Gas-permeable sealing member for drug containers and method of assembly - Patents.com

Abstract

A drug delivery device, a sealing member for a container housed within such a drug delivery device, and an associated assembly method are disclosed. The drug delivery device may include a housing, a container disposed within the housing and having an internal volume, a drug disposed within the internal volume, and a septum. The container may have an opening formed in an end surface and communicating with the internal volume. The septum may include a proximal end inserted into the internal volume of the container through the opening. Additionally, the septum may include a distal end disposed outside the proximal end and having a flange that contacts the end surface of the container. At least an end portion of the flange may be made of a material that is permeable to a gas sterilant.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The benefit of priority is claimed from U.S. Provisional Patent Application No. 62 / 535,777, filed July 21, 2017, the entire contents of which are expressly incorporated by reference herein.

[0002] The present disclosure relates generally to drug containers, and more particularly to the assembly and sterilization of such containers within an injection system. [Background technology]

[0003] Many drug containers or vials include an opening covered by a septum, sometimes referred to as a stopper. The septum is typically pierceable by a needle or other sharp member to seal the drug within the container and provide fluid communication with the drug. Conventional septa are typically constructed of materials that have very low gas and / or moisture permeability to prevent the ingress of contaminants and the leakage of the drug composition. Nonetheless, there is a risk of contamination along the interface where the septum meets the container.

[0004] Some drug containers are filled under sterile or aseptic conditions and closed with a septum, then stored in medical grade packaging until used by a patient or healthcare provider. Under such circumstances, the risk of contamination of the interface between the septum and the container is low. In other circumstances, the drug container may be exposed to non-sterile or non-sterile 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 or pen injector, for the purpose of creating a pre-filled and pre-loaded drug delivery device. Contamination can occur, for example, during transportation of the pre-filled drug container between a filling facility and an attachment facility, and / or within an area of ​​the attachment facility that is not operated under sterile or aseptic conditions. To address this risk of contamination, manufacturers often subject the drug delivery device to a sterilization process near the end of the assembly process.

[0005] However, at this stage, the available sterilization processes may be limited because certain sterilization processes may have deleterious effects on the drug in the container and / or the materials used to construct the container. Radiation sterilization (e.g., gamma sterilization or electron beam sterilization) may cause oxidation of the drug and / or discoloration of the glass of the container. Gas sterilization processes such as ethylene oxide (EtO) and water vapor treatments may not cause damage to the drug or container material, but they are often ineffective at killing bacteria or spores inoculated at the interface between a conventional septum and the container. Conventional septa have very low gas permeability, thus preventing gas sterilants from reaching the interface between the septum and the container. Even prolonged ethylene oxide treatments (e.g., up to 30 hours) have been found to be ineffective at sterilizing the interface between a conventional septum and the container. Furthermore, prolonged ethylene oxide treatment creates significant manufacturing challenges due to the need for extended aeration cycles (e.g., 30-60 days) to extract residual ethylene oxide from the container and other components of the drug delivery device. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure describes septa, container assemblies, drug delivery devices and related assembly methods that embody advantageous alternatives to existing types of such devices and methods and that may address one or more of the problems or needs noted herein, as well as provide other benefits and advantages.

[0007] One aspect of the present disclosure provides a drug delivery device including a housing, a container, a drug, and a septum. The container may be disposed within the housing and have an interior volume and an end surface. An opening may be formed in the end surface and communicate with the interior volume. The drug may be disposed within the interior volume of the container. The septum may include a proximal end and a distal end. The proximal end of the septum may be inserted into the interior volume of the container through the opening. The distal end of the septum may include a flange, the flange being disposed outside the proximal end and contacting the end surface of the container. At least an end portion of the flange may be made of a first material, and the first material may be permeable to a gas sterilant. Additionally, at least a portion of the distal end of the septum may be made of a second material.

[0008] Another aspect of the present disclosure provides a method of assembling a drug delivery device, the method including: (a) providing a container assembly including a container having an interior volume and an end surface, an opening formed in the end surface and in communication with the interior volume; and a septum including a proximal end and a distal end, the proximal end being inserted into the interior volume of the container through the opening and the distal end including a flange, the flange being disposed outside the proximal end and contacting the end surface of the container, at least an end portion of the flange being made of a first material, the first material being permeable to a gas sterilant; (b) sterilizing the container assembly with a gas sterilant such that the gas sterilant diffuses through the first material to sterilize the end surface of the container; (c) filling the interior volume of the container with a drug; and (d) attaching the container assembly to the drug delivery device.

[0009] Yet another aspect of the present disclosure provides a container assembly including a container and a septum. The container may have a container having an interior volume and an end surface. An opening may be formed in the end surface and communicate with the interior volume. The septum may include a proximal end and a distal end. The proximal end of the septum may be insertable into the interior volume of the container through the opening. The distal end of the assembly may include a flange disposed outside the proximal end. At least an end portion of the flange may be made of a first material, and the first material may be permeable to a gas sterilant. At least a portion of the distal end of the septum may be made of a second material.

[0010] A further aspect of the present disclosure provides a container assembly including a container, a septum, and an annular sealing member. The container may have an interior volume and an end surface. An opening may be formed in the end surface and communicate with the interior volume. The septum may include a proximal end and a distal end. The proximal end of the septum may be insertable into the interior volume of the container through the opening. The distal end of the septum may include a flange disposed outside the proximal end. The annular sealing member may be disposed between the flange and the end surface of the container. The annular sealing member may be made of a first material, and the first material may be permeable to a gas sterilant.

[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 the drug container, and a distal end including a flange disposed radially outward of the proximal end. The flange may include an exterior peripheral surface and a proximal facing surface. At least an end portion of the flange may be made of a first material. The first material is permeable to a gas sterilant such that the gas sterilant is permitted to diffuse through the first material between the exterior peripheral surface of the flange and the proximal facing surface of the flange. At least a portion of the distal end of the septum may be made of a second material.

[0012] Yet another aspect of the present disclosure provides a drug delivery device including a housing, a container, a drug, and a septum. The container may be disposed within the housing and may have an interior volume and an end surface. An opening may be formed in the end surface and may be in communication with the interior volume. The drug may be disposed within the interior volume of the container. The septum may include a proximal end and a distal end. The proximal end of the septum may be inserted into the interior volume of the container through the opening. The distal end of the septum may include a flange, the flange being disposed outside the proximal end and contacting the end surface of the container. Additionally, the entire septum may be made of a material that is permeable to a gas sterilant.

[0013] The present disclosure will be more fully understood from the following description read in conjunction with the accompanying drawings, in which: Some of the drawings may be simplified by omitting selected elements to more clearly show other elements. The omission of such elements in some drawings does not necessarily indicate the presence or absence of a particular element in any of the illustrative embodiments, unless expressly described in the corresponding written description. Additionally, none of the drawings are necessarily drawn to scale. [Brief description of the drawings]

[0014] [Figure 1] 1 shows a schematic cross-sectional view of one embodiment of a drug delivery device according to the principles of the present disclosure. [Figure 2A] 2 illustrates an exploded view of the container assembly shown in FIG. 1, with the container and stopper shown in cross-section. [Figure 2B] 2B shows an assembled view of the container assembly shown in FIG. 2A, with the container, stopper and fastener shown in cross-section. [Figure 3A] FIG. 2C is a top perspective view of the septum shown in FIGS. 1 to 2B. [Figure 3B] FIG. 3B is a bottom perspective view of the septum shown in FIG. 3A. [Figure 4] 1 is a cross-sectional view of one embodiment of a septum constructed in accordance with the principles of the present disclosure. [Diagram 5] 1 is a cross-sectional view of another embodiment of a septum constructed in accordance with the principles of the present disclosure. [Figure 6] 11 is a cross-sectional view of yet another embodiment of a septum constructed in accordance with the principles of the present disclosure. [Figure 7] 11 is a cross-sectional view of yet another embodiment of a septum constructed in accordance with the principles of the present disclosure. [Figure 8] FIG. 6 is a partial cross-sectional view of an embodiment of the septum of FIG. 5 coated with a resin film. [Figure 9A] 1 illustrates an exploded view of another embodiment of a container assembly, with the container, stopper and annular sealing member shown in cross-section. [Figure 9B] 9B shows an assembled view of the container assembly shown in FIG. 9A, with the container, stopper, annular sealing member and fastener shown in cross-section. [Figure 10] FIG. 9C is a top perspective view of the annular sealing member shown in FIGS. 9A and 9B. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The present disclosure generally relates to protecting drugs stored in containers (e.g., vials or ampoules) from microorganisms and other contaminants. Hermetic closure of the opening of such containers is often accomplished by a septum, or what some refer to as a stopper. The septum may include a proximal or lower end that is inserted into the container through the opening, and an enlarged distal or upper end that abuts an end surface or edge of the container. Engagement of the enlarged tip of the septum with the end surface of the container can prevent the ingress of contaminants. In addition to providing a contaminant barrier, the septum disclosed herein advantageously facilitates sterilization of the interface between the septum and the container during manufacture. This aspect of the septum disclosed herein is facilitated by constructing the septum, at least in part, from a material that is permeable to a gas sterilant, such as, for example, ethylene oxide (EtO) and / or steam. This permeability may allow the gas sterilant to diffuse through the septum to sterilize the interface between the septum and the container. Other parts of the septum may be constructed of different materials that are less permeable or even impermeable to the gas sterilant, resulting in a composite septum made of at least two different materials. Also, as described below, the embodiments of the septum according to the present disclosure advantageously allow a drug container, which may or may not be prefilled, to be attached or assembled to a drug delivery device under non-sterile or non-aseptic conditions and then subjected to a gas sterilization process without harming the drug stored in the container. Also disclosed is a sealing member, such as a gasket, that is separate from the septum and is disposed between the septum and the end surface of the container. The sealing member may be constructed of a material that is permeable to the gas sterilant to provide a diffusion path for the gas sterilant to remove or reduce contaminants present on the end surface of the container.

[0016] Each of the aforementioned components and methods of assembly of drug delivery devices containing these components will now be described in more detail.

[0017] Before describing various embodiments of septa constructed in accordance with the principles of the present disclosure, a general overview of a drug delivery device that may incorporate the septum embodiments described below is provided with reference to FIG.

[0018] FIG. 1 illustrates one embodiment of a drug delivery device 10 that can be operated to deliver a drug to a patient subcutaneously or transdermally. In the illustrated embodiment, the drug delivery device 10 is configured as a wearable drug delivery device, such as an on-body injector or a portable infusion pump, that is removably attached to the patient's tissue 11 (e.g., the patient's skin). In other embodiments (not shown), the drug delivery device 10 can be configured as a pen injector, such as an autoinjector or injection pen, that is temporarily held against the patient's tissue 11 for the course of an injection. The drug delivery device 10 can be configured to automatically deliver a fixed or patient / operator settable dose of a drug over a controlled or selected time period. Additionally, the drug delivery device 10 can be for self-administration by the patient or can be operated by formally trained medical personnel or other caregivers who perform the injection.

[0019] In general, the drug delivery device 10 may include an insertion mechanism 12, a reservoir 14, a fluid path assembly 22, a drive mechanism 24, and a controller 26, each of which may be disposed within an interior space of a main housing 29. An actuator 28 (e.g., a user-depressible button, a touch screen, a microphone, etc.) may protrude from or be disposed on an exterior surface of the housing 29 and may be configured to initiate operation of the drug delivery device 10 by activating the insertion mechanism 12, the fluid path assembly 22, the drive mechanism 24, the controller 26, and / or other mechanisms and / or electronics by mechanical and / or electrical means (shown in dashed lines in FIG. 1). In embodiments in which the actuator 28 is a button that is pressed or otherwise physically operated by a user or patient, the actuator 28 may be configured to exert the motive 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, either directly or indirectly through a mechanical linkage, to the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms such that manually pushing or otherwise interacting with the actuator 28 provides the motive force necessary to activate the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms. For example, in some embodiments, manually pushing the actuator 28 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 causing the container access needle to pierce the seal member and enter the reservoir or interior 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 embodiments, the controller 26 may include a processor (e.g., a microprocessor) and a non-transitory memory for storing programmable instructions executed by the processor. Additionally, in such embodiments, the drug delivery device 10 may include internal actuators (e.g., electric motors, pneumatic or hydraulic pumps, and / or pressurized gas or liquid sources) separate from the actuators 28 that apply the 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 electrical control signals received from the controller 26.

[0020] 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., lights, graphical displays, etc.) and / or a window 35 for viewing the container 14 and the drug 32 contained therein. The one or more visual indicators 42 may be used to communicate information to a user regarding the operational status of the drug delivery device 10 and / or the status of the drug 32. An opening 31 may be formed in the bottom wall 25, and optionally a pierceable sterile barrier 33 may extend across the opening 31 to seal the interior of the housing 29 prior to use. In some embodiments, the pierceable sterile barrier 33 may be omitted, and instead a removable sealing member (not shown) may cover and hermetically close the opening 31 prior to use.

[0021] More specifically, with regard to the window 35, this element may be constructed from a transparent or translucent material and may be generally aligned with the container 14 to allow the patient or user of the drug delivery device 10 to see the drug 32 in the container 14 and / or to confirm 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, the window 35 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 ranges. To protect drugs that are primarily sensitive to light in the UV and / or infrared ranges, a dark tint may be added to the window 35 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 light in the visible range, it may not be necessary to add a dark tint to the window 35 and / or shrink 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 identification of the drug 32 in the container 14 while blocking approximately (e.g., ±10%) 50% or less of the light in the visible range. In some embodiments, the portion of visible light blocked by the window 35 may range from approximately (e.g., ±10%) 0-50%, or 10-50%, or 20-50%, or 25-50%, or 0-40%, or 0-30%, or 0-25%, depending on the photosensitivity of the drug 32 and / or the typical visual acuity of the patient population for the drug 32, among other considerations. Adding a polarizing filter to window 35, instead of darkening window 35 and / or reducing the size of window 35, advantageously protects drug 35 from light in the visible range without substantially impairing the ability of a patient or user of drug delivery device 10 to see drug 32 prior to 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 may be actuated to move the delivery member from a retracted position within the housing 29 to a deployed position extending outside the housing 29. In this embodiment, this involves the insertion mechanism 12 inserting the trocar 21 and the hollow cannula 23 surrounding the trocar 21 through a pierceable sterile barrier 33 into the patient's tissue 11, as shown in FIG. 1. Immediately or shortly thereafter, the insertion mechanism 12 may automatically retract the trocar 21, leaving the distal open end of the cannula 23 inside the patient for subcutaneous delivery of the drug 32. The trocar 21 may be solid and have a sharp end for piercing the patient's skin 11. Additionally, the trocar 21 may be made of a more rigid material 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 the cannula 23 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 stiff 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 upon depression of the actuator 28 to insert the trocar 21 and cannula 23 or hollow needle into the patient. Additionally, retraction of the trocar 21 may be accomplished by automatic release of another spring after the trocar 21 and cannula 23 are inserted into the patient. Other power sources for insertion and / or retraction are also contemplated, including, for example, an electric motor, a hydraulic or pneumatic pump, or a canister that releases pressurized gas or liquid to provide the actuation energy.

[0024] Continuing to refer to FIG. 1 , the container 14, which in some contexts may be referred to as a primary container, may include walls 38 that define an interior volume 30 or reservoir that contains the drug 32. In some embodiments, the interior volume 30 may be pre-filled with the drug 32 by the drug manufacturer prior to attachment of the container 14 to the drug delivery device 10. In some embodiments, the container 14 may be rigidly connected to the housing 29 such that the container 14 cannot move relative to the housing, while in other embodiments, the container 14 may be slidably connected to the housing 29 such that the container 14 can move relative to the housing 29 during operation of the drug delivery device 10. The container 14 may have an elongated barrel-like or cylindrical shape that extends along a 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 or substantially perpendicular or otherwise non-parallel to the direction in which the insertion mechanism 12 inserts a delivery member, such as the cannula 23, into the patient. This configuration may allow the on-body injector to have a generally flat, low-profile shape that may be worn by a patient without impeding patient movement. First, a stopper 34 or other piston member may be disposed within the interior volume 30 at a proximal end 36 of the container 14. The stopper 34 may sealingly and slidably engage an inner surface 43 of a 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 within container 14 prior to delivery can be any amount within the range of about (e.g., ±10%) 0.5-20 mL, or any amount within the range of about (e.g., ±10%) 0.5-10 mL, or any amount within the range of about (e.g., ±10%) 1-10 mL, or any amount within the range of about (e.g., ±10%) 1-8 mL, or any amount within the range of about (e.g., ±10%) 1-5 mL, or any amount within the range of about (e.g., ±10%) 1-3.5 mL, or any amount within the range of about (e.g., ±10%) 1-3 mL, or any amount within the range of about (e.g., ±10%) 1-3 mL, or For example, the amount of drug 32 may be any amount within the range of about (e.g., ±10%) 1-2.5 mL, or any amount within the range of about (e.g., ±10%) 1-2 mL, or any amount within the range of about (e.g., ±10%) 4 mL or less, or any amount within the range of about (e.g., ±10%) 3.5 mL or less, or any amount within the range of about (e.g., ±10%) 3 mL or less, or any amount within the range of about (e.g., ±10%) 2.5 mL or less, or any amount within the range of about (e.g., ±10%) 2 mL or less, or any amount within the range of about (e.g., ±10%) 1.5 mL or less, or any amount within the range of about (e.g., ±10%) 1 mL or less. The internal volume 30 of the container 14 may be completely or partially filled with a drug 32. The drug 32 may be one or more of the drugs described below, such as, for example, a granulocyte colony stimulating factor (G-CSF), a PCSK9 (human proprotein convertase subtilisin / kexin type 9) specific antibody, a sclerostin antibody, or a calcitonin gene-related peptide (CGRP) antibody.

[0026] During operation of the drug delivery device 10, the drive mechanism 24 may push the stopper 34 along the longitudinal axis A from the proximal end 36 of the container 14 to the distal end 37 of the container 14 to expel 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 upon pressing the actuator 28. The springs may expand after their release to move the stopper 34 along the longitudinal axis A within the interior volume 30 from the proximal end 36 of the container 14 to the distal 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, including, for example, one or more sprocket gears, to cause axial movement of the stopper 34 within the interior volume 30. In yet another embodiment, the drive mechanism 24 may include both an electric motor and a spring, with the electric motor adjusting the extension of the spring via a tether or pulley system. In yet another embodiment, the drive mechanism 24 may include a canister that releases pressurized gas or liquid to provide the actuation energy.

[0027] An opening 45 (see FIG. 2A ) may be formed in the distal end 37 of the container 14 at a distal surface 72 (see FIG. 2A ) of the wall 38. At least prior to operation of the drug delivery device 10, the opening 45 may be covered and hermetically closed by a septum 40 connected to the distal end 37 of the container 14. Generally, the septum 40 may be configured to selectively allow access to the interior volume 30. During operation, the septum 40 may be physically altered to allow fluid communication with the drug 32 within the interior volume 30. As described below, the septum 40 may be constructed of a flexible or elastically deformable material, such as rubber, that can be penetrated or pierced by a tip, i.e., sharp end 66, of a container access needle 64 attached to the fluid pathway assembly 22. In some embodiments, the septum 40 may be fastened or otherwise secured to the tip surface 72 by a fastener 94 (see FIG. 2B) and / or may be attached directly to the tip surface 72 .

[0028] With further reference to FIG. 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 operation of the drug delivery device 10. Prior to use of the drug delivery device 10, the fluid pathway assembly 22 may not be in fluid communication with the container 14. During setup of the drug delivery device 10 or during an initial stage of operation of the drug delivery device 10 prior to drug delivery, the necessary connections may be enabled, connected, or opened manually by a user or automatically by the drug delivery device 10 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 to push the drug 32 stored in the container 14 through the sterile fluid path of the fluid pathway assembly 22 and into the cannula 23 or needle of the insertion mechanism 12 for subcutaneous delivery to a patient.

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

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

[0031] Prior to operation of the drug delivery device 10, a seal member 60 (e.g., a septum) connected to the first end 44 of the fluid pathway assembly 22 may cover and initially hermetically close an opening at the first end 44 of the fluid pathway assembly 22. In a general sense, the seal member 60 may be configured to control access to the fluid pathway 50. In some embodiments, the seal member 60 may be physically altered to allow fluid communication with the fluid pathway 50 during operation of the device 10. The seal member 60 may be axially aligned with the septum 40 such that a proximal exterior surface of the seal member 60 faces a distal surface of the septum 40. In some embodiments, both the septum 40 and the seal member 60 may be axially aligned along the longitudinal axis A of the container 14 when attached to the drug delivery device 10. Additionally, in some embodiments, the container access needle 64 may be axially aligned with the longitudinal axis A of the container 14.

[0032] 1 , a vessel access needle 64, which may be rigid and hollow, may extend from the first end 44 of the fluid pathway assembly 22. A first end 66 of the vessel access needle 64, which may be sharp, may protrude from the first end 44 of the fluid pathway assembly 22, and a second end 68 of the vessel access needle 64 may be in fluid communication with the fluid passageway 50. The first end 66 of the vessel access needle 64 may have an opening that is initially covered and sealed by the seal member 60 or embedded within the seal member 60. In some embodiments, the fluid pathway assembly 22 may include an attachment member 51 or connection hub for rigidly connecting the vessel access needle 64 to the remainder of the fluid pathway assembly 22 such that the vessel access needle 64 cannot move relative to the fluid pathway assembly 22, and to the extent that the fluid pathway assembly 22 moves relative to the housing 29, the fluid pathway assembly 22 and the vessel access needle 64 move together relative to the housing 29 as a single unit. Additionally, the seal member 60 may be attached to the vessel access needle 64 such that the seal member 60 is connected to the first end 44 of the fluid pathway assembly 22 via the vessel access needle 64. Additionally, in such embodiments, the seal member 60 may be constructed as a deformable septum or as a collapsible or rigid sleeve that defines a sterile interior chamber that seals the exposed first end 66 of the vessel access needle 64.

[0033] Additionally, where appropriate, any of the above-described subassemblies, features, components, features, functions, methods of manufacture, methods of use, and other aspects of drug delivery device 10 may be substituted and / or combined with any of the subassemblies, features, components, features, functions, methods of manufacture, methods of use, and other aspects of drug delivery devices described in any or all of the following documents, which are incorporated herein by reference in their entirety for all purposes: U.S. Pat. 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 entitled "INSERTION MECHANISM FOR DRUG DELIVERY DEVICE" ... and U.S. Provisional Patent Application No. 6 No. 62 / 469,226 entitled "INSERTION MECHANISM AND METHOD OF INSERTING A NEEDLE OF A DRUG DELIVERY DEVICE", U.S. Provisional Patent Application No. 62 / 468,190 entitled "DRUG DELIVERY DEVICE WITH STERILE FLUID FLOWPATH AND RELATED METHOD OF ASSEMBLY", U.S. Provisional Patent Application No. 62 / 460,559 entitled "DRUG DELIVERY DEVICE WITH STERILE FLUID FLOWPATH AND RELATED METHOD OF ASSEMBLY", U.S. Provisional Patent Application No. 62 / 294,842 entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE", U.S. Provisional Patent Application No. 62 / 297,718 entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE", U.S. Provisional Patent Application No. U.S. Provisional Patent Application No. 62 / 320, entitled "MANUFACTURE, AND METHOD OF USE,"No. 438, International Application PCT / US Publication No. 2017 / 017627 entitled “DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE” and International Application PCT / US Publication No. 2017 / 026524 entitled “DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE”.

[0034] 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 generally cylindrical shape with an inner diameter D1. At a distal end 37 of the container 14, the wall 38 may project radially outwardly and define a container flange 70. The container flange 70 may extend partially or entirely around the distal end 37 of the container 14. The container flange 70 may define a distal surface 72 of the container 14 that is perpendicular or otherwise non-parallel to the longitudinal axis A of the container 14 and faces generally in a distal direction. An opening 45 may be formed in the distal surface 72 and may communicate with the interior volume 30 of the container 14. In some embodiments, the container flange 70 may be omitted such that the distal surface 72 does not project radially outwardly of the remainder of the container 14. The wall 38 at the proximal end 36 of the container 14 may include a proximal surface 78 that is perpendicular or otherwise non-parallel to the longitudinal axis A of the container 14 and faces generally in a proximal direction. An opening 79 may be formed in the proximal surface 78 and may communicate with the interior volume 30. After the container 14 is filled with the drug 32, the stopper 34 may be inserted into the interior volume 30 through the opening 79. The container 14 may be constructed of glass, plastic, or any other suitably inert material that cannot chemically interact with the drug 32.

[0035] 2A and 2B, when the septum 40 is inserted into the container 14, the septum 40 may be centrally aligned with the longitudinal axis A of the container 14 such that the septum 40 and the container 14 share the same longitudinal axis A. The septum 40 may be divided into a proximal (or lower) end 80 and a distal (or upper) end 82 by an imaginary plane perpendicular to the longitudinal axis A. As shown in FIG. 2A, the proximal end 80 and the distal end 82 may each have a cylindrical shape and may have an outer diameter D2 and an outer diameter D3, respectively. The distal end 82 may be expanded relative to the proximal end 80 such that the outer diameter D3 (or other outer dimension) of the distal end 82 is greater than the outer diameter D2 (or other outer dimension) of the proximal end 80. The flange 84 of the septum 40 is defined by an outer peripheral (e.g., circumferential) portion of the distal end 82 of the septum 40 disposed radially outward of the proximal end 80 of the septum 40. The flange 84 can 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 proximal portion 86 and a distal portion 88, each of which has its boundaries shown by dashed lines in FIG. 2A. The proximal 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 distal portion 88 may have a length L3 parallel to the longitudinal axis A and a width W3 perpendicular to the longitudinal axis A. Each of the lengths L2 and L3 may be less than the overall length L1 of the flange 84, while each of the widths W2 and W3 may be equal to the overall width W1 of the flange 84a. The proximal portion 86 of the flange 84 may include a proximal surface 90 that is perpendicular or otherwise non-parallel to the longitudinal axis A and generally faces proximally, and an outer peripheral (e.g., circumferential) surface 92 that may be centered about and / or parallel to the longitudinal axis A.

[0037] 2B, when the septum 40 is attached to the container 14, the proximal end 80 of the septum 40 may be inserted into the interior volume 30 through the opening 45 and the proximal surface 90 of the proximal portion 86 of the flange 84 may directly contact and sealingly engage the distal surface 72 of the container 14. In some embodiments, each of the proximal surface 90 and the distal surface 72 may be flat such that they flushly engage with one another. In other embodiments, the flush engagement may be achieved by configuring the proximal surface 90 and the distal surface 72 with mating curvatures, such as one convex and the other concave.

[0038] 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 crimp ring that is applied to the container 14 and the septum 40 by a crimping tool. As shown in FIG. 2B, the fastener 94 may include radially inwardly extending flanges 96 and 98 that abut a proximal facing surface of the container flange 70 (or other exterior surface of the wall 38 of the container 14) and a distal facing end surface of the tip 82 of the septum 40, respectively, to tightly clamp or press the proximal surface 90 of the flange 84 of the septum 40 against the distal surface 72 of the container 70. The clamping force provided by the fastener 94 may help ensure an air-tight and / or fluid-tight seal between the proximal surface 90 of the flange 84 of the septum 40 and the distal surface 72 of the container 70. As described in more detail below, in some embodiments, the fasteners 94 may be made of a material that is permeable to a gas sterilant, such as EtO and / or steam.

[0039] 2B, the proximal end 80 of the septum 40 may include one or more radially outwardly projecting annular ribs 100 for sealingly engaging the inner surface 43 of the wall 38 of the container 14. The annular ribs 100 may provide a secondary barrier to prevent ingress contaminants from breaching the seal between the proximal surface 90 of the flange 84 of the septum 40 and the distal surface 72 of the container 70. Here, the outer diameter D2 of the proximal end 80 of the septum 40 may be equal to or less than the inner diameter D1 of the container 14. In other embodiments, the annular ribs 100 may be omitted (see FIGS. 3A and 3B), and the outer diameter D2 of the proximal 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 proximal end 80 of the septum 40 may be smaller than the inner diameter D1 of the container 14 such that no seal is formed between the proximal end 80 of the septum 40 and the container 14.

[0040] Before placing the drug delivery device 10 in its final packaging or sealing the interior space of the housing 29, it may be advantageous to subject the fully or partially assembled drug delivery device 10 to a sterilization process to reduce or eliminate airborne or stationary microorganisms or other contaminants in or on the housing 29. Such a sterilization process may be necessary if any of the previous assembly steps of the drug delivery device 10 were performed in a non-sterile or non-aseptic environment. The container 14 may be filled and covered with a septum 40 by the drug manufacturer in a sterile or aseptic environment with little risk of contamination before mounting it on the drug delivery device 10. However, if the container 14 is shipped to the manufacturer of the drug delivery device 10 and / or mounted by the device manufacturer under non-sterile or non-aseptic conditions, there is a risk that contaminants may break the seal between the septum 40 and the container 14 and may become lodged between the flange 84 of the septum 40 and the tip surface 72 of the container 14, or even possibly contaminate the drug 32. Radiation sterilization (e.g., gamma sterilization or electron beam sterilization) may be able to sterilize contaminants at the interface between the flange 84 of the septum 40 and the container 14, but radiation sterilization after installation of the prefilled container 14 in the drug delivery device 10 may not be feasible due to the possibility that the high energy sterilizing beam may harm the drug 32 within the container 14. Gas sterilization processes may not harm the drug 32, but 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 distal surface 72.

[0041] To address this challenge, the septum 40, fastener 94, and / or other components associated with the container 14 may be constructed partially or completely of a material that is permeable to a gas sterilant, including, but not limited to, EtO and / or steam. This material may provide a diffusion path for molecules of the gas sterilant to diffuse through at least the septum 40 to sterilize one or more surfaces, such as the proximal surface 90 and / or the distal surface 72, that would otherwise be unsterilizable due to the inability of the gas sterilant to penetrate the seal formed at the interface between the septum 40 and the container 14.

[0042] 4-7 show four types of septa 40 as described above, each having a different material composition, but each having the same dimensional and geometric characteristics as those shown in FIGS. 1-3B. Each type of septa 40 is designated with one of the suffixes "a," "b," "c," or "d." Common to all types of septa 40a, 40b, 40c, and 40d shown in FIGS. 4-7 is that at least a proximal portion 86 of flange 84, including its proximal surface 90 and outer peripheral surface 92, is made of a first material that is permeable to a gas sterilant, including at least one of EtO or steam. Thus, each septum 40a-40d has at least one diffusion path for the gas sterilant extending between the proximal surface 90 and the outer peripheral surface 92. Thus, during a sterilization procedure in which a partially or fully assembled drug delivery device 10 is exposed to a gas sterilant, the gas sterilant can enter the septum 40 through at least the outer peripheral surface 92 and exit the septum 40 through at least the proximal surface 90 to sterilize at least the interface between the septum 40 and the container 14, including the proximal surface 90 of the flange 84 and the distal surface 72 of the container 14. Other diffusion paths through the septum 40 may be possible, depending on the portion of the septum 40 that is constructed of a first material that is permeable to the gas sterilant. The rate at which the gas sterilant diffuses through each septum 40a, 40b, 40c, and 40d may depend on the proportion of the septum that is made of the first material. Also, although one or more annular ribs 100 are omitted from FIGS. 4-7, any of the embodiments of septum 40a, 40b, 40c, and 40d may include one or more annular ribs 100.

[0043] 4, an embodiment of a septum 40a is shown in which only a proximal portion 86a of the flange 84a may be made of a first material that is permeable to a gas sterilant, including at least one of EtO or steam. Thus, only the annular portion of the septum 40a defined by the proximal portion 86a of the flange 84a may be made of a first material that is permeable to the gas sterilant. The remaining portion of the septum 40a, including the distal portion 88 of the flange 84 and the proximal end 80a of the septum 40a, may be made of a second material that is less permeable to the gas sterilant than the first material. In some embodiments, the second material may be substantially or completely impermeable to the gas sterilant. Additionally, in some embodiments of the septum 40a, the gas sterilant may enter the septum 40a only through the exterior peripheral surface 92a of the flange 84a and exit the septum 40a primarily or only through the proximal surface 90a of the flange 84. This may be useful to prevent the gas sterilant from entering the interior volume 30 of the container 14 and interacting with the medicament 32.

[0044] FIG. 5 illustrates another embodiment of a septum 40b in which the gas sterilant may have additional pathways to enter the septum 40b, including the entire distal surface of the septum 40b as well as the entire exterior peripheral surface of the distal end 82b of the septum 40b. This approach may be accomplished by constructing the distal end 82b of the septum 40b entirely from a first material that is permeable to the gas sterilant, including at least one of EtO or steam. The proximal end 80b of the septum 40b may be made entirely from a second material that is less permeable to the gas sterilant than the first material. In some embodiments, the second material may be substantially or completely impermeable to the gas sterilant. As with septum 40a, the gas sterilant may exit the septum 40b primarily or only through the proximal surface 90b of the 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] 6, yet another embodiment of the septum 40c is shown. Here, a portion of the tip 82c of the septum 40c located distally 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 located distally to an imaginary plane perpendicular to the longitudinal axis A and in contact with the tip of the proximal 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 proximal portion 86 of the flange 84 and a portion of the tip 82c of the septum 40c located proximally to the imaginary plane described above, may be made of the first material described above. Also, in this embodiment of the septum 40c, the proximal portion 80c of the septum 40c may be completely made of the first material. One advantage of this embodiment of septum 40c is that the gas sterilant can reach the inner surface 43 of the container 14 by diffusing through the proximal end 80c of the septum 40c, sterilizing any contaminants placed on the inner surface 43 of the container 14.

[0046] FIG. 7 shows another embodiment of a septum 40d made entirely of the first material described above. Thus, both the proximal end 80d and the distal end 82d of the septum 40d may be entirely of a material permeable to a gas sterilant, including at least one of EtO or steam. This construction may maximize the number of diffusion paths for the gas sterilant. The gas sterilant may be able to enter or exit the septum 40d through any of the exterior surfaces 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 distal surface 72 of the container 14. Due to the relatively high permeability of the septum 40d, it may be beneficial to store the fully assembled drug delivery device 10 in a closed and / or sterile space in a bag or other secondary package prior to use. This can prevent any gases and / or contaminants from diffusing through septum 40d during the period between assembly of drug delivery device 10 and its use by a patient. In some embodiments, the secondary packaging can be constructed of a multi-layer material having gas barrier properties. Additionally, any of the septa disclosed herein, including septa 40a, 40b, 40c, and 40d, can be attached to a drug delivery device 10 that is subsequently placed into such secondary packaging to provide additional protection against contamination during the period between assembly of drug delivery device 10 and its use by a patient.

[0047] The following description of the first and second materials applies to any one of the septa 40a, 40b, 40c, and 40d above, as well as any other septa described herein. The composition of the first material may be selected depending on any one or any combination of the following non-exclusive list of characteristics of the sterilization procedure (e.g., terminal sterilization procedure) used to sterilize the container 14 and / or other components of the drug delivery device 10: the composition of the gas sterilant used in the sterilization procedure, the pressure of the gas sterilant used in the sterilization procedure, the amount or volume of the gas sterilant used in the sterilization procedure, the concentration of the gas sterilant used in the sterilization procedure, the length of time of the sterilization procedure, and the temperature of the gas sterilant used in the sterilization procedure. In some embodiments, the first material is permeable to any one or any combination of the gas sterilants selected from the following non-exclusive list of gas sterilants: EtO, ozone, chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurized water vapor). In some embodiments, the sterilization procedure using steam as the gas sterilant may be performed internally within an autoclave device. The first material may include any one or any combination of the following non-exclusive list of materials: polymer, rubber, and polybutadiene rubber. The second material may include any one or any combination of the following non-exclusive list of materials: polymer, rubber, chlorobutyl rubber, and halogenated butyl rubber. In any of septa 40a, 40b, 40c, and 40d above, as well as any other septa 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 is less permeable to the gaseous sterilant than the first material, including being substantially or completely impermeable to the gaseous sterilant, 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 greater than the permeability of the second material.

[0049] Any one of the septa 40a, 40b, 40c, and 40d described above, as well as any other septa described herein, may be constructed as a one-piece component in which the first and second materials are integrally formed together, such as by injection molding together. Alternatively, any one of the septa 40a, 40b, 40c, and 40d described above, as well as any other septa described herein, may be constructed as a multi-piece component in which the first and second materials are connected together by adhesives, fasteners, and / or any other suitable connecting elements.

[0050] In embodiments where fasteners 94 are used to retain septum 40 to container 14, fastener ring 94 may act as a gas barrier to prevent gas sterilant from diffusing through the permeable portion of septum 40. Thus, in some embodiments, one or more openings 99 (see FIG. 2B) may be formed in fastener ring 94 to allow gas sterilant to pass through fastener 94 and contact the permeable portion of septum 40. In some embodiments, openings 99 may be arranged and / or formed in a pattern on the exterior periphery or peripheral surface of fastener 94. In some embodiments, openings 99 may be located at the same axial location as exterior peripheral surface 92 of proximal end portion 86 of flange 84, as seen in FIG. 2B. In addition to or as an alternative to openings 99, fastener 94 may be constructed partially or completely of a material that is permeable to gas sterilant (e.g., EtO, ozone, chlorine dioxide, nitrogen dioxide and / or steam).

[0051] Referring to FIG. 8, another version of septum 40b is shown in which the exterior surface of septum 40b is partially coated with a chemically inert resin film 110. In some embodiments, resin film 110 can be a fluoropolymer film. Referring to FIGS. 5 and 8, resin film 110 can cover the entire exterior surface of septum 40b other than proximal surface 90b and exterior peripheral surface 92b of proximal portion 86b of flange 84b. Thus, resin film 110 may not prevent gas sterilant from diffusing through proximal surface 90b and exterior peripheral surface 92b of proximal portion 86b of flange 84b. In some embodiments, the portion of resin film 110 covering proximal end 80b and / or distal end 82b of septum 40b shown in FIG. 8 can be omitted. Also, any of the above configurations of resin film 110 can be applied to any of the septum embodiments disclosed herein, including septum 40a, 40c, and 40d.

[0052] Each of the foregoing embodiments relies on a septum to provide a diffusion path for the gas sterilant. However, the diffusion path may be achieved by other means. Figures 9A and 9B show one embodiment of a container assembly in which the diffusion path 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 that are similar to those shown in Figures 2A and 2B are designated by the same reference numerals, increased by 100. Descriptions of many of these elements have been omitted or eliminated for the sake of brevity.

[0053] 9B, the annular sealing member 300 is disposed between the proximal surface 190 of the flange 184 and the distal surface 172 of the container 114 when assembled to other components of the container assembly. As seen in FIG. 10, the annular sealing member 300 may include a central opening 302 extending between the proximal surface 304 and the distal surface 306. As seen in FIG. 9B, the proximal 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 circumferential surface 308 extending between the proximal surface 304 and the distal surface 306.

[0054] During a sterilization procedure, a gaseous sterilant can enter the annular sealing member 300 through the exterior peripheral surface 308, diffuse into the material of the annular sealing member 300, and exit the annular sealing member 300 through the proximal 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 a first material as described above. The above description of the first material incorporated into the septa 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 constructed partially or completely of a material that is less permeable to gas sterilant than the material used to construct the annular sealing member 300. In some embodiments, the septum 140 may be constructed partially or completely of the second material described above. In such embodiments, the above description of the second material incorporated into the septum 40a-40c applies to the second material incorporated into the septum 140. The annular sealing member 300 advantageously provides a diffusion path for the gas sterilant to sterilize the distal surface 172 of the container 114 when a conventional septum that is substantially or completely impermeable to the gas sterilant is used to stopper 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 septa disclosed herein, including any of the septum 40a-40d.

[0056] A method of assembly of the drug delivery device 10 will now be described. The following description will refer to septum 40, but is applicable to all types of septa disclosed herein, including at least septa 40a, 40b, 40c, 40d, and 140. First, an empty container 14 and septum 40 may be connected together and sterilized. This process may include inserting a proximal end 80 of the septum 40 through opening 45 into the interior volume 30 of the container 14 and moving a proximal surface 90 of flange 84 into direct contact with a distal surface 72 of the container 14. In some embodiments, connecting the container 14 and septum 40 may include fastening the two components with a fastener 94 to provide an air-tight and / or fluid-tight seal between the proximal surface 90 of flange 84 and the distal surface 72 of the container 14. In embodiments including the annular sealing member 300, an airtight and / or fluid-tight seal may be created between the distal surface 306 of the annular sealing member 300 and the proximal surface 190 of the septum 140, as well as between the proximal surface 304 of the annular sealing member 300 and the distal surface 172 of the container 114.

[0057] The partially assembled container 14 may then be exposed to a sterilization procedure or process. In some embodiments, this sterilization procedure may include placing the partially assembled container 14 in a sealed vacuum chamber which is then filled with a gaseous sterilant. The gaseous sterilant may be any one or any combination of gaseous sterilants selected from the following non-exclusive list of gaseous sterilants: EtO, ozone, chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurized water vapor). In embodiments where steam is used for sterilization, the chamber in which the sterilization procedure occurs 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 sterilant. The portion of the septum 40 and / or annular sealing member 300 constructed of the first material described above may allow for the diffusion of a gas sterilant such that the gas sterilant 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, as described above. Due to the effect that the gas sterilant may diffuse through the septum 40 and / or annular sealing member 300 and sterilize the interface of the container 14, the exposure time to the gas sterilant may be relatively short. In some embodiments, the exposure time to the gas sterilant may be within the range of about (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 within the range of about (e.g., ±10%) 1-4 hours, or 4-8 hours, or 4-12 hours, or 4-18, or 8-12 hours, or 8-18 hours, or 12-18 hours. The shorter the time that the container 14 is exposed to the gas sterilant, the shorter the time that may be required to aerate the container 14 after the sterilization procedure. Thus, the septa and annular sealing members disclosed herein can help streamline the manufacturing process for the container 14. In alternative embodiments, this sterilization step of the partially assembled container 14 may be omitted or may be performed after the filling procedure described in the following paragraphs.

[0058] The container 14 and septum 40 may then be aseptically transferred to a filling and capping environment, where the interior volume 30 of the container 14 may be filled with the drug 32, after which the proximal end 36 of the container 14 may be hermetically closed by a stopper 34 slidably inserted through an opening 79. This filling and capping environment may operate as a sterile or aseptic assembly environment to ensure that microorganisms and other contaminants are not introduced into the interior volume 30. This drug-filled, pre-assembled container assembly may then be packaged and shipped to a facility where final assembly of the drug delivery device 10 will take place. Also, as a preliminary step, the fluid pathway assembly 22 may be connected to the seal member 60 such that the seal member 60 hermetically closes the open end of the fluid pathway 50. The process of assembling the fluid pathway assembly 22 and the seal member 60 may be performed in a sterile or aseptic assembly environment to ensure that particulate contaminants are not introduced into the fluid pathway 50. Alternatively or additionally, the pre-assembled configuration of the fluid pathway assembly 22 and the seal member 60 may be exposed to a high energy sterilization beam (e.g., gamma beam, x-ray beam, electron beam, etc.), ethylene oxide, or other known techniques to ensure their sterility. This pre-assembled configuration may then be packaged and shipped to a facility where final assembly of the drug delivery device 10 will occur.

[0059] Thereafter, for example at a final assembly facility, the drug-filled, pre-assembled configuration of the drug container 14, septum 40 and stopper 34 and the pre-assembled configuration of the fluid pathway assembly 22 and seal member 60 may 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., bottom wall 25 of the housing 29) or a second housing portion (e.g., top wall 27 of the housing 29) of the drug delivery device 10, and connecting the pre-assembled configuration of the fluid pathway assembly 22 and seal member 60 to the first housing portion or the 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 within 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-filled, pre-assembled configuration of the drug container 14, septum 40 and stopper 34 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 pathway assembly 22 and seal member 60 are installed in the housing 29, the partially assembled version of the drug delivery device 10 may be subjected to a sterilization procedure or process. In some embodiments, the sterilization procedure may include placing the partially assembled version of the drug delivery device 10 in a sealed vacuum chamber that is then filled with a gaseous sterilant. The gaseous sterilant may be any one or any combination of gaseous sterilants selected from the following non-exclusive list of gaseous sterilants: EtO, ozone, chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurized water vapor). In embodiments where steam is used for sterilization, the chamber in which the sterilization procedure is performed may be an autoclave. During the sterilization procedure, the septum 40 and the annular sealing member 300, if included, may be exposed to the gaseous sterilant. The portion of the septum 40 and / or annular sealing member 300 constructed of the first material described above may allow for the diffusion of a gas sterilant such that the gas sterilant 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, as described above. Due to the effect that the gas sterilant may diffuse through the septum 40 and / or annular sealing member 300 and sterilize the interface of the container 14, the exposure time to the gas sterilant may be relatively short. In some embodiments, the exposure time to the gas sterilant may be within the range of about (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 within the range of about (e.g., ±10%) 1-4 hours, or 4-8 hours, or 4-12 hours, or 4-18, or 8-12 hours, or 8-18 hours, or 12-18 hours. The shorter the time that the drug delivery device 10 is exposed to the gas sterilant, the shorter the time that may be required to aerate the drug delivery device 10 after the sterilization procedure. Thus, the septa and annular sealing members disclosed herein can help streamline the manufacturing process of the drug delivery device 10.

[0061] After the sterilization procedure is completed, the first housing part can be connected to the second housing part to seal the drug-filled pre-assembled configuration of the drug container 14, the septum 40 and the stopper 34 and / or other components (e.g., the insertion mechanism 12, the fluid path assembly 22, the drive mechanism 24, the controller 26, etc.) in the sterile interior space of the drug delivery device 10. Thus, the sealing process can result in a preloaded and prefilled drug delivery device 10. In some embodiments, the connection between the first housing part and the second housing part can seal the interior of the drug delivery device 10 and prevent or block the ingress of contaminants. Furthermore, in some embodiments, the first housing part and the second housing part can be hermetically connected in the same environment or chamber where the gas sterilization process was performed.

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

[0063] Set forth below are the results of experimental testing comparing a composite septum constructed in accordance with the principles of the present disclosure against a conventional septum made entirely of a gas impermeable material. Both the composite septum and the conventional septum had a gas impermeable surface area of ​​about 10 mm on their flange proximal surface. 6The challenge microorganisms were inoculated. Each septum was then crimped onto the tip surface of a drug container. This process was repeated to create 30 samples using composite septa and 30 samples using conventional septa. The samples were then exposed to a gas sterilization process, using EtO as the gas sterilant. After 18 hours of EtO sterilization, all 30 samples showed no microbial growth at the interface between the composite septum and the drug container. 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 conventional septa showed no microbial growth at the interface with the drug container. Thus, it has been experimentally shown that the amount of time required to sterilize the interface between the composite septum disclosed herein and the container is significantly less than the amount of time required to sterilize the interface between the conventional septum and the container.

[0064] Drug Information As mentioned above, the container can be loaded with a drug, which can be any one or combination of the drugs listed below, although the following list should not be considered as all-inclusive or limiting.

[0065] For example, the syringe may be loaded with colony stimulating factors, such as granulocyte colony stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the syringe may be used with various pharmaceutical agents, such as erythropoietin stimulating agents (ESAs), which may be in liquid or lyophilized form.ESAs include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methyoxy polyethylene glycol epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo®, and others. Any molecule that stimulates erythropoiesis, such as epoetin zeta, Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, each of which is incorporated herein by reference in its entirety. The following patents or patent applications include U.S. Pat. No. 4,703,008, U.S. Pat. No. 5,441,868, U.S. Pat. No. 5,547,933, U.S. Pat. No. 5,618,698, U.S. Pat. No. 5,621,080, U.S. Pat. No. 5,756,349, U.S. Pat. No. 5,767,078, U.S. Pat. No. 5,773,569, U.S. Pat. No. 5,955,422, U.S. Pat. No. 5,986,047, U.S. Pat. No. 6 Nos. 5,583,272, 7,084,245 and 7,271,689, and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 96 / 40772, WO 00 / 24893, WO 01 / 81405 and WO 2007 / 136752, or variants or analogs thereof.

[0066] The ESA may be an erythropoiesis stimulating protein. As used herein, "erythropoiesis stimulating protein" refers to any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to the receptor and causing receptor dimerization. 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. Erythropoiesis stimulating proteins include, but are not limited to, epoetin alpha, epoetin beta, epoetin delta, epoetin omega, epoetin iota, epoetin zeta and analogs thereof, PEGylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1 / hematide), and mimetic antibodies. Exemplary erythropoiesis stimulating proteins include erythropoietin, darbepoietin, erythropoietin agonist variants, and peptides or antibodies that bind to and activate the erythropoietin receptor (as well as the compounds reported in U.S. Patent Application Publication Nos. 2003 / 0215444 and 2006 / 0040858, the disclosures of each of which are incorporated herein by reference in their entireties), as well as the compounds described in the following patents or patent applications, the disclosures of which are incorporated herein by reference in their entireties: U.S. Pat. No. 4,703,008; U.S. Pat. No. 5,441,868; U.S. Pat. No. 5,547,933; U.S. Pat. No. 5,618,662; 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 No. 7,030,226, U.S. Patent No. 7,084,245 and U.S. Patent No. 7,217,689, U.S. Patent Application Publication No. 2002 / 0155998, U.S. Patent Application Publication No. 2003 / 0077753, U.S. Patent Application Publication No. 2003 / 0082749, U.S. Patent Application Publication No. 2003 / 0143202, U.S. Patent Application Publication No. 2004 / 0009902, U.S. Patent Application Publication No. 2004 / 0071694, U.S. Patent Application Publication No. 2004 / 0091961 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 Details, 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 , 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 Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 99 / 66054, WO 00 / 24893, WO 01 / 81405, WO 00 / 61637, WO 01 / 36489, WO 02 / 014356, and WO 02 / 19963. , WO 02 / 20034, WO 02 / 49673, WO 02 / 085940, WO 03 / 029291, WO 2003 / 055526, WO 2003 / 084477, WO 2003 / 094858, WO 2004 / 002417, WO 2004 / 002424, WO 2004 / 009627, WO 2004 / 024 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 brochure, International Publication No. 2005 / 021579 pamphlet, International Publication No. 2005 / 025606 pamphlet, International Publication No. 2005 / 032460 pamphlet, International Publication No. 2005 / 051327 pamphlet, International Publication No. 2005 / 063808 pamphlet, International Publication No. 2005 / 063809 pamphlet, International Publication No. 2005 / 070451 pamphlet, International Publication No. 2005 / 081687 pamphlet, International Publication No. 2005 / 084711 pamphlet, International Publication No. 2005 / 103076 pamphlet,The erythropoietin molecules disclosed in WO 2005 / 100403, WO 2005 / 092369, WO 2006 / 50959, WO 2006 / 02646 and WO 2006 / 29094, or variants or analogs thereof, are included.

[0067] Examples of other pharmaceutical agents for use with the device may include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab) and Prolia™ (denosumab), other biologics such as Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, PEGylated filgastrimm, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF) and Nplate® (romiplostim), small molecule drugs such as Sensipar® (cinacalcet). The device may be used with therapeutic antibodies, polypeptides, proteins or other chemicals such as iron, e.g., ferumoxytol, iron dextran, ferric glyconate and ferric oxide. The pharmaceutical agent may be in liquid form or may be reconstituted from a lyophilized form.

[0068] Among specific exemplary proteins are the specific proteins discussed below, including fusions, fragments, analogs, variants or derivatives thereof.

[0069] and / or a heavy chain of SEQ ID NO:4 as set forth in FIG. 4 of the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications: OPGL-specific antibodies having either a light chain of SEQ ID NO:2 as set forth in FIG. 2 of the following publications and / or a heavy chain of SEQ ID NO:4 as set forth in FIG. 4 of the following publications; with regard to OPGL-specific antibodies and antibody related proteins, in particular those having the sequences described in the following publications, specifically but not limited to those shown in the following publications (9H7, 18B2, 2D8, 2E11, 16E1 and 22B3), including but not limited to the antibodies described in PCT Publication WO 03 / 002713, which is incorporated herein in its entirety, OPGL-specific antibodies (also referred to as RANKL-specific antibodies, peptibodies, etc.), peptibodies and related proteins, including fully humanized and human OPGL-specific antibodies, in particular fully humanized monoclonal antibodies.

[0070] The following publications are individually and specifically incorporated by reference in their entirety as disclosed in the following publications: TN8-19-1 to TN8-19-40, TN8-19 con1 and TN8-19 Myostatin binding proteins, peptibodies and related proteins, including myostatin-specific peptibodies, particularly those described in U.S. Patent Application Publication No. 2004 / 0181033 and PCT Publication No. WO 2004 / 058988, which are incorporated by reference in their entireties, include, but are not limited to, the mTN8-19 family of peptibodies, including those of SEQ ID NOs: 305-351, including con2, 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 peptibodies of SEQ ID NOs: 615-631.

[0071] IL-4 receptor specific antibodies, particularly those disclosed in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety, include, but are not limited to, 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: and the like, particularly those that inhibit activity mediated by the binding of IL-4 and / or IL-13 to the receptor, including, in part, those described in the following publications, particularly those described in PCT Publication WO 2005 / 047331 or International Application PCT / US Publication No. 2004 / 37242 and US Publication No. 2005 / 112694, the entireties of which are incorporated herein by reference, and IL-4 receptor-specific antibodies, peptibodies and related proteins, etc.

[0072] Interleukin 1-receptor 1 ("IL1-R1") specific antibodies, peptibodies and related proteins, including, but not limited to, those set forth in the following publications, each of which is individually and specifically incorporated by reference in its entirety as disclosed in the following publications: 15CA, 26F5, 27F2, 24E12 and 10H7, in part, IL1-R1 specific binding proteins, particularly those described in U.S. Patent Application Publication No. 2004 / 097712, which is incorporated by reference in its entirety, particularly with respect to monoclonal antibodies:

[0073] The sequences of the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, in particular those sequences described in the following publications: L1(N), L1(N)WT, L1(N)1K WT, 2xL1(N), 2xL1(N)WT, Con4(N), Con4(N)1K WT, 2xCon4(N)1K, L1C, L1C 1K, 2xL1C, Con4C, Con4C 1K, 2xCon4C and Ang2 specific antibodies and peptibodies, including, but not limited to, those described in PCT Publication No. WO 03 / 057134 and U.S. Patent Application Publication No. 2003 / 0229023, each of which is incorporated by reference in its entirety in part with particular reference to Ang2 antibodies and formulations, including, but not limited to, Ab526, Ab528, Ab531, Ab541, Ab542, Ab543, Ab544, Ab545, Ab546, Ab547, Ab548, Ab549 ... Ang2 specific antibodies, peptibodies and related proteins, including anti-Ang2 antibodies and formulations such as those described in PCT Publication WO 2003 / 030833, which is incorporated by reference in its entirety with respect to Ab533, 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 AblP.

[0074] NGF-specific antibodies, peptibodies and related proteins, including but not limited to those described in U.S. Patent Application Publication No. 2005 / 0074821 and U.S. Patent No. 6,919,426, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, specifically including but not limited to the NGF-specific antibodies 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11 set forth in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications:

[0075] For example, humanized and fully human antibodies, including but not limited to, humanized and fully human monoclonal antibodies, including but not limited to, human CD22 specific IgG antibodies, such as, but not limited to, a dimer of human-mouse monoclonal hLL2 gamma chain disulfide linked to human-mouse monoclonal hLL2 kappa chain, including, but not limited to, humanized and fully human antibodies, including but not limited to, human CD22 specific IgG antibodies, specifically, human CD22 specific antibodies, CD22 specific antibodies, peptibodies and related proteins, such as those described in U.S. Pat. No. 5,789,554, the entirety of which is incorporated herein by reference with respect to CD22 specific antibodies and related proteins.

[0076] The IGF-1 specific antibodies L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, and the like are set forth in the following publications, each of which is individually and specifically incorporated by reference in its entirety herein: L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L and IGF-1 receptor specific antibodies, peptibodies and related proteins, 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-1 R-binding fragments and derivatives thereof, such as those described in PCT Publication WO 06 / 069202, which is incorporated by reference in its entirety for IGF-1 receptor specific antibodies and related proteins.

[0077] Also among the non-limiting examples of anti-IGF-1R antibodies for use in the methods and compositions of the invention are each of those described below.

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

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

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

[0081] (iv) including, but not limited to, 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 described in U.S. Patent Application Publication No. 2005 / 0084906 (published April 21, 2005).

[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, as described in U.S. Patent Application Publication No. 2005 / 0249728 (published November 10, 2005), U.S. Patent Application Publication No. 2005 / 0186203 (published August 25, 2005), U.S. Patent Application Publication No. 2004 / 0265307 (published December 30, 2004) and U.S. Patent Application Publication No. 2003 / 0235582 (published December 25, 2003), and Maloney et al. (2003), Cancer Res. 63:5073-5083.

[0083] (vi) U.S. Pat. No. 7,037,498, issued 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 Res. 11:2063-2073, and each of the antibodies produced by hybridomas having ATCC Accession Nos. 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, such as, but not limited to, antibody CP-751,871.

[0084] (vii) including, but not limited to, antibody 19D12, as 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 antibodies comprising a heavy chain encoded by the polynucleotides of plasmid 15H12 / 19D12 HCA(gamma4), deposited with the ATCC under accession number PTA-5214, and a light chain encoded by the polynucleotides of plasmid 15H12 / 19D12 LCF(kappa), deposited with the ATCC under accession number PTA-5220.

[0085] (viii) With respect to the foregoing antibodies, peptibodies and related proteins specifically targeting the IGF-1 receptor, including, but not limited to, 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, each of which is incorporated by reference in its entirety herein.

[0086] B-7 related protein 1 specific antibodies, peptibodies, related proteins and the like ("B7RP-1," also referred to in the literature as B7H2, ICOSL, B7h and CD275), particularly B7RP specific fully human monoclonal IgG2 antibodies, particularly fully human IgG2 monoclonal antibodies that bind to an epitope in the first immunoglobulin-like domain of B7RP-1, particularly those that inhibit the interaction of B7RP-1 with ICOS, the natural receptor for B7RP-1, particularly on activated T cells, and particularly as disclosed in the following publications, each of which is individually and specifically incorporated by reference in its entirety herein: 16H (within which the light chain variable sequence and heavy chain variable sequence have SEQ ID NO:1 and SEQ ID NO:7, respectively), 5D (within which the light chain variable sequence and heavy chain variable sequence have SEQ ID NO:1 and SEQ ID NO:7, respectively), and 5E (within which the light chain variable sequence and heavy chain variable sequence have SEQ ID NO:1 and SEQ ID NO:7, respectively), each of which is individually and specifically incorporated by reference in its entirety herein, as disclosed in the following publications: and SEQ ID NO:9), 2H (having therein light chain variable and heavy chain variable sequences, SEQ ID NO:3 and SEQ ID NO:10, respectively), 43H (having therein light chain variable and heavy chain variable sequences, SEQ ID NO:6 and SEQ ID NO:14, respectively), 41H (having therein light chain variable and heavy chain variable sequences, SEQ ID NO:5 and SEQ ID NO:13, respectively), and 15H (having therein light chain variable and heavy chain variable sequences, SEQ ID NO:4 and SEQ ID NO:12, respectively) and those disclosed in U.S. Patent Application Publication No. 2008 / 0166352 and PCT Publication No. WO 07 / 011941, which are incorporated by reference in their entireties with respect to such antibodies and related proteins, including, but not limited to, the antibodies set forth in the following publications:

[0087] For example, those disclosed in U.S. Patent Application Publication Nos. 2003 / 0138421, 2003 / 023586 and 2004 / 0071702, and U.S. Patent No. 7,153,507, each of which is incorporated herein by reference in its entirety, for IL-15 specific antibodies and related proteins, including, inter alia, peptibodies, including, but not limited to, HuMax IL-15 antibodies and related proteins, such as 146B7, in particular antibodies, particularly IL-15 specific antibodies, such as humanized monoclonal antibodies, peptibodies and related proteins.

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

[0089] As disclosed in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety, and with respect to TALL-1 binding proteins, particularly 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 herein by reference in its entirety with respect to the molecules in Tables 4 and 5B, TALL-1 specific antibodies, peptibodies and related proteins, and other TALL specific binding proteins.

[0090] Parathyroid hormone ("PTH")-specific antibodies, peptibodies and related proteins, such as those described in U.S. Pat. No. 6,756,480, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind PTH.

[0091] Thrombopoietin receptor ("TPO-R")-specific antibodies, peptibodies and related proteins, such as those described in U.S. Pat. No. 6,835,809, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind to TPO-R.

[0092] With particular reference in part to proteins that bind HGF, hepatocyte growth factor ("HGF")-specific antibodies, peptibodies and related proteins, including those that target the HGF / SF:c-Met axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / scatter (HGF / SF), as described in U.S. Patent Application Publication No. 2005 / 0118643 and PCT Publication No. WO 2005 / 017107, huL2G7, as described in U.S. Patent No. 7,220,410, and OA-5d5, as described in U.S. Patent Nos. 5,686,292 and 6,468,529, and PCT Publication No. WO 96 / 38557, each of which is incorporated by reference in its entirety herein.

[0093] Particularly relevant in part to proteins that bind TRAIL-R2 are those described in U.S. Pat. No. 7,521,048, the entirety of which is incorporated herein by reference, including TRAIL-R2 specific antibodies, peptibodies, related proteins, and the like.

[0094] Activin A-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent Application Publication No. 2009 / 0234106, the entirety of which is incorporated herein by reference, particularly in part, with reference to proteins that bind activin A.

[0095] Particularly relevant to proteins that bind TGF-β are TGF-β specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Pat. No. 6,803,453 and U.S. Patent Application Publication No. 2007 / 0110747, each of which is incorporated by reference in its entirety herein.

[0096] Amyloid β protein specific antibodies, peptibodies, related proteins, etc., including but not limited to those described in PCT Publication WO 2006 / 081171, which is incorporated herein by reference in its entirety with particular reference to proteins that bind to amyloid β protein. One contemplated antibody is an antibody having a heavy chain variable region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID NO:6, as disclosed in the aforementioned publication.

[0097] c-Kit specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Patent Application Publication No. 2007 / 0253951, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind c-Kit and / or other stem cell factor receptors.

[0098] OX40L-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent Application Publication No. 2006 / 0002929, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind OX40L and / or other ligands of the OX40 receptor.

[0099] Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon-beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-alpha4beta7 mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), 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 alpha con-1), Natrecor® (nesiritide, recombinant human B-type natriuretic peptide (hBNP), Kineret® (anakinra), Leukine® (sargamostim, rhuGM-CSF), LymphoCide® (epratuzumab, anti-CD22 mAb), Benlysta™ (lymphostat B, belimumab, anti-BlySmAb), Metalyse® (tenecteplase, t-PA analog), Mircera® (methoxypolyethylene glycol-epoetin beta), Mylotarg® (gemtuzumab ozogamicin), Raptiva® (efalizumab), Cimzia® (certolizumab pegol, CDP870), Soliris™ (eculizumab), pexelizumab (anti-complement C5), Numax® (MEDI-524), Lucentis® (ranibizumab), Panorex® (17-1A, edrecolomab), Trabio® (lerdelimumab), TheraCim hR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem® (IDM-1), OvaRex® (B43.13), Nuvion® (vigilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Neulasta® (PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GPIL6 / IL1 receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alfa-2a), Simulect® (basiliximab), Prexige® (lumib racoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Pat. No. 7,153,507), Tysabri® (natalizumab, an anti-α4 integrin mAb), Valortim® (MDX-1303, an anti-anthrax protective antigen mAb), ABthrax™, Vectibix® (panitumumab), Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)), VEGF trap (the Ig domain of VEGFR1 fused to IgG1 Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimibe), 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 mAb), HGS-ETR1 (mapatuzumab, human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (zalutumumab), M200 (volociximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. difficile toxin A and toxin BC mAbsMDX-066 (CDA-1) and MDX-1388), anti-CD22 dsFv-PE38 conjugates (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax-TAC), anti-CD3 mAb (NI-0401), adecatumumab, anti-CD30 mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMax CD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF idiopathic pulmonary fibrosis phase 1 fibrinogen (FG-3019), anti-CTLA4 mAb, anti-eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2 mAb, anti-ganglioside GM2 mAb, anti-GDF-8 human 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-mannose receptor / hCGβ mAb (MDX-1307), anti-mesothelin 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 human mAb (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, anti-ZP3 mAb (HuMax-ZP3), other exemplary proteins including NVS antibody No. 1 and NVS antibody No. 2.

[0100] Sclerostin antibodies may also be included, such as, but not limited to, romosozumab, brosozumab, or BPS804 (Novartis). Further therapeutic agents may be included, such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX, or XGEVA. Additionally, a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9) may be included in the device. Such PCSK9-specific antibodies include those described in the following patents or patent applications, each of which is incorporated herein by reference in its entirety for all purposes: U.S. Pat. No. 8,030,547, U.S. Pat. No. 8,563,698, U.S. Pat. No. 8,829,165, U.S. Pat. No. 8,859,741, U.S. Pat. No. 8,871,913, U.S. Pat. No. 8,871,914, U.S. Pat. No. 8,883,983, U.S. Pat. No. 8,889,834, U.S. Pat. No. 8,981,064, U.S. Pat. No. 9,056,915, U.S. Pat. No. 8,168,762, U.S. Pat. No. 9,045,547, U.S. Pat. No. 8,030,457, U.S. Pat. No. 8,030,457, U.S. Pat. No. 8,829,165, U.S. Pat. No. 8,981,064, U.S. Pat. No. 8,030,457, 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, U.S. US Patent Application Publication No. 2015 / 0031870, US Patent Application Publication No. 2013 / 0085265, US Patent Application Publication No. 2013 / 0079501, US Patent Application Publication No. 2012 / 0213797, US Patent Application Publication No. 2012 / 0251544, US Patent Application Publication No. 2013 / 0072665, US Patent Application Publication No. 2013 / 0058944, US Patent Application Publication No. 201 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 Application No. 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 / 777,371, International Application PCT / US Publication No. 2013 / 048714, International Application PCT / US Publication No. 2015 / 040211, International Application PCT / US Publication No. 2015 / 056972, International Publication No. WO 2008 / 057457, International Publication No. WO 2008 / 057458, International Publication No. WO 2008 / 057459, International Publication No. WO 2008 / 063382, International Publication No. WO 2008 International Publication No. WO 2009 / 100297, International Publication No. WO 2009 / 100318, International Publication No. WO 2011 / 037791, International Publication No. WO 2011 / 053759, International Publication No. WO 2011 / 053783, International Publication No. WO 2008 / 125623, International Publication No. WO 2011 / 072263, International Publication No. WO 2009 / 055783, International Publication No. International Publication 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, Examples of suitable anti-cancer drugs include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab), and molecules, variants, analogs or derivatives thereof, as disclosed in International Publication Nos. WO 2001 / 031007, WO 2009 / 026558, WO 2009 / 131740, WO 2013 / 166448 and WO 2014 / 150983.

[0101] Also included may be talimogene laherparepvec or another oncolytic HSV for the treatment of melanoma or other cancers. Examples of oncolytic HSV include, but are not limited to, talimogene laherparepvec (U.S. Pat. Nos. 7,223,593 and 7,537,924), OncoVEXGALV / CD (U.S. Pat. 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), Cancer Gene Ther., 9(12):967-978).

[0102] Also included are TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) and are important in many natural processes. TIMP-3 is expressed by various cells and / or present in the extracellular matrix, inhibits all major cartilage-degrading metalloproteases, and may play a role in many degradative diseases of connective tissue, 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 DNA encoding TIMP-3 are disclosed in U.S. Patent No. 6,562,596, issued May 13, 2003, the disclosure of which is incorporated herein by reference. Descriptions of TIMP mutations can be found in U.S. Patent Application Publication No. 2014 / 0274874 and PCT Publication No. WO 2014 / 152012.

[0103] Also included are antagonistic antibodies to the human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecules targeting the CGRP receptor and other headache targets. Further information regarding these molecules can be found in PCT Publication WO 2010 / 075238.

[0104] In addition, bispecific T cell-inducing antibodies (BiTe), such as blinatumomab, can be used in the device. Alternatively, APJ macromolecular agonists, such as apelin or analogs thereof, can be included in the device. Information regarding such molecules can be found in PCT Publication WO 2014 / 099984.

[0105] In certain embodiments, the medicament comprises a therapeutically effective amount of anti-thymic stromal lymphopoietin (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 Nos. 7,982,016 and 8,232,372 and U.S. Patent 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 medicament comprises a therapeutically effective amount of the anti-TSLP antibody designated A5 in U.S. Patent No. 7,982,016.

[0106] While the disclosure has been described in connection with various embodiments, it will be understood that the disclosure is capable of further modifications. The disclosure is generally intended to cover any variations, uses, or adaptations of the disclosed subject matter that are in accordance with the principles of the disclosure and that are within known and customary practice in the art to which the disclosure pertains, including departures from the disclosure.

[0107] It should be noted that the structure and configuration of the drug delivery device and its various components and assemblies as shown in the various exemplary embodiments are merely exemplary. Although the present disclosure describes in detail only a few embodiments of the subject matter at issue, those skilled in the art who review the present disclosure will readily appreciate that many modifications (e.g., variations in the size, dimensions, configuration, shape and proportions of the various elements, parameter values, mounting configurations, use of materials, colors, orientations, etc.) are possible without substantially departing from the novel teachings and advantages of the subject matter disclosed herein. For example, elements shown as integrally formed may be composed of multiple parts or elements, and vice versa. Also, the positions of elements may be reversed or otherwise changed, and the nature or number of separate elements or positions may be modified or changed. Accordingly, all such modifications are intended to be included within the scope of the present disclosure as defined in the appended claims. Furthermore, the order or sequence of any process or method steps may be changed or rearranged in accordance with alternative embodiments. Other substitutions, modifications, variations and omissions may be made in the design, operating conditions and arrangements of the various exemplary embodiments without departing from the scope of the present disclosure.

Claims

1. 1. A drug delivery device comprising: Housing and a container disposed within the housing and having an interior volume and a tip surface, an opening formed in the tip surface and in communication with the interior volume; a drug disposed within the interior volume of the container; a septum including a proximal end and a distal end, the proximal end being inserted into the interior volume of the container through the opening, the distal end including a flange and a distal surface, the flange being disposed outside the proximal end, at least an end portion of the flange contacting the distal surface of the container and made of a first material; a needle disposed or configured to be disposed through at least a first portion of the septum; Including, the first material is permeable to a gaseous sterilant and provides a diffusion path that allows the gaseous sterilant to contact at least the end portion of the flange of the septum during sterilization and sterilize at least a portion of the tip surface of the container; A drug delivery device, wherein at least the tip surface of a first portion of the septum is made of a second material that is less permeable to the gas sterilant than the first material.

2. 10. The drug delivery device of claim 1, wherein a proximal facing surface of the end portion of the flange sealingly engages the distal surface of the container to prevent ingress of contaminants.

3. 3. The drug delivery device of claim 1 or 2, wherein the gas sterilant comprises at least one of ethylene oxide or steam.

4. The drug delivery device of any one of claims 1 to 3, wherein the proximal end of the septum is made of the second material.

5. The drug delivery device of claim 4 , wherein the tip of the septum is made entirely of the second material, except for the end portion of the flange.

6. 6. The drug delivery device of claim 4 or 5, wherein the end portion of the flange has an outer peripheral surface that is exposed to the gaseous sterilant during a sterilization procedure.

7. A drug delivery device described in any one of claims 4 to 6, wherein the length of the end portion of the flange along the longitudinal axis of the container is shorter than the total length of the flange along the longitudinal axis of the container, and the width of the end portion of the flange perpendicular to the longitudinal axis of the container is equal to the total width of the flange perpendicular to the longitudinal axis of the container.

8. A drug delivery device as described in any one of claims 1 to 3, wherein a portion of the tip of the septum is made of the second material.

9. The drug delivery device of claim 8 , wherein the proximal end of the septum is made of the first material.

10. 10. The drug delivery device of claim 8 or 9, wherein the end portion of the flange has an outer peripheral surface that is exposed to the gaseous sterilant during a sterilization procedure.

11. A drug delivery device described in any one of claims 8 to 10, wherein the length of the end portion of the flange along the longitudinal axis of the container is shorter than the total length of the flange along the longitudinal axis of the container, and the width of the end portion of the flange perpendicular to the longitudinal axis of the container is equal to the total width of the flange perpendicular to the longitudinal axis of the container.

12. 3. The drug delivery device of claim 2, further comprising a fluoropolymer film completely covering the septum except for the proximal facing surface of the end portion of the flange and the outer peripheral surface of the end portion of the flange.

13. 13. The drug delivery device of claim 1, further comprising a fastener that engages a distal facing surface of the septum and an exterior surface of the container to secure the flange against the distal surface of the container, the fastener being permeable to the gas sterilant.

14. A drug delivery device according to any one of claims 1 to 13, comprising an annular rib extending outwardly of the proximal end of the septum and configured to sealingly engage an inner surface of the container.

15. The drug delivery device of any one of claims 1 to 14, wherein the exterior surface of the housing is removably attachable to a patient.

16. The drug delivery device of any one of claims 1 to 15, comprising an insertion mechanism configured to move a delivery member from a retracted position within the housing to a deployed position extending outside the housing.

17. 17. The drug delivery device of claim 16, including a hollow piercing member insertable through the septum to establish a fluid flow path between the container and the delivery member upon activation of the drug delivery device.

18. A drug delivery device according to any one of claims 1 to 17, comprising a drive mechanism configured to expel the drug from the reservoir upon activation of the drug delivery device.

19. 1. A method of assembling a drug delivery device, comprising: a container having an interior volume and a tip surface, an opening formed in the tip surface and in communication with the interior volume; a septum including a proximal end and a distal end, the proximal end being inserted into the interior volume of the container through the opening, the distal end including a flange and a distal surface, the flange being disposed outside the proximal end, at least an end portion of the flange contacting the distal surface of the container, and the septum being made of a first material, the first material being permeable to a gas sterilant; a needle disposed or configured to be disposed through at least a first portion of the septum; wherein at least the tip surface of a first portion of the septum is made of a second material that is less permeable to the gas sterilant than the first material; sterilizing the container assembly with a gaseous sterilant such that the gaseous sterilant diffuses through the first material and contacts at least an end portion of the flange of the septum to sterilize at least a portion of the tip surface of the container; filling the interior volume of the container with a drug; attaching the container assembly to the drug delivery device; The method includes:

20. 20. The method of claim 19, wherein the gas sterilant comprises at least one of ethylene oxide or steam.

21. 21. The method of claim 19 or 20, wherein the proximal end of the septum is made of the second material.

22. 22. The method of claim 21, wherein the tip of the septum is made entirely of the second material, except for the end portion of the flange.

23. 21. The method of claim 19 or 20, wherein the proximal end of the septum is made of the first material and a portion of the distal end of the septum disposed distally relative to the flange is made of the second material.

24. 21. The method of claim 19 or 20, wherein the container assembly is sterilized with the gas sterilant after the container assembly is attached to the drug delivery device.

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