a period of time without causing pain or significant discomfort to the patient. In other embodiments (not shown), the trocar 21 and cannula 23 may be omitted, and instead, the insertion mechanism 12 may insert only a rigid hollow needle into the patient for subcutaneous delivery of the drug 32.

[0023] In some embodiments, the insertion mechanism 12 may include one or more springs (e.g., coil springs, torsion springs, etc.) that are initially held in a biased state and released when the actuator 28 is pressed to insert the trocar 21 and cannula 23 or hollow needle into the patient. Furthermore, the retraction of the trocar 21 may be achieved by the automatic release of another spring after the trocar 21 and cannula 23 have been inserted into the patient. Other power sources for insertion and / or retraction are also conceivable, including, for example, an electric motor, a hydraulic or pneumatic pump or a canister that provides operating energy by releasing pressurized gas or pressurized liquid.

[0024] Continuing to refer to Figure 1, the container 14, sometimes referred to as the primary container in some contexts, may include an internal volume 30 for containing the drug 32 or a wall 38 defining the reservoir. In some embodiments, the internal volume 30 may be pre-filled with the drug 32 by the drug manufacturer before the container 14 is attached to the drug delivery device 10. In some embodiments, the container 14 may be rigidly connected to the housing 29 so that the container 14 cannot be moved relative to the housing, while in other embodiments, the container 14 may be slidably connected to the housing 29 so that the container 14 can be moved relative to the housing 29 during operation of the drug delivery device 10. The container 14 may have an elongated barrel-shaped or cylindrical shape extending along its longitudinal axis A. In embodiments in which the drug delivery device 10 is configured as an on-body injector, the longitudinal axis A of the container 14 may be perpendicular, substantially perpendicular, or otherwise non-parallel to the direction in which the insertion mechanism 12 inserts a delivery member, such as a cannula 23, into the patient. This configuration may allow an on-body injector that can be fitted by the patient without hindering the patient's movement to have a substantially flat, thin shape. First, a stopper 34 or other piston member may be positioned within the internal volume 30 at the base end 36 of the container 14. The stopper 34 may engage tightly and slidably with the inner surface 43 of the wall 38 of the container 14 and may be movable relative to the wall 38 of the container 14.

[0025] The amount of drug 32 contained in container 14 before delivery is any amount within the range of approximately (e.g., ±10%) 0.5 to 20 mL, or any amount within the range of approximately (e.g., ±10%) 0.5 to 10 mL, or any amount within the range of approximately (e.g., ±10%) 1 to 10 mL, or any amount within the range of approximately (e.g., ±10%) 1 to 8 mL, or any amount within the range of approximately (e.g., ±10%) 1 to 5 mL, or any amount within the range of approximately (e.g., ±10%) 1 to 3.5 mL, or any amount within the range of approximately (e.g., ±10%) 1 to 3 mL, or approximately (e.g., For example, any amount in the range of 1 to 2.5 mL (±10%), or any amount in the range of 1 to 2 mL (approximately ±10%), or any amount of 4 mL or less (approximately ±10%), or any amount of 3.5 mL or less (approximately ±10%), or any amount of 3 mL or less (approximately ±10%), or any amount of 2.5 mL or less (approximately ±10%), or any amount of 2 mL or less (approximately ±10%), or any amount of 1.5 mL or less (approximately ±10%), or any amount of 1 mL or less (approximately ±10%). The internal volume 30 of the container 14 can be completely or partially filled with the drug 32. The drug 32 may be one or more of the drugs listed below, such as granulocyte colony-stimulating factor (G-CSF), PCSK9 (human proprotein convertase subtilisin / kexin type 9) specific antibody, sclerostin antibody, or calcitonin gene-related peptide (CGRP) antibody.

[0026] During the operation of the drug delivery device 10, the drive mechanism 24 can push a stopper 34 along the longitudinal axis A from the base end 36 to the tip end 37 of the container 14 to discharge the drug 32 from the container 14. In some embodiments, the drive mechanism 24 may include one or more springs (e.g., coil springs, torsion springs, etc.) that are initially held in a biased state and released when the actuator 28 is pressed. The springs extend after their release, allowing the stopper 34 to move within the internal volume 30 along the longitudinal axis A from the base end 36 to the tip end 37 of the container 14. In other embodiments, the drive mechanism 24 may include an electric motor (not shown) that rotates a gear mechanism, for example, including one or more sprocket gears, to produce the axial motion of the stopper 34 within the internal volume 30. In yet another embodiment, the drive mechanism 24 may include both an electric motor and springs, the electric motor regulating the extension of the springs via a tether or pulley system. In yet another embodiment, the drive mechanism 24 may include a canister that releases pressurized gas or pressurized liquid to provide operating energy.

[0027] At the tip 37 of the container 14, an opening 45 (see Figure 2A) may be formed in the tip surface 72 (see Figure 2A) of the wall 38. At least before the operation of the drug delivery device 10, the opening 45 may be covered and sealed by a septum 40 connected to the tip 37 of the container 14. Generally, the septum 40 may be configured to selectively allow access to the internal volume 30. During operation, the septum 40 may be physically modified to allow fluid communication with the drug 32 in the internal volume 30. As described below, the septum 40 may be constructed of a flexible or elastically deformable material such as rubber, which can be pierced or perforated by the tip, i.e., sharp end 66, of a container access needle 64 attached to the fluid path assembly 22. In some embodiments, the septum 40 may be fastened to the tip surface 72 by a fastener 94, or otherwise fixed (see Figure 2B), and / or attached directly to the tip surface 72.

[0028] Referring further to Figure 1, the fluid pathway assembly 22 may be configured to establish fluid communication between the container 14 and the insertion mechanism 12 via a sterile fluid path during the operation of the drug delivery device 10. Before use of the drug delivery device 10, the fluid pathway assembly 22 may not be in fluid communication with the container 14. During the setup of the drug delivery device 10 or during the initial stages of operation of the drug delivery device 10 before drug delivery, the user may manually or the drug delivery device 10 may automatically enable, connect, or open the necessary connections to establish fluid communication between the container 14 and the fluid pathway assembly 22. The drive mechanism 24 may then move the stopper 34 distally, pushing the drug 32 stored in the container 14 through the sterile fluid path of the fluid pathway assembly 22 into the cannula 23 or needle of the insertion mechanism 12 for subcutaneous delivery to the patient.

[0029] In some embodiments, the fluid path assembly 22 may be rigidly connected to the housing 29 so as not to move relative to the housing, while in other embodiments, the fluid path assembly 22 may be slidably connected to the housing 29 so as to move relative to the housing 29 during operation of the drug delivery device 10.

[0030] The fluid path assembly 22 may include a first end 44 having an opening, a second end 48 fluidly connected to the insertion mechanism 12, and a fluid passage 50 extending between the first end 44 and the second end 48. The fluid passage 50 may be sterilizable and partially or fully made of flexible tubing 52. Initially, the flexible tubing 52 may have slack to allow the fluid path assembly 22 to move relative to the housing 29 and / or to allow the components of the insertion mechanism 12 to which the fluid path assembly 22 is attached to move relative to the housing 29. In some embodiments, the fluid passage 50 may include a rigid fluid limiting element (not shown) in addition to the flexible tubing 52. The fluid limiting element may have an inner diameter smaller than the inner diameter of the flexible tubing 52 to regulate the flow rate of the drug 32 as it passes through the fluid path assembly 22. Furthermore, the fluid limiting element may be made of a material that is more rigid than the flexible tubing 52. For example, the fluid limiting element may be made of metal, and the flexible tube 52 may be made of a polymer material such as plastic.

[0031] Before the drug delivery device 10 is operational, a sealing member 60 (e.g., a septum) connected to the first end 44 of the fluid path assembly 22 may cover and initially seal the opening of the first end 44 of the fluid path assembly 22. In a general sense, the sealing member 60 may be configured to control access to the fluid passage 50. In some embodiments, the sealing member 60 may be physically modified to allow fluid communication with the fluid passage 50 during the operation of the device 10. The sealing member 60 may be axially aligned with the septum 40 such that the outer surface of the base end of the sealing member 60 faces the tip surface of the septum 40. In some embodiments, both the septum 40 and the sealing member 60 may be axially aligned along the longitudinal axis A of the container 14 when attached to the drug delivery device 10. In addition, in some embodiments, the container access needle 64 may be axially aligned with the longitudinal axis A of the container 14.

[0032] Referring further to Figure 1, a container access needle 64, which may be rigid and hollow, may extend from a first end 44 of the fluid path assembly 22. The first end 66 of the container access needle 64, which may be sharp, may protrude from the first end 44 of the fluid path assembly 22, and a second end 68 of the container access needle 64 may be in fluid communication with the fluid passage 50. The first end 66 of the container access needle 64 may have an opening that is initially covered and sealed by or embedded within the sealing member 60. In some embodiments, the fluid path assembly 22 may include a mounting member 51 or connecting hub for firmly connecting the container access needle 64 to the rest of the fluid path assembly 22 so that the container access needle 64 cannot move relative to the fluid path assembly 22, and so that the fluid path assembly 22 and the container access needle 64 move together as a single unit relative to the housing 29 to the extent that the fluid path assembly 22 moves relative to the housing 29. Furthermore, the sealing member 60 may be attached to the container access needle 64 such that the sealing member 60 is connected to the first end 44 of the fluid path assembly 22 via the container access needle 64. In addition, in such embodiments, the sealing member 60 may be constructed as a deformable septum or as a foldable or rigid sleeve defining a sterile internal chamber that seals the exposed first end 66 of the container access needle 64.

[0033] Furthermore, any of the above-described subassemblies, mechanisms, components, features, functions, manufacturing methods, methods of use, and other embodiments of the drug delivery device 10 may, if necessary, be replaced and / or combined with any of the subassemblies, mechanisms, components, features, functions, manufacturing methods, methods of use, and other embodiments of the drug delivery device described in some or all of the following documents, which are incorporated herein by reference in their entirety for any purpose: U.S. Patent No. 9,061,097, U.S. Patent Application Publication No. 2017 / 0124284, U.S. Patent Application Publication No. 2017 / 0119969, U.S. Patent Application Publication No. 2017 / 0098058, U.S. Patent Application Publication No. 2017 / 0124285, U.S. Patent Application Publication No. 2017 / 0103186, U.S. Provisional Patent Application No. 62 / 460,501 titled "INSERTION MECHANISM FOR DRUG DELIVERY DEVICE", "INSERTION MECHANISM FOR DRUG U.S. Provisional Patent Application No. 62 / 469,226 titled "DRUG DELIVERY DEVICE", U.S. Provisional Patent Application No. 62 / 468,190 titled "INSERTION MECHANISM AND METHOD OF INSERTING A NEEDLE OF A DRUG DELIVERY DEVICE", U.S. Provisional Patent Application No. 62 / 460,559 titled "DRUG DELIVERY DEVICE WITH STERILE FLUID FLOWPATH AND RELATED METHOD OF ASSEMBLY", U.S. Provisional Patent Application No. 62 / 294,842 titled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE", U.S. Provisional Patent Application No. 62 / 297,718 titled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE", "DRUG DELIVERY DEVICE, METHOD OF U.S. Provisional Patent Application No. 62 / 320, entitled “MANUFACTURE, AND METHOD OF USE”International patent application PCT / US Patent Publication No. 2017 / 017627, titled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE", and international patent application PCT / US Patent Publication No. 2017 / 026524, also titled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE".

[0034] Referring to Figures 2A and 2B, an enlarged view of the container assembly of the drug delivery device 10 is shown. The container assembly includes a container 14, a septum 40, and a stopper 34. The container 14 may have a substantially cylindrical shape with an inner diameter D1. At the tip 37 of the container 14, the wall 38 may project radially outward and define a container flange 70. The container flange 70 may extend partially or entirely around the tip 37 of the container 14. The container flange 70 may define the tip surface 72 of the container 14 perpendicular to or otherwise non-parallel to the longitudinal axis A of the container 14 and generally facing distally. An opening 45 may be formed in the tip surface 72 and may communicate with the internal volume 30 of the container 14. In some embodiments, the container flange 70 may be omitted so that the tip surface 72 does not project radially outward from the rest of the container 14. The wall 38 at the base end 36 of the container 14 may include a base end surface 78 perpendicular to or otherwise non-parallel to the longitudinal axis A of the container 14 and generally facing proximal. An opening 79 may be formed in the base end surface 78 and communicate with the internal volume 30. After the container 14 is filled with the drug 32, the stopper 34 may be inserted into the internal volume 30 through the opening 79. The container 14 may be constructed from glass, plastic, or any other appropriately inert material that cannot chemically interact with the drug 32.

[0035] Referring further to Figures 2A and 2B, when the septum 40 is inserted into the container 14, the septum 40 can be centered with the longitudinal axis A of the container 14 so that the septum 40 and the container 14 share the same longitudinal axis A. The septum 40 can be divided into a base (or lower) end 80 and a tip (or upper) end 82 by an imaginary plane perpendicular to the longitudinal axis A. As shown in Figure 2A, the base end 80 and the tip end 82 may each have a cylindrical shape and may have outer diameters D2 and D3, respectively. The tip end 82 may be extended relative to the base end 80 so that its outer diameter D3 (or other external dimensions) is greater than the outer diameter D2 (or other external dimensions) of the base end 80. The flange 84 of the septum 40 is defined by the outer peripheral (e.g., periphery) portion of the tip portion 82 of the septum 40, which is located radially outward from the base portion 80 of the septum 40. The flange 84 may have a length L1 parallel to the longitudinal axis A and a width W1 perpendicular to the longitudinal axis A.

[0036] The flange 84 of the septum 40 may include a base portion 86 and a tip portion 88, each having its boundary shown by a dashed line in Figure 2A. The base portion 86 may have a length L2 parallel to the longitudinal axis A and a width W2 perpendicular to the longitudinal axis A. Similarly, the tip portion 88 may have a length L3 parallel to the longitudinal axis A and a width W3 perpendicular to the longitudinal axis A. Lengths L2 and L3 may each be less than the total length L1 of the flange 84, while widths W2 and W3 may each be equal to the total width W1 of the flange 84a. The base portion 86 of the flange 84 may include a base surface 90 perpendicular to or otherwise non-parallel to the longitudinal axis A and generally facing proximal, and an external peripheral (e.g., periphery) surface 92 which may be centered on the longitudinal axis A and / or parallel to the longitudinal axis A.

[0037] Referring to Figure 2B, when the septum 40 is attached to the container 14, the base end 80 of the septum 40 may be inserted into the internal volume 30 through the opening 45, and the base end surface 90 of the base end portion 86 of the flange 84 may directly contact and tightly engage with the tip end surface 72 of the container 14. In some embodiments, the base end surface 90 and the tip end surface 72 may each be flat so that they engage flush with each other. In other embodiments, flush engagement may be achieved by configuring the base end surface 90 and the tip end surface 72 to have a fitting curvature such that one is convex and the other is concave.

[0038] Referring to Figure 2B, the fastener 94 may be configured to hold the septum 40 against the container 14. In some embodiments, the fastener 94 may take the form of a crimping ring applied to the container 14 and the septum 40 by a crimping tool. As shown in Figure 2B, the fastener 94 may include radially inwardly extending flanges 96 and 98 that abut the opposing surface on the base end of the container flange 70 (or another external surface of the wall 38 of the container 14) and the opposing surface on the tip end of the septum 40 82, respectively, to tightly fasten or press the base end surface 90 of the flange 84 of the septum 40 against the tip end surface 72 of the container 70. The clamping force provided by the fastener 94 may help ensure an airtight and / or fluid-tight seal between the base end surface 90 of the flange 84 of the septum 40 and the tip end surface 72 of the container 70. As will be described in more detail below, in some embodiments, the fastener 94 may be made of a material that is permeable to gaseous sterilizers such as EtO and / or vapor.

[0039] Referring further to Figure 2B, the base end 80 of the septum 40 may include one or more radially outward projecting annular ribs 100 for a tightly engaging with the inner surface 43 of the wall 38 of the container 14. The annular ribs 100 may provide a secondary barrier to prevent intrusive contaminants from breaking the seal between the base end surface 90 of the flange 84 of the septum 40 and the front end surface 72 of the container 70. Here, the outer diameter D2 of the base end 80 of the septum 40 may be less than or equal to the inner diameter D1 of the container 14. In other embodiments, the annular ribs 100 may be omitted (see Figures 3A and 3B), and the outer diameter D2 of the base end 80 of the septum 40 may be slightly larger than the inner diameter D1 of the container 14 to provide a tight fit and seal. In yet another embodiment, the annular rib 100 may be omitted, and the outer diameter D2 of the base end 80 of the septum 40 may be smaller than the inner diameter D1 of the container 14, so that there is no seal formed between the base end 80 of the septum 40 and the container 14.

[0040] Before placing the drug delivery device 10 into its final package or sealing the internal space of the housing 29, it may be advantageous to sterilize the fully or partially assembled drug delivery device 10 to reduce or remove airborne or stationary microorganisms or other contaminants within or on the housing 29. Such sterilization may be necessary if any of the preceding assembly steps of the drug delivery device 10 are performed in a non-sterile or non-sterile environment. The container 14 may be filled by the drug manufacturer in a sterile or sterile environment with little risk of contamination and covered with the septum 40 before being attached to the drug delivery device 10. However, if the container 14 is transported to and / or attached by the device manufacturer under non-sterile or non-sterile conditions, there is a risk that contaminants may break the seal between the septum 40 and the container 14, adhere between the flange 84 of the septum 40 and the tip surface 72 of the container 14, or even contaminate the drug 32. Radiation sterilization (e.g., gamma ray sterilization or electron beam sterilization) can sterilize contaminants at the interface between the flange 84 of the septum 40 and the container 14, but radiation sterilization after the pre-filled container 14 has been attached to the drug delivery device 10 may not be feasible due to the possibility that the high-energy sterilization beam could harm the drug 32 in the container 14. Gas sterilization may not harm the drug 32, but it may not be able to penetrate the seal between the flange 84 of the septum 40 and the container 14 to sterilize the proximal surface 90 and / or the tip surface 72.

[0041] To address this challenge, the septum 40, the fastener 94 and / or other components associated with the container 14 may be constructed, partially or completely, from a material permeable to gaseous sterilizers, including but not limited to EtO and / or vapor. This material can provide a diffusion pathway for the gaseous sterilizer molecules to diffuse at least through the septum 40, thereby sterilizing one or more surfaces, such as the proximal surface 90 and / or tip surface 72, which would otherwise be unable to be sterilized due to the gaseous sterilizer being unable to penetrate the seal formed at the interface between the septum 40 and the container 14.

[0042] Figures 4 to 7 show four types of the septum 40 described above, each having a different material composition but the same dimensions and geometric properties as those shown in Figures 1 to 3B. Each type of septum 40 is denoted by one of the suffixes "a", "b", "c", or "d". What all types of septums 40a, 40b, 40c, and 40d shown in Figures 4 to 7 have in common is that at least the proximal portion 86 of the flange 84, including its proximal surface 90 and outer peripheral surface 92, is made of a first material that allows permeability of a gaseous disinfectant containing at least one of EtO or vapor. Therefore, each septum 40a to 40d has at least one diffusion path for the gaseous disinfectant extending between the proximal surface 90 and the outer peripheral surface 92. Therefore, during a sterilization procedure in which a partially or fully assembled drug delivery device 10 is exposed to a gaseous disinfectant, the gaseous disinfectant can enter the septum 40 through at least the outer peripheral surface 92 and exit the septum 40 through at least the proximal end surface 90, thereby sterilizing the interface between the septum 40 and the container 40, including at least the proximal end surface 90 of the flange 84 and the tip surface 72 of the container 14. Depending on the portion of the septum 40 constructed from the first material that allows the gaseous disinfectant to permeate, other diffusion paths through the septum 40 may also be possible. The rate at which the gaseous disinfectant diffuses through each septum 40a, 40b, 40c, and 40d may depend on the ratio of septums made from the first material. In addition, although one or more annular ribs 100 are omitted from Figures 4 to 7, each embodiment of septums 40a, 40b, 40c, and 40d may include one or more annular ribs 100.

[0043] Figure 4 shows one embodiment of septum 40a in which only the proximal portion 86a of flange 84a may be made from a first material that is permeable to gaseous disinfectant containing at least one of EtO or vapor. Thus, only the annular portion of septum 40a defined by the proximal portion 86a of flange 84a may be made from the first material that is permeable to gaseous disinfectant. The remaining portion of septum 40a, including the tip portion 88 of flange 84 and the proximal portion 80a of septum 40a, may be made from a second material that is less permeable to gaseous disinfectant than the first material. In some embodiments, the second material may not be substantially or completely permeable to gaseous disinfectant. Furthermore, in some embodiments of the septum 40a, the gaseous disinfectant may enter the septum 40a only through the outer peripheral surface 92a of the flange 84a and exit the septum 40a mainly through the base end surface 90a of the flange 84 or only through the base end surface 90a of the flange 84. This may be useful in preventing the gaseous disinfectant from entering the internal volume 30 of the container 14 and interacting with the drug 32.

[0044] Figure 5 shows another embodiment of septum 40b in which the gaseous sterilizer may have an additional pathway into septum 40b, including not only the entire outer peripheral surface of the tip portion 82b of septum 40b, but also the entire tip surface of septum 40b. This technique can be achieved by constructing the tip portion 82b of septum 40b entirely from a first material that is permeable to a gaseous sterilizer containing at least one of EtO or vapor. The proximal portion 80b of septum 40b may be entirely fabricated from a second material that is less permeable to the gaseous sterilizer than the first material. In some embodiments, the second material may not be substantially or completely permeable to the gaseous sterilizer. Similar to septum 40a, the gaseous sterilizer may exit septum 40b mainly through the proximal surface 90b of flange 84b or only through the proximal surface 90b of flange 84b. In some embodiments, the first material of the septum 40b may be made of polybutadiene rubber, and the second material of the septum 40b may be made of chlorobutyl rubber.

[0045] Referring to Figure 6, yet another embodiment of the septum 40c is shown. Here, a portion of the tip 82c of the septum 40c, positioned distal to the flange 80c, is made of the second material described above. In other words, the portion of the tip 82c of the septum 40c that is positioned distal to an imaginary plane perpendicular to the longitudinal axis A and in contact with the tip of the base portion 86c of the flange 84c may be made of the second material. The remaining portion of the tip 82c of the septum 40c, including the base portion 86 of the flange 84 and a portion of the tip 82c of the septum 40c that is positioned proximal to the imaginary plane described above, may be made of the first material described above. Furthermore, in this embodiment of the septum 40c, the base portion 80c of the septum 40c may be made entirely of the first material. One advantage of this embodiment of the septum 40c is that the gaseous sterilizer can reach the inner surface 43 of the container 14 by diffusing through the proximal end 80c of the septum 40c, thereby sterilizing any contaminants placed on the inner surface 43 of the container 14.

[0046] Figure 7 shows another embodiment of the septum 40d made entirely of the first material described above. Thus, both the proximal end 80d and the tip end 82d of the septum 40d can be made of a material that is completely permeable to a gaseous sterilizer containing at least one of EtO or vapor. This structure can maximize the number of diffusion paths for the gaseous sterilizer. The gaseous sterilizer can enter and exit the septum 40d through any external surface of the septum 40d. Thus, it may be possible to sterilize the interface between the proximal end 80d of the septum 40d and the inner surface 43 of the container 14, as well as the interface between the flange 84d and the tip end surface 72 of the container 14. The relatively high permeability of the septum 40d may be beneficial to store the fully assembled drug delivery device 10 in a sealed and / or sterile space in a bag or other secondary package before use. This prevents any gases and / or contaminants from diffusing through the septum 40d during the period between the assembly of the drug delivery device 10 and its use by a patient. In some embodiments, the secondary package may be constructed of a multilayer material having gas barrier properties. Furthermore, any of the septums disclosed herein, including septums 40a, 40b, 40c, and 40d, may be attached to the drug delivery device 10, which is later placed in such a secondary package, to provide additional protection against contamination during the period between the assembly of the drug delivery device 10 and its use by a patient.

[0047] The following descriptions of the first and second materials apply to any one of the septums 40a, 40b, 40c, and 40d described above, as well as any other septums described herein. The composition of the first material may be selected according to the characteristics of the sterilization procedure (e.g., final sterilization procedure) used to sterilize the container 14 and / or other components of the drug delivery device 10, namely, one or any combination of the non-exclusive list of the composition of the gaseous sterilizer used in the sterilization procedure, the pressure of the gaseous sterilizer used in the sterilization procedure, the amount or volume of the gaseous sterilizer used in the sterilization procedure, the concentration of the gaseous sterilizer used in the sterilization procedure, the length of time of the sterilization procedure, and the temperature of the gaseous sterilizer used in the sterilization procedure. In some embodiments, the first material may be permeable to one or any combination of the gaseous sterilizers selected from the following non-exclusive list of gaseous sterilizers, namely EtO, ozone, chlorine dioxide, nitrogen dioxide, and vapor (e.g., pressurized steam). In some embodiments, the sterilization procedure using vapor as the gaseous sterilizer may be carried out inside an autoclave device. The first material may comprise one or any combination of the following non-exclusive list of materials: polymers, rubbers, and polybutadiene rubbers. The second material may comprise one or any combination of the following non-exclusive list of materials: polymers, rubbers, chlorobutyl rubbers, and halogenated butyl rubbers. In the above septums 40a, 40b, 40c, and 40d, and any other septums described herein, the first material may be made of polybutadiene rubber, and the second material may be made of chlorobutyl rubber.

[0048] Generally, the second material has lower permeability to gaseous disinfectants than the first material, which includes the second material being substantially or completely impermeable to gaseous disinfectants. In some embodiments, the permeability of the first material can be at least 10 times, or at least 20 times, or at least 30 times, or at least 40 times, or at least 50 times, or at least 60 times, or at least 70 times, or at least 80 times, or at least 90 times, or at least 100 times higher than the permeability of the second material.

[0049] Any one of the septums 40a, 40b, 40c, and 40d described herein, as well as any other septums described herein, may be constructed as a single component formed integrally with each other, such as by injection molding of the first material and the second material with respect to each other. Alternatively, any one of the septums 40a, 40b, 40c, and 40d described herein, as well as any other septums described herein, may be constructed as a multi-component component in which the first material and the second material are connected to each other by adhesives, fasteners, and / or any other suitable connecting elements.

[0050] In embodiments where a fastener 94 is used to hold the septum 40 in a container 14, the fastening ring 94 may act as a gas barrier to prevent the gaseous sterilizer from diffusing through the permeable portion of the septum 40. Therefore, in some embodiments, one or more openings 99 (see Figure 2B) may be formed in the fastening ring 94 to allow the gaseous sterilizer to pass through the fastener 94 and come into contact with the permeable portion of the septum 40. In some embodiments, the openings 99 may be arranged and / or formed in a pattern on the outer periphery or surrounding surface of the fastener 94. In some embodiments, as seen in Figure 2B, the openings 99 may be located in the same axial position as the outer periphery surface 92 of the base end portion 86 of the flange 84. In addition to or instead of the openings 99, the fastener 94 may be partially or completely constructed of a material that is permeable to gaseous sterilizers (e.g., EtO, ozone, chlorine dioxide, nitrogen dioxide, and / or vapors).

[0051] Referring to Figure 8, another type of septum 40b is shown in which the outer surface of the septum 40b is partially coated with a chemically inert resin film 110. In some embodiments, the resin film 110 may be a fluoropolymer film. Referring to Figures 5 and 8, the resin film 110 may cover the entire outer surface of the septum 40b, except for the proximal surface 90b and the outer peripheral surface 92b of the proximal end portion 86b of the flange 84b. Thus, the resin film 110 does not need to prevent the gaseous sterilizer from diffusing through the proximal surface 90b and the outer peripheral surface 92b of the proximal end portion 86b of the flange 84b. In some embodiments, the portion of the resin film 110 covering the proximal end 80b and / or tip 82b of the septum 40b shown in Figure 8 may be omitted. Furthermore, any of the above configurations of the resin film 110 may be applied to any of the embodiments of septums disclosed herein, including septums 40a, 40c, and 40d.

[0052] Each of the embodiments described above relies on the septum to provide a diffusion pathway for the gaseous sterilizer. However, the diffusion pathway may also be realized by other means. Figures 9A and 9B show one embodiment of a container assembly in which the diffusion pathway is provided by an annular sealing member 300 or gasket separate from the septum 140. Elements of the container assembly shown in Figures 9A and 9B, similar to those shown in Figures 2A and 2B, are indicated by the same reference numerals plus 100. Much of the description of these elements is omitted or excluded for brevity.

[0053] Referring to Figure 9B, the annular sealing member 300 is positioned between the base end surface 190 of the flange 184 and the front end surface 172 of the container 114 when assembled to other components of the container assembly. As seen in Figure 10, the annular sealing member 300 may include a central opening 302 extending between the base end surface 304 and the front end surface 306. As seen in Figure 9B, the base end 180 of the septum 140 may be inserted through the central opening 302. The annular sealing member 300 may also include an outer peripheral or surrounding surface 308 extending between the base end surface 304 and the front end surface 306.

[0054] During sterilization, the gaseous sterilizer can enter the annular sealing member 300 through the outer peripheral surface 308, diffuse into the material of the annular sealing member 300, and exit the annular sealing member 300 through the proximal end surface 304. Thus, any microorganisms or other contaminants adhering to the interface between the annular sealing member 300 and the container 114 can be reduced or eliminated. The permeability of the annular sealing member 300 can be achieved by constructing the annular sealing member 300 from the first material described above. The foregoing description of the first material incorporated into septums 40a-40d applies equally to the first material incorporated into the annular sealing member 300.

[0055] With respect to the septum 140 used in conjunction with the annular sealing member 300, it may be partially or completely constructed of a material with lower gaseous sterilizer permeability than the material used to construct the annular sealing member 300. In some embodiments, the septum 140 may be partially or completely constructed of the second material described above. In such embodiments, the foregoing description of the second material incorporated into the septums 40a-40c applies to the second material incorporated into the septum 140. The annular sealing member 300 advantageously provides a diffusion path for gaseous sterilizer to sterilize the tip surface 172 of the container 114 when using a conventional septum that is substantially or completely impermeable to gaseous sterilizer to seal the container 114. Furthermore, the annular sealing member 300 is not limited to use with the septum 140, and the annular sealing member 300 may be used in conjunction with any of the septums disclosed herein, including any of the septums 40a-40d.

[0056] Herein, a method for assembling the drug delivery device 10 will be described. The following description refers to the septum 40, but is applicable to all types of septums disclosed herein, including at least septums 40a, 40b, 40, c, 40d, and 140. First, the empty container 14 and the septum 40 can be connected and sterilized together. This step may include inserting the proximal end 80 of the septum 40 into the internal volume 30 of the container 14 through the opening 45 and moving the proximal end surface 90 of the flange 84 into direct contact with the tip surface 72 of the container 14. In some embodiments, connecting the container 14 and the septum 40 may include fastening the two components together with a fastener 94 to provide an airtight and / or fluid-tight seal between the proximal end surface 90 of the flange 84 and the tip surface 72 of the container 14. In embodiments including the annular sealing member 300, an airtight and / or fluid-tight seal can be created not only between the base end surface 304 of the annular sealing member 300 and the front end surface 172 of the container 114, but also between the front end surface 306 of the annular sealing member 300 and the base end surface 190 of the septum 140.

[0057] Next, the partially assembled container 14 may be subjected to a sterilization procedure or treatment. In some embodiments, this sterilization procedure may involve placing the partially assembled container 14 in a sealed vacuum chamber which will later be filled with a gaseous sterilizer. The gaseous sterilizer may be one or any combination of gaseous sterilizers selected from the following non-exclusive list of gaseous sterilizers, namely EtO, ozone, chlorine dioxide, nitrogen dioxide, and vapor (e.g., pressurized steam). In embodiments in which vapor is used for sterilization, the chamber in which the sterilization procedure is performed may be an autoclave. During this sterilization procedure, the septum 40 and the annular sealing member 300, if included, may be exposed to the gaseous sterilizer. The portion of the septum 40 and / or annular sealing member 300 constructed from the first material described above may allow for the diffusion of the gaseous sterilizer, as described above, so that the gaseous sterilizer diffuses through the septum 40 and / or annular sealing member 300 and sterilizes the interface between the septum 40 or annular sealing member 300 and the container 14. Due to the effect that the gaseous sterilizer can diffuse through the septum 40 and / or annular sealing member 300 and sterilize the interface of the container 14, the exposure time to the gaseous sterilizer can be relatively short. In some embodiments, the exposure time to the gaseous sterilizer may be approximately (e.g., ±10%) 24 hours, or 18 hours, or 12 hours, or 8 hours, or 4 hours, or 2 hours, or 1 hour or less, or approximately (e.g., ±10%) 1 to 4 hours, or 4 to 8 hours, or 4 to 12 hours, or 4 to 18 hours, or 8 to 12 hours, or 8 to 18 hours, or 12 to 18 hours. The shorter the time the container 14 is exposed to the gaseous sterilizer, the shorter the time required for aeration of the container 14 after sterilization. Therefore, the septum and annular sealing members disclosed herein can help streamline the manufacturing process of the container 14. In alternative embodiments, the sterilization step of this partially assembled container 14 may be omitted or performed after the filling procedure described in the following paragraphs.

[0058] Next, the container 14 and septum 40 can be aseptically transferred to a filling and capping environment. Here, the drug 32 can be filled into the internal volume 30 of the container 14, and then the base end 36 of the container 14 can be sealed by a stopper 34 that is slidably inserted through the opening 79. This filling and capping environment may be operated as a sterile or aseptic assembly environment to ensure that microorganisms and other contaminants are not taken into the internal volume 30. The container assembly, which is then filled with the drug and pre-assembled, can then be packaged and transported to a facility where the final assembly of the drug delivery device 10 takes place. As a preliminary step, the fluid path assembly 22 may be connected to the seal member 60 so that the seal member 60 seals the open end of the fluid passage 50. The process of assembling the fluid path assembly 22 and the seal member 60 may be carried out in a sterile or aseptic assembly environment to ensure that particulate contaminants are not taken into the fluid passage 50. Alternatively, or in addition, the pre-assembled configurations of the fluid path assembly 22 and the sealing member 60 may be exposed to a high-energy sterilization beam (e.g., gamma-ray beam, X-ray beam, electron beam, etc.), ethylene oxide, or other known techniques to ensure their sterilization. These pre-assembled configurations may then be packaged and transported to a facility where the final assembly of the drug delivery device 10 takes place.

[0059] Subsequently, for example in a final assembly facility, the drug-filled, pre-assembled configuration of the drug container 14, septum 40, and stopper 34, along with the pre-assembled configuration of the fluid path assembly 22 and sealing member 60, can be installed within the housing 29 of the drug delivery device 10. In some embodiments, this installation process may include connecting the drug-filled, pre-assembled configuration of the drug container 14, septum 40, and stopper 34 to a first housing portion (e.g., the bottom wall 25 of the housing 29) or a second housing portion (e.g., the top wall 27 of the housing 29), and connecting the pre-assembled configuration of the fluid path assembly 22 and sealing member 60 to the first or second housing portion of the drug delivery device 10. In some embodiments, the installation of the drug-filled, pre-assembled configuration of the drug container 14, septum 40, and stopper 34 into the housing 29 and / or other assembly steps of the drug delivery device 10 may be performed in a non-sterile or non-sterile environment. In other embodiments, the installation of the drug container 14, septum 40, and stopper 34, which are pre-assembled and filled with the drug, into the housing 29, as well as some or all other assembly steps of the drug delivery device 10, may be performed in a sterile or aseptic environment.

[0060] After the drug-filled, pre-assembled configuration of the drug container 14, septum 40, and stopper 34, and / or the pre-assembled configuration of the fluid path assembly 22 and sealing member 60, are installed in the housing 29, the partially assembled version of the drug delivery device 10 may be subjected to sterilization or processing. In some embodiments, this sterilization may involve placing the partially assembled version of the drug delivery device 10 into a sealed vacuum chamber which will later be filled with a gaseous sterilizer. The gaseous sterilizer may be one or any combination of gaseous sterilizers selected from the following non-exclusive list of gaseous sterilizers, namely EtO, ozone, chlorine dioxide, nitrogen dioxide, and vapor (e.g., pressurized steam). In embodiments where vapor is used for sterilization, the chamber in which the sterilization is performed may be an autoclave. During this sterilization, the septum 40 and, if included, the annular sealing member 300 may be exposed to the gaseous sterilizer. The portion of the septum 40 and / or annular sealing member 300 constructed from the first material described above may allow for the diffusion of the gaseous sterilizer, as described above, so that the gaseous sterilizer diffuses through the septum 40 and / or annular sealing member 300, sterilizing the interface between the septum 40 or annular sealing member 300 and the container 14. Due to the effect that the gaseous sterilizer can diffuse through the septum 40 and / or annular sealing member 300 and sterilize the interface of the container 14, the exposure time to the gaseous sterilizer can be relatively short. In some embodiments, the exposure time to the gaseous sterilizer may be approximately (e.g., ±10%) 24 hours, or 18 hours, or 12 hours, or 8 hours, or 4 hours, or 2 hours, or 1 hour or less, or approximately (e.g., ±10%) 1 to 4 hours, or 4 to 8 hours, or 4 to 12 hours, or 4 to 18 hours, or 8 to 12 hours, or 8 to 18 hours, or 12 to 18 hours. The shorter the time the drug delivery device 10 is exposed to the gaseous sterilizer, the shorter the time required for aeration of the drug delivery device 10 after sterilization. Therefore, the septum and annular sealing members disclosed herein can help streamline the manufacturing process of the drug delivery device 10.

[0061] After the sterilization process is complete, the first housing portion may be connected to the second housing portion to seal the drug-filled, pre-assembled components of the drug container 14, septum 40, and stopper 34, as well as other components within the sterilized internal space of the drug delivery device 10 (e.g., insertion mechanism 12, fluid path assembly 22, drive mechanism 24, controller 26, etc.). Thus, the sealing process can result in a pre-loaded and pre-filled drug delivery device 10. In some embodiments, the connection between the first and second housing portions can seal the interior of the drug delivery device 10, preventing or blocking the entry of contaminants. Furthermore, in some embodiments, the first and second housing portions may be sealed together within the same environment or chamber where gas sterilization is performed.

[0062] It should be noted that the assembly method described above may be performed in any of the embodiments of the septum 40, including septums 40a, 40b, 40c, 40d, and 140, and / or in the annular sealing member 300. [Examples]

[0063] The following are the results of experimental tests comparing a composite septum constructed according to the principles of this disclosure with a conventional septum fabricated from a completely gas-impermeable material. Both the composite septum and the conventional septum had approximately 10% of the base surface of their flanges. 6Each septum was inoculated with a challenge microorganism. Then, each septum was pressed onto the tip surface of a drug container. This process was repeated to create 30 samples using the composite septum and 30 samples using the conventional septum. Next, the samples were subjected to gas sterilization. EtO was used as the gas sterilizer. After 18 hours of EtO sterilization, no microbial growth was observed at the interface between the composite septum and the drug container in all 30 samples. Some composite septum samples showed no microbial growth after only 8 hours of EtO sterilization. In comparison, after 30 hours of EtO sterilization, only 15 of the 30 samples using the conventional septum showed no microbial growth at the interface with the drug container. Therefore, it was experimentally demonstrated that the amount of time required to sterilize the interface between the composite septum and the container disclosed herein is significantly less than the amount of time required to sterilize the interface between the conventional septum and the container.

[0064] Drug information As stated above, the container can be filled with drugs. These drugs may be any one or a combination of the drugs listed below, however, the following list should not be considered to be either all or limited.

[0065] For example, a syringe may be filled with a colony-stimulating factor such as granulocyte colony-stimulating factor (G-CSF). Examples of such G-CSF preparations include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the syringe may be used with various pharmaceuticals such as erythropoiesis-stimulating agents (ESAs), which may be in liquid or lyophilized form.ESA includes Epogen® (epoetin α), Aranesp® (darbepoetin α), Dynepo® (epoetin δ), Mircera® (methyoxy polyethylene glycol epoetin β), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin ζ), Neorecormon® (epoetin β), and Silapo® (registered trademark). Any molecule that stimulates erythrocyte production, such as epoetin ζ, Binocrit® (epoetin α), epoetin α Hexal, Abseamed® (epoetin α), Ratioepo® (epoetin θ), Eporatio® (epoetin θ), Biopoin® (epoetin θ), epoetin α, epoetin β, epoetin ζ, epoetin θ, and epoetin δ, as well as any whole thereof, incorporated herein by reference. The following patents or patent applications are included: U.S. Patent No. 4,703,008, U.S. Patent No. 5,441,868, U.S. Patent No. 5,547,933, U.S. Patent No. 5,618,698, U.S. Patent No. 5,621,080, U.S. Patent No. 5,756,349, U.S. Patent No. 5,767,078, U.S. Patent No. 5,773,569, U.S. Patent No. 5,955,422, U.S. Patent No. 5,986,047, U.S. Patent No. 6 These are molecules or their variants or analogues disclosed in U.S. Patent No. 583,272, U.S. Patent No. 7,084,245 and U.S. Patent No. 7,271,689, and PCT International Publication Nos. 91 / 05867, 95 / 05465, 96 / 40772, 00 / 24893, 01 / 81405 and 2007 / 136752.

[0066] ESA can be an erythropoiesis-stimulating protein. In the present invention, "erythropoiesis-stimulating protein" means any protein that directly or indirectly causes activation of the erythropoietin receptor by binding to the receptor and causing receptor dimerization. Examples of erythropoiesis-stimulating proteins include erythropoietin and its variants, analogs, or derivatives that bind to and activate the erythropoietin receptor, antibodies that bind to and activate the erythropoietin receptor, or peptides that bind to and activate the erythropoietin receptor. Examples of erythropoiesis-stimulating proteins include, but are not limited to, epoetin α, epoetin β, epoetin δ, epoetin ω, epoetin ι, epoetin ζ and their analogs, PEGylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1 / hematide), and mimetic antibodies. Exemplary erythrocyte-stimulating proteins include erythropoietin, darbepoetin, erythropoietin agonist variants and peptides or antibodies that bind to and activate the erythropoietin receptor (as well as compounds reported in U.S. Patent Application Publication No. 2003 / 0215444 and U.S. Patent Application Publication No. 2006 / 0040858, which are incorporated herein by reference in their entirety) and the following patents or patent applications, U.S. Patent No. 4,703,008, U.S. Patent No. 5,441,868, U.S. Patent No. 5,547,933, and U.S. Patent No. 5,618,6, which are incorporated herein by reference in their entirety. U.S. Patent No. 98, U.S. Patent No. 5,621,080, U.S. Patent No. 5,756,349, U.S. Patent No. 5,767,078, U.S. Patent No. 5,773,569, U.S. Patent No. 5,955,422, U.S. Patent No. 5,830,851, U.S. Patent No. 5,856,298, U.S. Patent No. 5,986,047, U.S. Patent No. 6,030,086, U.S. Patent No. 6,310,078, U.S. Patent No. 6,391,633, U.S. Patent No. 6,583,272, U.S. Patent No. 6,586,398, U.S. Patent No. 6,900,292, U.S. Patent No. 6,750,369,U.S. Patent Nos. 7,030,226, 7,084,245, and 7,217,689, U.S. Patent Publication No. 2002 / 0155998, U.S. Patent Publication No. 2003 / 0077753, U.S. Patent Publication No. 2003 / 0082749, U.S. Patent Publication No. 2003 / 0143202, U.S. Patent Publication No. 2004 / 0009902, U.S. Patent Publication No. 2004 / 0071694, and U.S. Patent Publication No. 2004 / 0091961 Specifications, U.S. Patent Application Publication No. 2004 / 0143857, U.S. Patent Application Publication No. 2004 / 0157293, U.S. Patent Application Publication No. 2004 / 0175379, U.S. Patent Application Publication No. 2004 / 0175824, U.S. Patent Application Publication No. 2004 / 0229318, U.S. Patent Application Publication No. 2004 / 0248815, U.S. Patent Application Publication No. 2004 / 0266690, U.S. Patent Application Publication No. 2005 / 0019914, U.S. Patent Application Publication No. 2005 / 0026834 Detailed specifications, U.S. Patent Application Publication No. 2005 / 0096461, U.S. Patent Application Publication No. 2005 / 0107297, U.S. Patent Application Publication No. 2005 / 0107591, U.S. Patent Application Publication No. 2005 / 0124045, U.S. Patent Application Publication No. 2005 / 0124564, U.S. Patent Application Publication No. 2005 / 0137329, U.S. Patent Application Publication No. 2005 / 0142642, U.S. Patent Application Publication No. 2005 / 0143292, U.S. Patent Application Publication No. 2005 / 0153879 details The documents, U.S. Patent Application Publication No. 2005 / 0158822, U.S. Patent Application Publication No. 2005 / 0158832, U.S. Patent Application Publication No. 2005 / 0170457, U.S. Patent Application Publication No. 2005 / 0181359, U.S. Patent Application Publication No. 2005 / 0181482, U.S. Patent Application Publication No. 2005 / 0192211, U.S. Patent Application Publication No. 2005 / 0202538, U.S. Patent Application Publication No. 2005 / 0227289, U.S. Patent Application Publication No. 2005 / 0244409,U.S. Patent Application Publication No. 2006 / 0088906 and U.S. Patent Application Publication No. 2006 / 0111279, and PCT International Publication Nos. 91 / 05867, 95 / 05465, 99 / 66054, 00 / 24893, 01 / 81405, 00 / 61637, 01 / 36489, 02 / 014356, and 02 / 19963. International Publication Brochure No. 02 / 20034, International Publication Brochure No. 02 / 49673, International Publication Brochure No. 02 / 085940, International Publication Brochure No. 03 / 029291, International Publication Brochure No. 2003 / 055526, International Publication Brochure No. 2003 / 084477, International Publication Brochure No. 2003 / 094858, International Publication Brochure No. 2004 / 002417, International Publication Brochure No. 2004 / 002424, International Publication Brochure No. 2004 / 009627, International Publication Brochure No. 2004 / 024 Pamphlet No. 761, International Publication No. 2004 / 033651, International Publication No. 2004 / 035603, International Publication No. 2004 / 043382, International Publication No. 2004 / 101600, International Publication No. 2004 / 101606, International Publication No. 2004 / 101611, International Publication No. 2004 / 106373, International Publication No. 2004 / 018667, International Publication No. 2005 / 001025, International Publication No. 2005 / 001136 Brochures, International Publication No. 2005 / 021579, International Publication No. 2005 / 025606, International Publication No. 2005 / 032460, International Publication No. 2005 / 051327, International Publication No. 2005 / 063808, International Publication No. 2005 / 063809, International Publication No. 2005 / 070451, International Publication No. 2005 / 081687, International Publication No. 2005 / 084711, International Publication No. 2005 / 103076,Examples include the erythropoietin molecule or its variants or analogues disclosed in International Publication No. 2005 / 100403, International Publication No. 2005 / 092369, International Publication No. 2006 / 50959, International Publication No. 2006 / 02646, and International Publication No. 2006 / 29094.

[0067] Other pharmaceuticals for use with this device may include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva® (denosumab), and Prolia® (denosamab); other biological agents such as Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker); Neulasta® (pegfilgrastim, PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF); Neupogen® (filgrastim, G-CSF, hu-MetG-CSF); and Nplate® (romiplostim); and small molecule drugs such as Sensipar® (cinacalcet). This device may be used with therapeutic antibodies, polypeptides, proteins, or other chemicals such as iron, e.g., fermoxyitol, iron dextran, ferric glyconate, and ferric saccharocet. Pharmaceuticals may be in liquid form or may be reconstituted from lyophilized form.

[0068] Certain exemplary proteins include, but are not limited to, fusions, fragments, analogues, variants, or derivatives of the specific proteins described below.

[0069] This includes OPGL-specific antibodies having either the light chain of Sequence ID No. 2 shown in Figure 2 of the following publications and / or the heavy chain of Sequence ID No. 4 shown in Figure 4 of the following publications, each of which is individually and specifically incorporated herein by reference in its entirety, as disclosed herein, and with respect to OPGL-specific antibodies and antibody-related proteins having sequences described herein, in particular those shown herein (9H7, 18B2, 2D8, 2E11, 16E1 and 22B3), but not limited to those, and antibodies described herein by PCT International Publication No. 03 / 002713, which is incorporated herein in its entirety, including fully humanized and human OPGL-specific antibodies, in particular fully humanized monoclonal antibodies, OPGL-specific antibodies, peptide bodies and related proteins, etc. (also referred to as RANKL-specific antibodies, peptide bodies, etc.).

[0070] TN8-19-1 to TN8-19-40, TN8-19 con1 and TN8-19 are each incorporated individually and specifically herein by reference in their entirety, as disclosed in the following publications. Myostatin-binding proteins, peptide bodies, and related proteins, including myostatin-specific peptide bodies described in U.S. Patent Application Publication No. 2004 / 0181033 and PCT International Publication No. 2004 / 058988, which are incorporated herein by reference in whole, particularly in relation to myostatin-specific peptide bodies, including the mTN8-19 family peptide bodies including con2, including those of SEQ ID NOs. 305-351, the mL2 family of SEQ ID NOs. 357-383, the mL15 family of SEQ ID NOs. 384-409, the mL17 family of SEQ ID NOs. 410-438, the mL20 family of SEQ ID NOs. 439-446, the mL21 family of SEQ ID NOs. 447-452, the mL24 family of SEQ ID NOs. 453-454, and the peptide bodies of SEQ ID NOs. 615-631.

[0071] L1H1, L1H2, L1H3, L1H4, L1H5, L1H6, L1H7, L1H8, L1H9, L1H10, L1H11, L2H1, L2H2, L2H3, L2H4, L2H5, L2H6, L2H7, L2H8, L2H9, L2H10, L2H11, L2H12, L2H13, L2H14, L3H1, L4H1, L5H1, L6H1, each in whole being fully incorporated individually and specifically by reference as disclosed in the following publications, but not limited to these, IL-4 receptor specific antibodies, particularly the following publications Antibodies, etc., as described in the publication, particularly those that suppress the activity mediated by binding to IL-4 and / or IL-13 receptors, including those described in PCT International Publication No. 2005 / 047331 or International Application PCT / U.S. Patent Application Publication No. 2004 / 37242 and U.S. Patent Application Publication No. 2005 / 112694, which are incorporated herein by reference in whole, particularly in relation to those shown in the following publications, including IL-4 receptor-specific antibodies, peptide bodies and related proteins.

[0072] Interleukin 1-receptor 1 ("IL1-R1") specific antibodies, peptide bodies, and related proteins, including, but not limited to, those described in the following publications, namely 15CA, 26F5, 27F2, 24E12, and 10H7, each of which is incorporated individually and specifically by reference in its entirety, as disclosed in the following publications.

[0073] Each whole is incorporated individually and specifically by reference in this specification, in particular the sequences described in the following publications: L1(N), L1(N)WT, L1(N)1KWT, 2xL1(N), 2xL1(N)WT, Con4(N), Con4(N)1KWT, 2xCon4(N)1K, L1C, L1C 1K, 2xL1C, Con4C, Con4C 1K, 2xCon4C This includes, but is not limited to, Ang2-specific antibodies and peptide bodies, including, 1K, Con4-L1(N), Con4-L1C, TN-12-9(N), C17(N), TN8-8(N), TN8-14(N), and Con1(N), each of which is incorporated herein by reference in whole and in particular in relation to Ang2-specific antibodies and peptide bodies, including, but is not limited to, those described in PCT International Publication No. 03 / 057134 and U.S. Patent Application Publication No. 2003 / 0229023, and in particular in relation to anti-Ang2 antibodies and formulations, various permutations of Ab526, Ab528, Ab531, A described in the following publications. Ang2-specific antibodies, peptide bodies, and related proteins, including anti-Ang2 antibodies and formulations such as those described in PCT International Publication No. 2003 / 030833, which is incorporated herein in whole by reference, including b533, Ab535, Ab536, Ab537, Ab540, Ab543, Ab544, Ab545, Ab546, A551, Ab553, Ab555, Ab558, Ab559, Ab565, AbF1AbFD, AbFE, AbFJ, AbFK, AbG1D4, AbGC1E8, AbH1C12, AblA1, AblF, AblK, AblP, and those described in PCT International Publication No. 2003 / 030833, which is incorporated herein in its entirety by reference in relation to AblP.

[0074] NGF-specific antibodies, peptide bodies, and related proteins, etc., including, but not limited to, those described in U.S. Patent Application Publication No. 2005 / 0074821 and U.S. Patent No. 6,919,426, which are incorporated herein by reference in their entirety, each in its entirety in whole, as disclosed in the following publications, specifically including, but not limited to, those described herein in their entirety in whole, U.S. Patent Application Publication No. 2005 / 0074821 and U.S. Patent No. 6,919,426.

[0075] For example, this includes, but is not limited to, human CD22-specific fully humanized antibodies such as epratuzumab (CAS registry number 501423-23-0), such as a human-mouse monoclonal hLL2 γ-chain disulfide dimer conjugated to a human-mouse monoclonal hLL2 κ chain, and in particular, human CD22-specific IgG antibodies, but is not limited to humanized and fully human monoclonal antibodies, such as humanized and fully human antibodies, but is not limited to human CD22-specific antibodies, such as those described in U.S. Patent No. 5,789,554, which is incorporated herein by reference in its entirety, CD22-specific antibodies, peptide bodies and related proteins, etc.

[0076] The IGF-1 specific antibodies shown in the following publications, L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, are each incorporated individually and specifically herein by reference in their entirety. L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L IGF-1 receptor-specific antibodies, peptide bodies and related proteins, etc., including but not limited to 34H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52 and IGF-1R-binding fragments and their derivatives, as described in PCT International Publication No. 06 / 069202, which is incorporated herein by reference in its entirety.

[0077] Furthermore, non-limiting examples of anti-IGF-1R antibodies for use in the methods and compositions of the present invention include each of those described below.

[0078] (i) Including, but not limited to, antibodies described in U.S. Patent Publication No. 2006 / 0040358 (published February 23, 2006), U.S. Patent Publication No. 2005 / 0008642 (published January 13, 2005), and U.S. Patent Publication No. 2004 / 0228859 (published November 18, 2004), such as antibody 1A (DSMZ accession number DSM ACC 2586), antibody 8 (DSMZ accession number DSM ACC 2589), antibody 23 (DSMZ accession number DSM ACC 2588), and antibody 18,

[0079] (ii) Including, but not limited to, the antibodies 2F8, A12, and IMC-A12 described in PCT International Publication No. 06 / 138729 (published December 28, 2006) and PCT International Publication No. 05 / 016970 (published February 24, 2005) and Lu et al. (2004), J. Biol. Chem. 279:2856-2865,

[0080] (iii) PCT International Publication No. 07 / 012614 (published February 1, 2007), PCT International Publication No. 07 / 000328 (published January 4, 2007), PCT International Publication No. 06 / 013472 (published February 9, 2006), PCT International Publication No. 05 / 058967 (published June 30, 2005), and PCT International Publication No. 03 / 059951 (published July 24, 2003).

[0081] (iv) Includes, but is not limited to, the antibodies described in U.S. Patent Application Publication No. 2005 / 0084906 (published April 21, 2005): antibody 7C10, chimeric antibody C7C10, antibody h7C10, antibody 7H2M, chimeric antibody *7C10, antibody GM607, humanized antibody 7C10 version 1, humanized antibody 7C10 version 2, humanized antibody 7C10 version 3, and antibody 7H2HM.

[0082] (v) Including, but not limited to, the antibodies EM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164 v1.1, huEM164 v1.2 and huEM164 v1.3 described in U.S. Patent Publication No. 2005 / 0249728 (published November 10, 2005), U.S. Patent Publication No. 2005 / 0186203 (published August 25, 2005), U.S. Patent Publication No. 2004 / 0265307 (published December 30, 2004), and U.S. Patent Publication No. 2003 / 0235582 (published December 25, 2003), as well as Maloney et al. (2003), Cancer Res. 63:5073-5083.

[0083] (vi) U.S. Patent No. 7,037,498 (published May 2, 2006), U.S. Patent Application Publication No. 2005 / 0244408 (published November 30, 2005), and U.S. Patent Application Publication No. 2004 / 0086503 (published May 6, 2004), and Cohen, et al. (2005), Clinical Cancer This includes, but is not limited to, each of the antibodies produced by hybridomas having ATCC accession numbers PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793 and antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3, as described in Res.11:2063-2073, for example, antibodies CP-751,871.

[0084] (vii) The antibody 19D12 described in U.S. Patent Application Publication No. 2005 / 0136063 (published June 23, 2005) and U.S. Patent Application Publication No. 2004 / 0018191 (published January 29, 2004), and the antibody comprising a heavy chain encoded by polynucleotides of plasmid 15H12 / 19D12 HCA(γ4) deposited with ATCC under accession number PTA-5214 and a light chain encoded by polynucleotides of plasmid 15H12 / 19D12 LCF(κ) deposited with ATCC under accession number PTA-5220, but not limited to these.

[0085] (viii) The antibodies PINT-6A1, PINT-7A2, PINT-7A4, PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1, PINT-11A2, PINT-11A3, PINT-11A4, PINT-11A5, PINT-11A7, PINT-11A12, PINT-12A1, PINT-12A2, PINT-12A3, PINT-12A4, and PINT-12A5 described in U.S. Patent Application Publication No. 2004 / 0202655 (published October 14, 2004), which are incorporated herein by reference in whole, in relation to the aforementioned antibodies, peptide bodies, and related proteins, etc., that target the IGF-1 receptor in particular.

[0086] B7-related protein 1 specific antibody, peptide body, related protein, etc. (also referred to in the literature as B7H2, ICOSL, B7h, and CD275, "B7RP-1"), in particular B7RP-specific fully human monoclonal IgG2 antibody, in particular fully human IgG2 monoclonal antibody that binds to the epitope of the first immunoglobulin-like domain of B7RP-1, in particular inhibits the interaction between B7RP-1 and ICOS, the natural receptor of B7RP-1 on activated T cells, in particular as each whole is fully incorporated herein by reference in its entirety, as disclosed below: 16H (containing a light chain variable sequence and a heavy chain variable sequence, SEQ ID NO: 1 and SEQ ID NO: 7, respectively), 5D (containing a light chain variable sequence and a heavy chain variable sequence, respectively) This includes, but is not limited to, the antibodies shown in the following publications: antibodies with number 2 and sequence number 9, 2H (containing a light chain variable sequence and a heavy chain variable sequence, with sequence numbers 3 and 10, respectively), 43H (containing a light chain variable sequence and a heavy chain variable sequence, with sequence numbers 6 and 14, respectively), 41H (containing a light chain variable sequence and a heavy chain variable sequence, with sequence numbers 5 and 13, respectively), and 15H (containing a light chain variable sequence and a heavy chain variable sequence, with sequence numbers 4 and 12, respectively). Such antibodies and related proteins are disclosed in their entirety in U.S. Patent Application Publication No. 2008 / 0166352 and PCT International Publication No. 07 / 011941, which are incorporated herein by reference.

[0087] For example, with respect to IL-15 specific antibodies and related proteins, including, but not limited to, 146B7, those disclosed in whole in U.S. Patent Publication No. 2003 / 0138421, U.S. Patent Publication No. 2003 / 023586, and U.S. Patent Publication No. 2004 / 0071702 and U.S. Patent No. 7,153,507, such as antibodies, specifically IL-15 specific antibodies such as humanized monoclonal antibodies, peptide bodies and related proteins, etc., each of which is incorporated herein by reference.

[0088] IFN γ-specific antibodies, peptide bodies and related proteins, etc., in particular human IFN γ-specific antibodies, in particular, for example, IFN γ-specific antibodies, in particular, those described in U.S. Patent Application Publication No. 2005 / 0004353, which is incorporated herein by reference in its entirety, with respect to antibodies indicated as 1118, 1118*, 1119, 1121 and 1121* in the following patent publication. The entire sequences of the heavy and light chains of each of these antibodies, and the sequences of the variable regions and complementarity-determining regions of these heavy and light chains, are incorporated herein by reference in their entirety, individually and specifically, as disclosed in the aforementioned publication and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115, respectively. In addition, the descriptions of the properties of these antibodies as described in the aforementioned publication are also incorporated herein by reference in their entirety. Specific antibodies include, as disclosed in the aforementioned public release, those having the heavy chain of SEQ ID NO: 17 and the light chain of SEQ ID NO: 18, those having the heavy chain variable region of SEQ ID NO: 6 and the light chain variable region of SEQ ID NO: 8, those having the heavy chain of SEQ ID NO: 19 and the light chain of SEQ ID NO: 20, those having the heavy chain variable region of SEQ ID NO: 10 and the light chain variable region of SEQ ID NO: 12, those having the heavy chain of SEQ ID NO: 32 and the light chain of SEQ ID NO: 20, those having the heavy chain variable region of SEQ ID NO: 30 and the light chain variable region of SEQ ID NO: 12, those having the heavy chain sequence of SEQ ID NO: 21 and the light chain sequence of SEQ ID NO: 22, those having the heavy chain variable region of SEQ ID NO: 14 and the light chain variable region of SEQ ID NO: 16, those having the heavy chain of SEQ ID NO: 21 and the light chain of SEQ ID NO: 33, and those having the heavy chain variable region of SEQ ID NO: 14 and the light chain variable region of SEQ ID NO: 31. The specific antibody intended is antibody 1119 disclosed in the aforementioned U.S. patent application publication, which has a complete heavy chain of SEQ ID NO: 17 and a complete light chain of SEQ ID NO: 18 disclosed in the aforementioned U.S. patent application publication.

[0089] TALL-1 specific antibodies, peptide bodies and related proteins, and other TALL-specific binding proteins, such as those described in U.S. Patent Application Publication No. 2003 / 0195156 and U.S. Patent Application Publication No. 2006 / 0135431, each of which is incorporated individually and specifically by reference in its entirety, as disclosed in the following publications, particularly with respect to the molecules in Tables 4 and 5B.

[0090] Parathyroid hormone ("PTH")-specific antibodies, peptide bodies, and related proteins, such as those described in U.S. Patent No. 6,756,480, which is incorporated herein by reference in whole, particularly in relation to proteins that bind to PTH.

[0091] Thrombopotiene receptor ("TPO-R")-specific antibodies, peptide bodies, and related proteins, such as those described in U.S. Patent No. 6,835,809, which is incorporated herein by reference in whole, particularly in relation to proteins that bind to TPO-R.

[0092] Hepatocyte growth factor ("HGF")-specific antibodies, peptide bodies, and related proteins, including those targeting the HGF / SF:cMet axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / dispersion (HGF / SF) as described in U.S. Patent Application Publication No. 2005 / 0118643 and PCT International Publication No. 2005 / 017107, huL2G7 as described in U.S. Patent No. 7,220,410, and OA-5d5 as described in U.S. Patent No. 5,686,292 and U.S. Patent No. 6,468,529 and PCT International Publication No. 96 / 38557, each incorporated herein in whole by reference, particularly in relation to proteins that bind to HGF.

[0093] TRAIL-R2 specific antibodies, peptide bodies, and related proteins, such as those described in U.S. Patent No. 7,521,048, which is partially related to proteins that bind to TRAIL-R2 and is incorporated herein by reference in whole.

[0094] Activin A-specific antibodies, peptide bodies, related proteins, etc., including, but not limited to, those described in U.S. Patent Application Publication No. 2009 / 0234106, which is incorporated herein by reference in whole, and which are particularly related in part to proteins that bind to activin A.

[0095] TGF-β-specific antibodies, peptide bodies, related proteins, etc., including, but not limited to, those described in U.S. Patent No. 6,803,453 and U.S. Patent Application Publication No. 2007 / 0110747, each incorporated herein in whole by reference, particularly in relation to proteins that bind to TGF-β.

[0096] Proteins that bind to amyloid-beta protein include, but are not limited to, those described in PCT International Publication No. 2006 / 081171, which is incorporated herein by reference in whole, particularly in relation to proteins that bind to amyloid-beta protein. One antibody intended is one having a heavy chain variable region containing SEQ ID NO: 8 and a light chain variable region containing SEQ ID NO: 6, as disclosed in the aforementioned publication.

[0097] Proteins that bind to c-Kit and / or other stem cell factor receptors, including but not limited to those described in U.S. Patent Application Publication No. 2007 / 0253951, which is incorporated herein by reference in whole, including c-Kit-specific antibodies, peptide bodies, related proteins, etc., which are particularly related in part to these proteins.

[0098] Proteins that bind to OX40L and / or other ligands of the OX40 receptor, including, but not limited to, those described in U.S. Patent Application Publication No. 2006 / 0002929, which is incorporated herein by reference in whole, OX40L-specific antibodies, peptide bodies, associated proteins, etc., particularly in part with respect to such proteins.

[0099] Activase® (alteplase, tPA), Aranesp® (darbepoetin α), Epogen® (epoetin α or erythropoietin), GLP-1, Avonex® (interferon β-1a), Bexxar® (tositumomab, anti-CD22 monoclonal antibody), Betaseron® (interferon-β), Campath® (alemtuzumab, anti-CD52 monoclonal antibody), Dynepo® (epoetin δ), Velcade® (bortezomib), MLN0002 (anti-α4β7) mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin α), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Huma trope® (somatropin, human growth hormone), Humira® (adalimumab), insulin in solution, Infergen® (interferon αcon-1), Natrecor® (nesiritide, recombinant human type B natriuretic peptide (hBNP)), Kineret® (anakinra), Leukine® (sargamostim, rhuGM-CSF), LymphoCide® (epiratuzumab, anti-CD22 mAb), Benlysta® (lymphostat B, belimumab, anti-BlySmAb), Metalyse® (Tenecteplase, t-PA analog), Mircera® (Methoxypolyethylene glycol-epoetin β), Mylotarg® (Gemtuzumab ozogamicin), Raptiva® (Ephalizumab), Cimzia® (Certolizumab pegol, CDP870), Soliris® (Eculizumab), pexelizumab (Anti-complement C5), Numax® (MEDI-524), Lucentis® (Ranivizumab), Panorex® (17-1A, edrecolomab), Trabio® (Reldelimumab), TheraCim hR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem (registered trademark) (IDM-1), OvaRex (registered trademark) (B43.13), Nuvion (registered trademark) (vizilizumab), cantuzumab meltansine (huC242-DM1), NeoRecormon (registered trademark) (epoetin β), Neumega (registered trademark) (oprelbequin, human interleukin-11), Neulasta (registered trademark) (PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen (registered trademark) (filgrastim, G-CSF, hu-MetG-CSF), Orthoclone OKT3 (registered trademark) (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit (registered trademark) (epoetin α), Remicade (registered trademark) (infliximab, anti-TNFα monoclonal antibody), Reopro (registered trademark) (absiximab, anti-GP)(Ib / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanorimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alfa-2a), Simulect® (basiliximab), Prexige® (lumi Lacoxib, Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Patent No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax®, Vectibix® (panitumumab), Xolair® (omalizumab), ETI211 (anti-MRSA) mAb), IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor co-protein)), VEGF trap (Ig domain of VEGFR1 fused with IgG1 Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimabe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23 mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist), CNTO148 (golimumab, anti-TNFα mAbs), HGS-ETR1 (mapatuzumab, human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (saltumumab), M200 (boroximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. Clostridium difficile toxin A and toxin BC mAbs)MDX-066 (CDA-1 and MDX-1388), anti-CD22 dsFv-PE38 complex (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax-TAC), anti-CD3 mAb (NI-0401), adekum mab, anti-CD30 mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMax CD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF stage 1 fibroblast (FG-3019), anti-CTLA4 mAb, anti-Eotakisin 1 mAb (CAT-213), anti-FGF8 mAb, anti-GD2 mAb, anti-GM2 mAb, anti-GDF-8 HIT mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12 mAb (ABT-874), anti-IL12 / IL23 mAb (CNTO1275), anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-Integrin receptor mAb (MDX-018, CNTO95), anti-IP10 ulcerative colitis mAb (MDX-1100), anti-LLY antibody, BMS-66513, anti-mannos receptor / hCGβ mAb (MDX-1307), anti-mesotrelin dsFv-PE38 conjugate (CAT-5001), anti-PD1 mAb (MDX-1106 (ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβ mAb (GC-1008), anti-TRAIL receptor-2 HIT mAb (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, anti-ZP3 mAb (HuMax-ZP3), NVS Antibody Phase 1, and NVS Antibody Phase 2 contain the NANONA antibodies as exemplified by others.

[0100] Examples of sclerostin antibodies include, but are not limited to, romosozumab, brosozumab, or BPS804 (Novartis). Further therapeutic agents such as rilotumumab, bixalomer, trevananib, ganitumumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX, or XGEVA may also be included. In addition, monoclonal antibodies (IgG) that bind to human proprotein convertase subtilisin / kexin type 9 (PCSK9) may be included in the device. Such PCSK9-specific antibodies include the following patents or patent applications, each incorporated herein by reference in whole for any purpose: U.S. Patent No. 8,030,547, U.S. Patent No. 8,563,698, U.S. Patent No. 8,829,165, U.S. Patent No. 8,859,741, U.S. Patent No. 8,871,913, U.S. Patent No. 8,871,914, U.S. Patent No. 8,883,983, U.S. Patent No. 8,889,834, U.S. Patent No. 8,981,064, U.S. Patent No. 9,056,915, U.S. Patent No. 8,168,762, U.S. Patent No. 9,045,547, U.S. Patent No. 8,030,457, U.S. Patent No. 8,030,457, U.S. Patent No. 8,829,165, U.S. Patent No. 8,981,064, U.S. Patent No. 8,030,Specifications No. 457, U.S. Patent Application Publication No. 2013 / 0064825, U.S. Patent Application Publication No. 2012 / 0093818, U.S. Patent Application Publication No. 2013 / 0079502, U.S. Patent Application Publication No. 2014 / 0357850, U.S. Patent Application Publication No. 2011 / 0027287, U.S. Patent Application Publication No. 2014 / 0357851, U.S. Patent Application Publication No. 2014 / 0357854, United States U.S. Patent Application Publication No. 2015 / 0031870, U.S. Patent Application Publication No. 2013 / 0085265, U.S. Patent Application Publication No. 2013 / 0079501, U.S. Patent Application Publication No. 2012 / 0213797, U.S. Patent Application Publication No. 2012 / 0251544, U.S. Patent Application Publication No. 2013 / 0072665, U.S. Patent Application Publication No. 2013 / 0058944, U.S. Patent Application Publication No. 201 Specifications 3 / 0052201, U.S. Patent Application Publication No. 2012 / 0027765, U.S. Patent Application Publication No. 2015 / 0087819, U.S. Patent Application Publication No. 2011 / 0117011, U.S. Patent Application Publication No. 2015 / 0004174, U.S. Provisional Patent Application No. 60 / 957,668, U.S. Provisional Patent Application No. 61 / 008,965, U.S. Provisional Patent Application No. 61 / 010,630, U.S. Provisional Patent U.S. Provisional Patent Application No. 61 / 086,133, U.S. Provisional Patent Application No. 61 / 125,304, U.S. Provisional Patent Application No. 61 / 798,970, U.S. Provisional Patent Application No. 61 / 841,039, U.S. Provisional Patent Application No. 62 / 002,623, U.S. Provisional Patent Application No. 62 / 024,399, U.S. Provisional Patent Application No. 62 / 019,729, U.S. Provisional Patent Application No. 62 / 067,637, U.S. Patent Application No. 14 / 777,Specification No. 371, International Application PCT / US Patent Publication No. 2013 / 048714, International Application PCT / US Patent Publication No. 2015 / 040211, International Application PCT / US Patent Publication No. 2015 / 056972, International Publication No. 2008 / 057457 Brochure, International Publication No. 2008 / 057458 Brochure, International Publication No. 2008 / 057459 Brochure, International Publication No. 2008 / 063382 Brochure, International Publication No. 2008 Pamphlet No. / 133647, International Publication No. 2009 / 100297, International Publication No. 2009 / 100318, International Publication No. 2011 / 037791, International Publication No. 2011 / 053759, International Publication No. 2011 / 053783, International Publication No. 2008 / 125623, International Publication No. 2011 / 072263, International Publication No. 2009 / 055783, International Publication No. 2 Pamphlet No. 012 / 0544438, International Publication No. 2010 / 029513, International Publication No. 2011 / 111007, International Publication No. 2010 / 077854, International Publication No. 2012 / 088313, International Publication No. 2012 / 101251, International Publication No. 2012 / 101252, International Publication No. 2012 / 101253, International Publication No. 2012 / 109530, Country Examples include, but are not limited to, Repatha® (evolocumab) and Praluent® (alilocuma), as disclosed in International Publication No. 2001 / 031007, International Publication No. 2009 / 026558, International Publication No. 2009 / 131740, International Publication No. 2013 / 166448, and International Publication No. 2014 / 150983, as well as their molecules, variants, analogues, or derivatives.

[0101] This may also include tarimodine laharpalepvek or other oncolytic HSVs for the treatment of melanoma or other cancers. Examples of oncolytic HSVs include, but are not limited to, tarimodine laharpalepvek (U.S. Patent Nos. 7,223,593 and 7,537,924), OncoVEXGALV / CD (U.S. Patent No. 7,981,669), OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143), G207, 1716, NV1020, NV12023, NV1034 and NV1042 (Vargehes et al. (2002), CancerGene Ther., 9(12):967-978).

[0102] TIMP is also included. TIMP is an endogenous tissue inhibitor (TIMP) of metalloproteinases, which is important in many natural processes. TIMP-3 is expressed by various cells and / or present in the extracellular matrix, and inhibits all major cartilage-degrading metalloproteinases, and may play a role in many connective tissue degradation diseases, including rheumatoid arthritis and osteoarthritis, as well as in cancer and cardiovascular conditions. The amino acid sequence of TIMP-3 and the nucleic acid sequence of the DNA encoding TIMP-3 are disclosed in U.S. Patent No. 6,562,596, issued May 13, 2003, which is incorporated herein by reference. A description of TIMP mutations can be found in U.S. Patent Publication No. 2014 / 0274874 and PCT International Publication No. 2014 / 152012.

[0103] This includes antagonistic antibodies against the human calcitonin gene-related peptide (CGRP) receptor, as well as bispecific antibody molecules that target the CGRP receptor and other headache targets. Further information on these molecules can be found in PCT International Publication No. 2010 / 075238.

[0104] In addition, bispecific T cell-inducing antibodies (BiTe), such as blinatumomab, can be used in the device. Alternatively, APJ macroagonists, such as apelin or analogues, can be included in the device. Information on such molecules can be found in PCT International Publication No. 2014 / 099984.

[0105] In certain embodiments, the drug comprises a therapeutically effective amount of anti-thymocrine interstitial lymphocyte generating factor (TSLP) or TSLP receptor antibody. Examples of anti-TSLP antibodies that may be used in such embodiments include, but are not limited to, those described in U.S. Patent No. 7,982,016, U.S. Patent No. 8,232,372, and U.S. Patent Application Publication No. 2009 / 0186022. Examples of anti-TSLP receptor antibodies include, but are not limited to, those described in U.S. Patent No. 8,101,182. In a particularly preferred embodiment, the drug comprises a therapeutically effective amount of anti-TSLP antibody as indicated as A5 in U.S. Patent No. 7,982,016.

[0106] While the Disclosure has been described in relation to various embodiments, it will be understood that the Disclosure is subject to further modification. Generally, the Disclosure is intended to encompass any variations, uses, or adaptations of the disclosed subject matter, including deviations from the Disclosure, that are within the scope of known and customary practices in the Art to which the Disclosure belongs, in accordance with the principles of the Disclosure.

[0107] It should be noted that the structure and configuration of drug delivery devices and their various components and assemblies, as shown in various exemplary embodiments, are merely illustrative. While this disclosure describes in detail only a few embodiments of the subject of interest, a person skilled in the art considering this disclosure will readily understand that many modifications (e.g., variations in the size, dimensions, structure, shape and proportions of various elements, parameter values, mounting configurations, material use, color, orientation, etc.) are possible without substantially departing from the novel teachings and merits of the subject disclosed herein. For example, elements shown as integrally formed may consist of multiple parts or elements, and vice versa. The positions of elements may also be reversed or otherwise modified, and the nature or number of separate elements or positions may be partially altered or changed. Thus, all such modifications are intended to be included within the scope of this disclosure as defined in the appended claims. Furthermore, the order or sequence of any process or method steps may be modified or rearranged according to alternative embodiments. Without departing from the scope of this disclosure, other substitutions, modifications, variations, and omissions may be made in the design, operating conditions, and arrangement of various exemplary embodiments.

Claims

1. A container assembly, A container having an internal volume and an end surface, wherein the opening is formed on the end surface and communicates with the internal volume, A septum including a proximal end and an distal end, The base end extends into the internal volume of the container through the opening, the tip end includes a flange positioned outside the base end and a tip-side opposing end surface configured to be penetrated or pierced by a needle, at least the end portion of the flange contacts the end surface of the container and is made of a first material, at least the base end and the tip-side opposing end surface are made of a second material, the first material is permeable to gaseous sterilizer and the second material is less permeable to gaseous sterilizer than the first material, and the septum and A container assembly including the container.

2. The container assembly according to claim 1, wherein the gaseous sterilizer comprises at least one of ethylene oxide or vapor.

3. The container assembly according to claim 1, wherein the tip of the septum is made entirely from the second material, except for the end portion of the flange.

4. The container assembly according to claim 1, wherein a portion of the tip of the septum is made of a second material.

5. A container assembly according to any one of claims 1 to 4, comprising a stopper slidably disposed within the internal volume of the container, and a drug disposed between the stopper and the septum.

6. The container assembly according to any one of claims 1 to 5, further comprising a fluoropolymer film that completely covers the septum, in addition to the proximal end-facing surface of the end portion of the flange and the outer peripheral surface of the end portion of the flange.

7. A container assembly according to any one of claims 1 to 6, comprising a fastener that engages with the tip-side opposing surface of the septum and the outer surface of the container to fix the flange to the end surface of the container, wherein the fastener allows the gaseous sterilizer to pass through.

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