Gas-permeable sealing member for drug container and methods of assembly

Abstract

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

Description

Technical Field

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

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

Background Art

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

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

[0005] However, at this stage, the available sterilization processes may be limited. This is because certain sterilization processes can have a detrimental effect on the drug within the container and / or the materials used to construct the container. Radiation sterilization (e.g., gamma-ray sterilization or electron beam sterilization) can cause oxidation of the drug and / or discoloration of the glass of the container. Gas sterilization processes such as ethylene oxide (EtO) and steam treatment may not cause damage to the drug or container materials, but they are often not effective in killing bacteria or spores inoculated at the interface between a conventional septum and the container. Conventional septa have a very low gas permeability, preventing the gas sterilant from reaching the interface between the septum and the container. Extended ethylene oxide treatment (e.g., up to 30 hours) has also been found to be ineffective in sterilizing the interface between a conventional septum and the container. Additionally, extended ethylene oxide treatment creates significant manufacturing challenges because it requires long-term 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 Problems

[0006] The present disclosure embodies advantageous alternatives to existing types of such devices and methods, can address one or more of the problems or needs referred to herein, and can provide other benefits and advantages, and describes a septum, a container assembly, a drug delivery device, and related assembly methods.

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

[0008] Another aspect of the present disclosure is a method of assembling a drug delivery device, comprising: (a) providing a container assembly including a container having an internal volume and an end surface, an opening being formed in the end surface and communicating with the internal volume, and a septum including a proximal end and a distal end, the proximal end being inserted through the opening into the internal volume of the container, 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 that is permeable to a gaseous sterilant; (b) sterilizing the container assembly with a gaseous sterilant such that the gaseous sterilant diffuses through the first material to sterilize the end surface of the container; (c) filling the internal volume of the container with a drug; and (d) attaching the container assembly to a 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 internal volume and an end surface. An opening may be formed in the end surface and may communicate with the internal volume. The septum may include a proximal end portion and a distal end portion. The proximal end portion of the septum may be insertable into the internal volume of the container through the opening. The distal end portion of the assembly may include a flange disposed outside the proximal end portion. At least an end portion of the flange may be made of a first material, and the first material may be permeable to a gaseous sterilant. At least a portion of the distal end portion 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 internal volume and an end surface. An opening may be formed in the end surface and may communicate with the internal volume. The septum may include a proximal end portion and a distal end portion. The proximal end portion of the septum may be insertable into the internal volume of the container through the opening. The distal end portion of the septum may include a flange disposed outside the proximal end portion. 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 gaseous 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 portion insertable into the drug container, and a distal end portion including a flange disposed radially outside the proximal end portion. The flange may include an outer peripheral surface and a proximal-side opposing surface. At least an end portion of the flange may be made of a first material. The first material may be permeable to a gaseous sterilant such that the gaseous sterilant is allowed to diffuse between the outer peripheral surface of the flange and the proximal-side opposing surface of the flange through the first material. At least a portion of the distal end portion 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 internal volume and an end surface. An opening may be formed in the end surface and may communicate with the internal volume. The drug may be disposed within the internal 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 internal volume of the container through the opening. The distal end of the septum may include a flange, which may be disposed outside the proximal end and may contact the end surface of the container. Further, the entire septum may be made of a material that permits permeation of a gaseous sterilant.

[0013] The present disclosure is considered to be more particularly understood from the following description when read in conjunction with the accompanying drawings. Some of the drawings may be simplified by omitting selected elements to more clearly show other elements. The omission of such elements in some of the drawings does not necessarily indicate the presence or absence of a particular element in any of the exemplary embodiments, except as specifically described in the corresponding written description. Also, the drawings are not necessarily to scale.

Brief Description of the Drawings

[0014]

Figure 1

Figure 2A

Figure 2B

Figure 3A

Figure 3B

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9A

Figure 9B

Figure 10

DETAILED DESCRIPTION OF THE INVENTION

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

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

[0017] Before describing various embodiments of a septum constructed in accordance with the principles of the present disclosure, a general overview of a drug delivery device into which the septum embodiments described below can be incorporated is provided with reference to FIG. 1.

[0018] FIG. 1 shows an embodiment of a drug delivery device 10 that can be operated to deliver a drug subcutaneously or transdermally to a patient. 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-type injector such as an autoinjector or an injection pen that is temporarily held against the patient's tissue 11 during the injection process. The drug delivery device 10 can be configured to automatically deliver a fixed or patient / operator-settable dose of the drug over a controlled or selected period of time. Further, the drug delivery device 10 can be for self-administration by the patient or can be operated by a formally trained healthcare provider or other caregiver who performs the infusion.

[0019] Generally, the drug delivery device 10 can include an insertion mechanism 12, a container 14, a fluid path assembly 22, a drive mechanism 24, and a controller 26, which can each be disposed within the internal space of a main housing 29. An actuator 28 (e.g., a button that a user can press, a touch screen, a microphone, etc.) can protrude from the outer surface of the housing 29 or be disposed on the outer surface of the housing 29 and can be configured to initiate the 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 where the actuator 28 is a button that is pressed by a user or patient or physically actuated in another manner, the actuator 28 can be configured to apply 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, by pressing the actuator 28 by hand or interacting with it in other ways, the actuator 28 can be physically connected to the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms either directly or indirectly via a mechanical linkage mechanism so as to supply 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, pressing the actuator 28 by hand moves the fluid path assembly 22 towards the fixed container 14 or moves the container 14 towards the fixed fluid path assembly 22, thereby causing the container access needle to penetrate the seal member and enter the reservoir or internal volume of the container 14. Additionally or alternatively, the actuator 28 can operate as an input device that transmits electrical and / or mechanical signals to the controller 26, and the controller 26 can further execute programmable instructions for controlling the operation of the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms.In such an embodiment, the controller 26 may include a processor (e.g., a microprocessor) and a non-transitory memory for storing programable instructions executed by the processor. Further, in such an embodiment, the drug delivery device 10 may include a prime mover (e.g., an electric motor, a pneumatic or hydraulic pump, and / or a pressurized gas or liquid source) that is separate from the actuator 28 and that acts to apply motive power necessary to activate the insertion mechanism 12, the drive mechanism 24, the fluid path assembly 22, and / or other mechanisms in response to an electrical control signal received from the controller 26.

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

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

[0022] After the bottom wall 25 of the housing 29 is attached to the patient's tissue 13, the insertion mechanism 12 can be activated to move the delivery member from a retracted position within the housing 29 to a deployed position extending outside the housing 29. In this embodiment, this includes inserting the insertion mechanism 12, as shown in FIG. 1, through a pierceable sterilization barrier 33 that includes a trocar 21 and a hollow cannula 23 surrounding the trocar 21 into the patient's tissue 11. Immediately thereafter or shortly thereafter, the insertion mechanism 12 can automatically retract the trocar 21 and leave the distal end opening of the cannula 23 inside the patient for subcutaneous delivery of the drug 32. The trocar 21 can be solid and have a sharp end for piercing the patient's skin 11. Further, the trocar 21 can be made of a material that is more rigid than the cannula 23. In some embodiments, the trocar 21 can be made of metal and the cannula 23 can be made of plastic or another polymer. The relative flexibility of the cannula 23 can allow the cannula 23 to be subcutaneously placed 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 the cannula 23 can be omitted, and instead, the insertion mechanism 12 can insert only a rigid hollow needle into the patient for subcutaneous delivery of the drug 32.

[0023] In some embodiments, the insertion mechanism 12 can include one or more springs (e.g., coil springs, torsion springs, etc.) that are initially held in a biased state and are released to insert the trocar 21 and the cannula 23 or the hollow needle into the patient when the actuator 28 is pushed. Further, the retraction of the trocar 21 can be achieved by the automatic release of another spring after the trocar 21 and the cannula 23 have been 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 operating energy.

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

[0025] The amount of the drug 32 contained in the container 14 before delivery can be any amount within the range of about (for example, ±10%) 0.5 to 20 mL, or about (for example, ±10%) 0.5 to 10 mL, or about (for example, ±10%) 1 to 10 mL, or about (for example, ±10%) 1 to 8 mL, or about (for example, ±10%) 1 to 5 mL, or about (for example, ±10%) 1 to 3.5 mL, or about (for example, ±10%) 1 to 3 mL, or about (for example, ±10%) 1 to 2.5 mL, or about (for example, ±10%) 1 to 2 mL, or any amount of about (for example, ±10%) 4 mL or less, or about (for example, ±10%) 3.5 mL or less, or about (for example, ±10%) 3 mL or less, or about (for example, ±10%) 2.5 mL or less, or about (for example, ±10%) 2 mL or less, or about (for example, ±10%) 1.5 mL or less, or about (for example, ±10%) 1 mL or less. The inner volume 30 of the container 14 can be completely or partially filled with the drug 32. The drug 32 can be one or more of the drugs described below, such as, for example, 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 can 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 can include one or more springs (e.g., coil springs, torsion springs, etc.) that are initially held in a biased state and released when the actuator 28 is pushed. The springs can expand after their release and move the stopper 34 along the longitudinal axis A within the internal 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 can 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 internal volume 30. In yet another embodiment, the drive mechanism 24 can include both an electric motor and a spring, and the electric motor adjusts the expansion of the spring via a tether or pulley system. In yet another embodiment, the drive mechanism 24 can include a canister that releases pressurized gas or liquid to provide operating energy.

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

[0028] Referring further to FIG. 1, the fluid path assembly 22 can 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 path 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 user can manually or the drug delivery device 10 can automatically enable, connect, or open the necessary connections to establish fluid communication between the container 14 and the fluid path assembly 22. Thereafter, the drive mechanism 24 can move the stopper 34 in the distal direction to push the drug 32 stored in the container 14 through the sterile fluid path of the fluid path assembly 22 into the cannula 23 or needle of the insertion mechanism 12 for subcutaneous delivery to the patient.

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

[0030] The fluid path assembly 22 may include a first end 44 having an opening, a second end 48 fluidly connected to the insertion mechanism 12, and a fluid passage 50 extending between the first end 44 and the second end 48. The fluid passage 50 may be sterilizable and may be made, in part or in whole, of a flexible tube 52. Initially, the flexible tube 52 may have slack so as to allow the fluid path assembly 22 to move relative to the housing 29 and / or to allow components of the insertion mechanism 12 to which the fluid path assembly 22 is attached to move relative to the housing 29. In some embodiments, the fluid passage 50 may include, in addition to the flexible tube 52, a rigid fluid restriction element (not shown). The fluid restriction 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 path assembly 22. Further, the fluid restriction element may be made of a material that is more rigid than the flexible tube 52. For example, the fluid restriction 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, the seal member 60 (e.g., a septum) connected to the first end 44 of the fluid path assembly 22 may cover and initially hermetically seal the opening of the first end 44 of the fluid path assembly 22. In a general sense, the seal member 60 may be configured to control access to the fluid passage 50. In some embodiments, the seal member 60 may be physically altered during operation of the device 10 to allow fluid communication with the fluid passage 50. The seal member 60 may be axially aligned with the septum 40 such that the outer surface of the proximal end of the seal member 60 faces the tip 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] Referring further to FIG. 1, a container access needle 64, which can be rigid and hollow, can extend from a first end 44 of the fluid path assembly 22. A first end 66 of the container access needle 64, which can be sharp, can project from the first end 44 of the fluid path assembly 22, and a second end 68 of the container access needle 64 can be in fluid communication with the fluid passage 50. The first end 66 of the container access needle 64 can have an opening that is initially covered and sealed by, or buried within, the seal member 60. In some embodiments, the fluid path assembly 22 includes a mounting member 51 or connection hub for rigidly connecting the container access needle 64 to the remainder of the fluid path assembly 22 such that the container access needle 64 cannot move relative to the fluid path assembly 22 and the fluid path assembly 22 and the container access needle 64 move together as a single unit relative to the housing 29 to the extent that the fluid path assembly 22 can move relative to the housing 29. Further, the seal member 60 can be attached to the container access needle 64 such that the seal member 60 is connected to the first end 44 of the fluid path assembly 22 via the container access needle 64. Further, in such embodiments, the seal member 60 can be constructed as a deformable septum or as a collapsible or rigid sleeve that defines a sterile internal chamber that seals the exposed first end 66 of the container access needle 64.

[0033] Furthermore, if necessary, any of the above subassemblies, mechanisms, components, features, functions, manufacturing methods, usage methods, and other aspects of the drug delivery device 10 can be replaced and / or combined with any of the subassemblies, mechanisms, components, features, functions, manufacturing methods, usage methods, and other aspects of the drug delivery device described in some or all of the following documents, which are hereby incorporated by reference in their entirety for all purposes: U.S. Patent No. 9,061,097, U.S. Patent Application Publication No. 2017 / 0124284, U.S. Patent Application Publication No. 2017 / 0119969, U.S. Patent Application Publication No. 2017 / 0098058, U.S. Patent Application Publication No. 2017 / 0124285, U.S. Patent Application Publication No. 2017 / 0103186, U.S. Provisional Patent Application No. 62 / 460,501 entitled "INSERTION MECHANISM FOR DRUG DELIVERY DEVICE", U.S. Provisional Patent Application No. 62 / 469,226 entitled "INSERTION MECHANISM FOR DRUG DELIVERY DEVICE", U.S. Provisional Patent Application No. 62 / 468,190 entitled "INSERTION MECHANISM AND METHOD OF INSERTING A NEEDLE OF A DRUG DELIVERY DEVICE", 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. 62 / 320,Specification No. 438, International Application PCT / US Patent Application Publication No. 2017 / 017627 entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE", and International Application PCT / US Patent Application Publication No. 2017 / 026524 entitled "DRUG DELIVERY DEVICE, METHOD OF MANUFACTURE, AND METHOD OF USE".

[0034] Referring to FIGS. 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 the distal end 37 of the container 14, the wall 38 may project radially outward to 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 end surface 72 of the container 14 that is perpendicular or otherwise non-parallel to the longitudinal axis A of the container 14 and generally faces distally. An opening 45 may be formed in the distal end surface 72 and may communicate with the internal volume 30 of the container 14. In some embodiments, the container flange 70 may be omitted so that the distal end surface 72 does not project radially outward from the remainder of the container 14. The wall 38 at the proximal end 36 of the container 14 may include a proximal end surface 78 that is perpendicular or otherwise non-parallel to the longitudinal axis A of the container 14 and generally faces proximally. An opening 79 may be formed in the proximal end surface 78 and may communicate with the internal volume 30. After the container 14 is filled with the drug 32, the stopper 34 may be inserted into the internal volume 30 through the opening 79. The container 14 may be constructed from glass, plastic, or any other suitable inert material that cannot chemically interact with the drug 32.

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

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

[0038] Referring to FIG. 2B, the fastener 94 can be configured to hold the septum 40 against the container 14. In some embodiments, the fastener 94 can take the form of a crimping ring that is applied to the container 14 and the septum 40 by a crimping tool. As shown in FIG. 2B, the fastener 94 can include radially inwardly extending flanges 96 and 98 that abut, respectively, the proximal side opposing surface of the container flange 70 (or other outer surface of the wall 38 of the container 14) and the distal side opposing end surface of the distal end portion 82 of the septum 40 to tightly clamp or press the proximal end surface 90 of the flange 84 of the septum 40 against the distal end surface 72 of the container 70. The clamping force provided by the fastener 94 can help ensure an airtight and / or fluid-tight seal between the proximal end surface 90 of the flange 84 of the septum 40 and the distal end surface 72 of the container 70. As will be described in more detail below, in some embodiments, the fastener 94 can be made of a material that allows a gaseous sterilant, such as EtO and / or vapor, to permeate through it.

[0039] Referring further to FIG. 2B, the proximal end portion 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 rib 100 may provide a secondary barrier for preventing ingress contaminants that break the seal between the proximal end surface 90 of the flange 84 of the septum 40 and the distal end surface 72 of the container 70. Here, the outer diameter D2 of the proximal end portion 80 of the septum 40 may be less than or equal to the inner diameter D1 of the container 14. In other embodiments, the annular rib 100 may be omitted (see FIGS. 3A and 3B), and the outer diameter D2 of the proximal end portion 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 portion 80 of the septum 40 may be smaller than the inner diameter D1 of the container 14 such that there is no seal formed between the proximal end portion 80 of the septum 40 and the container 14.

[0040] Before placing the drug delivery device 10 into its final package or sealing the internal space of the housing 29, it may be advantageous to subject the fully or partially assembled drug delivery device 10 to a sterilization process to reduce or remove airborne or stationary microorganisms or other contaminants within or on the housing 29. Such a sterilization process may be essential 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 can be filled by the drug manufacturer in a sterilized or aseptic environment with little risk of contamination and covered with a septum 40 before attaching it to the drug delivery device 10. However, if the container 14 is transported to the manufacturer of the drug delivery device 10 and / or attached 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, adhere between the flange 84 of the septum 40 and the tip surface 72 of the container 14, or even contaminate the drug 32 in some cases. 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 attaching the prefilled container 14 to the drug delivery device 10 may not be achievable due to the possibility that the high-energy sterilization beam may harm the drug 32 within the container 14. Gas sterilization treatment may not harm the drug 32, but there is a possibility that it may not be able to sterilize the base end surface 90 and / or the tip surface 72 by penetrating the seal between the flange 84 of the septum 40 and the container 14.

[0041] To address this problem, the septum 40, the fastener 94, and / or other components associated with the container 14 can be constructed of a material that allows the partial or complete permeation of a gas sterilant, including but not limited to EtO and / or vapor. This material can provide a diffusion path for the molecules of the gas sterilant to diffuse at least through the septum 40, enabling the gas sterilant to penetrate and sterilize one or more surfaces, such as the base end surface 90 and / or the tip surface 72, which were previously impossible to sterilize because the seal formed at the interface between the septum 40 and the container 14 was impermeable to the gas sterilant.

[0042] Figures 4 - 7 show four types of the above - described septum 40, each having a different material composition but the same dimensions and geometric properties as those shown in Figures 1 - 3B. Each type of the septum 40 is assigned one of the suffixes "a", "b", "c", or "d". What is common to all types of the septum 40a, 40b, 40c, and 40d shown in Figures 4 - 7 is that at least the base - end portion 86 of the flange 84, which includes the base - end surface 90 and the outer peripheral surface 92, is made of a first material that permits a gaseous sterilant containing at least one of EtO or vapor to permeate. Thus, each septum 40a - 40d has at least one diffusion path for the gaseous sterilant that extends between the base - end 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 the gaseous sterilant, the gaseous sterilant enters the septum 40 at least through the outer peripheral surface 92, exits the septum 40 at least through the base - end surface 90, and can sterilize at least the interface between the septum 40 and the container 14, which includes the base - end surface 90 of the flange 84 and the tip surface 72 of the container 14. Depending on the portion of the septum 40 constructed of the first material that permits the gaseous sterilant to permeate, other diffusion paths through the septum 40 may also be possible. The rate at which the gaseous sterilant diffuses through each septum 40a, 40b, 40c, and 40d may depend on the ratio of the septum made of the first material. Also, although one or more annular ribs 100 are omitted from Figures 4 - 7, any of the embodiments of the septum 40a, 40b, 40c, and 40d may include one or more annular ribs 100.

[0043] Referring to FIG. 4, there is shown an embodiment of a septum 40a where only the base end portion 86a of the flange 84a can be made of a first material that permits a gaseous sterilant containing at least one of EtO or vapor to permeate therethrough. Thus, only the annular portion of the septum 40a defined by the base end portion 86a of the flange 84a can be made of the first material that permits the gaseous sterilant to permeate therethrough. The remaining portion of the septum 40a, including the tip portion 88 of the flange 84 and the base end 80a of the septum 40a, can be made of a second material that is less permeable to the gaseous sterilant than the first material. In some embodiments, the second material may not substantially or completely permit the gaseous sterilant to permeate therethrough. Further, in some embodiments of the septum 40a, the gaseous sterilant can enter the septum 40a only through the outer peripheral surface 92a of the flange 84a and can exit the septum 40a mainly through or only through the base end surface 90a of the flange 84. This can be useful to prevent the gaseous sterilant from entering the internal volume 30 of the container 14 and interacting with the drug 32.

[0044] FIG. 5 shows another embodiment of a septum 40b where the gaseous sterilant can have an additional path into the septum 40b that includes not only the entire outer peripheral surface of the tip portion 82b of the septum 40b but also the entire tip surface of the septum 40b. This approach can be achieved by constructing the tip portion 82b of the septum 40b entirely of a first material that permits a gaseous sterilant containing at least one of EtO or vapor to permeate therethrough. The base end 80b of the septum 40b can be entirely made of a second material that is less permeable to the gaseous sterilant than the first material. In some embodiments, the second material may not substantially or completely permit the gaseous sterilant to permeate therethrough. Similar to the septum 40a, the gaseous sterilant can exit the septum 40b mainly through or only through the base end surface 90b of the flange 84b. In some embodiments, the first material of the septum 40b can be made of polybutadiene rubber and the second material of the septum 40b can be made of chlorobutyl rubber.

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

[0046] FIG. 7 shows another embodiment of a septum 40d made entirely of the above-described first material. Thus, both the proximal end portion 80d and the distal end portion 82d of the septum 40d can be entirely made of a material that permits the passage of a gaseous sterilant containing at least one of EtO or vapor. This structure can maximize the number of diffusion paths for the gaseous sterilant. The gaseous sterilant can enter and exit the septum 40d through any outer surface of the septum 40d. Thus, it may be possible to sterilize not only the interface between the flange 84d and the distal surface 72 of the container 14 but also the interface between the proximal end portion 80d of the septum 40d and the inner surface 43 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 sealed and / or sterile space within a bag or other secondary package prior to use. This can prevent any gas and / or contaminants from diffusing through the septum 40d during the period between the assembly of the drug delivery device 10 and its use by a patient. In some embodiments, the secondary package can be constructed of a multi-layer material having gas barrier properties. Further, any of the septa disclosed herein, including septa 40a, 40b, 40c, and 40d, can be attached to the drug delivery device 10 that is later placed within such a secondary package to provide additional protection against contamination during the period between the assembly of the drug delivery device 10 and its use by a patient.

[0047] The following description of the first material and the second material applies to any one of the septa 40a, 40b, 40c, and 40d above and any other septum described herein. The composition of the first material is selected according to the characteristics of the sterilization treatment (e.g., final sterilization treatment) used to sterilize the container 14 and / or other components of the following drug delivery device 10, i.e., the composition of the gaseous sterilant used in the sterilization treatment, the pressure of the gaseous sterilant used in the sterilization treatment, the amount or volume of the gaseous sterilant used in the sterilization treatment, the concentration of the gaseous sterilant used in the sterilization treatment, the length of time of the sterilization treatment, and any one or any combination of the non-exclusive list of the temperature of the gaseous sterilant used in the sterilization treatment. In some embodiments, the first material can permeate any one or any combination of the gaseous sterilants selected from the non-exclusive list of the following gaseous sterilants, i.e., EtO, ozone, chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurized steam). In some embodiments, the sterilization treatment using steam as the gaseous sterilant can be carried out inside an autoclave device. The first material can include any one or any combination of the non-exclusive list of the following materials, i.e., polymers, rubbers, and polybutadiene rubbers. The second material can include any one or any combination of the non-exclusive list of the following materials, i.e., polymers, rubbers, chlorobutyl rubber, and halogenated butyl rubber. In any of the above septa 40a, 40b, 40c, and 40d and any other septum described herein, the first material can be made of polybutadiene rubber, and the second material can be made of chlorobutyl rubber.

[0048] Generally, the second material has lower permeability to the gaseous sterilant than the first material, which includes that the second material cannot substantially or completely permeate the gaseous sterilant. In some embodiments, the permeation rate of the first material can be at least 10 times, or at least 20 times, or at least 30 times, or at least 40 times, or at least 50 times, or at least 60 times, or at least 70 times, or at least 80 times, or at least 90 times, or at least 100 times higher than the permeation rate of the second material.

[0049] Any one of the septums 40a, 40b, 40c, and 40d described above and any other septum described herein can be constructed as an integral component that is integrally formed with each other, such as when the first material and the second material are injection molded together. Alternatively, any one of the septums 40a, 40b, 40c, and 40d described above and any other septum described herein can be constructed as a multi-component component in which the first material and the second material are connected to each other by an adhesive, a fastener, and / or any other suitable connecting element.

[0050] In embodiments where a fastener 94 is used to hold the septum 40 in the container 14, the fastening ring 94 can serve as a gas barrier that prevents the gaseous sterilant from diffusing through the permeable portion of the septum 40. Thus, in some embodiments, one or more openings 99 (see FIG. 2B) can be formed in the fastening ring 94 to allow the gaseous sterilant to pass through the fastening ring 94 and contact the permeable portion of the septum 40. In some embodiments, the openings 99 can be arranged and / or formed in a pattern on the outer peripheral or circumferential surface of the fastener 94. In some embodiments, as seen in FIG. 2B, the openings 99 can be located at the same axial position as the outer peripheral surface 92 of the base end portion 86 of the flange 84. In addition to or instead of the openings 99, the fastener 94 can be partially or completely constructed of a material that allows the gaseous sterilant (e.g., EtO, ozone, chlorine dioxide, nitrogen dioxide, and / or steam) to permeate.

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

[0052] Each of the foregoing embodiments provides a diffusion path for the gaseous sterilant depending on the septum. However, the diffusion path can also be realized by other means. FIGS. 9A and 9B show an 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 FIGS. 9A and 9B, similar to those shown in FIGS. 2A and 2B, are indicated by the same reference numerals incremented by 100. Many descriptions of these elements are omitted or excluded for brevity.

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

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

[0055] Regarding the septum 140 used in conjunction with the annular sealing member 300, it can be partially or completely constructed of a material that is less permeable to the gaseous sterilant than the material used to construct the annular sealing member 300. In some embodiments, the septum 140 can be partially or completely constructed of the second material described above. In such embodiments, the foregoing description of the second material incorporated into septa 40a-40c applies to the second material incorporated into septum 140. The annular sealing member 300 advantageously provides a diffusion path for the gaseous sterilant for sterilizing the tip surface 172 of the container 114 when using a conventional septum that is substantially or completely impermeable to the gaseous sterilant for plugging the container 114. Further, the annular sealing member 300 is not limited to use with the septum 140, and the annular sealing member 300 can be used in combination with any of the septa disclosed herein including any of septa 40a-40d.

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

[0057] Next, the partially assembled container 14 can be exposed to a sterilization treatment or process. In some embodiments, this sterilization treatment can include placing the partially assembled container 14 within a sealed vacuum chamber that will later be filled with a gaseous sterilant. The gaseous sterilant can be any one or any combination of gaseous sterilants selected from the following non-exclusive list of gaseous sterilants, namely EtO, ozone, chlorine dioxide, nitrogen dioxide, and vapor (e.g., pressurized steam). In embodiments where steam is used for sterilization, the chamber in which the sterilization treatment is performed can be an autoclave. During this sterilization treatment, if the septum 40 and the annular sealing member 300 are included, the annular sealing member 300 can be exposed to the gaseous sterilant. The portion of the septum 40 and / or the annular sealing member 300 constructed of the first material described above can, as described above, allow for the diffusion of the gaseous sterilant through the septum 40 and / or the annular sealing member 300 to sterilize the interface between the septum 40 or the annular sealing member 300 and the container 14. Due to the effect that the gaseous sterilant can diffuse through the septum 40 and / or the annular sealing member 300 to sterilize the interface of the container 14, the exposure time to the gaseous sterilant can be relatively short. In some embodiments, the exposure time to the gaseous sterilant can be in 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 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 the container 14 is exposed to the gaseous sterilant, the shorter the time that may be required for aeration of the container 14 after the sterilization treatment. Thus, the septum and the annular sealing member disclosed herein can assist in streamlining the manufacturing process of the container 14. In an alternative embodiment, this sterilization step of the partially assembled container 14 can be omitted or can be performed after the filling procedure described in the following paragraphs.

[0058] Next, the container 14 and the septum 40 can be aseptically transferred to a filling and capping environment. Here, the drug 32 can be filled into the internal volume 30 of the container 14, and then the proximal end portion 36 of the container 14 can be hermetically sealed by a stopper 34 that is slidably inserted through the opening 79. This filling and capping environment can be operated as a sterilized or aseptic assembly environment to ensure that microorganisms and other contaminants are not introduced into the internal volume 30. Thereafter, the drug-filled and pre-assembled container assembly can be packaged and transported to a facility where the final assembly of the drug delivery device 10 is performed. Also, as a preliminary step, the fluid path assembly 22 can be connected to the seal member 60 such that the seal member 60 seals the open end of the fluid path 50. The process of assembling the fluid path assembly 22 and the seal member 60 can be performed in a sterilized or aseptic assembly environment to ensure that particulate contaminants are not introduced into the fluid path 50. Alternatively or in addition, the pre-assembled configuration of the fluid path assembly 22 and the seal member 60 can be exposed to high-energy sterilization beams (e.g., gamma ray beams, x-ray beams, electron beams, etc.), ethylene oxide, or other known techniques to ensure their sterility. Thereafter, this pre-assembled configuration can be packaged and transported to a facility where the final assembly of the drug delivery device 10 is performed.

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

[0060] After the pre-assembled configuration of the drug container 14, the septum 40, and the stopper 34 filled with the drug and / or the pre-assembled configuration of the fluid path assembly 22 and the seal member 60 are installed within the housing 29, the partially assembled version of this drug delivery device 10 can be exposed to a sterilization treatment or process. In some embodiments, this sterilization treatment can include placing the partially assembled version of the drug delivery device 10 within a sealed vacuum chamber that will later be filled with a gaseous sterilant. The gaseous sterilant can be any one or any combination of gaseous sterilants selected from the following non-exclusive list of gaseous sterilants, namely EtO, ozone, chlorine dioxide, nitrogen dioxide, and steam (e.g., pressurized steam). In embodiments where steam is used for sterilization, the chamber in which the sterilization treatment is performed can be an autoclave. During this sterilization treatment, if the septum 40 and the annular sealing member 300 are included, the annular sealing member 300 can be exposed to the gaseous sterilant. The portion of the septum 40 and / or the annular sealing member 300 constructed of the above-described first material can, as described above, allow for the diffusion of the gaseous sterilant through the septum 40 and / or the annular sealing member 300 to sterilize the interface between the septum 40 or the annular sealing member 300 and the container 14. Due to the effect that the gaseous sterilant can diffuse through the septum 40 and / or the annular sealing member 300 to sterilize the interface of the container 14, the exposure time to the gaseous sterilant can be relatively short. In some embodiments, the exposure time to the gaseous sterilant can be in 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 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 the drug delivery device 10 is exposed to the gaseous sterilant, the shorter the time that may be required for aeration of the drug delivery device 10 after the sterilization treatment. Therefore, the septum and the annular sealing member disclosed herein can contribute to the rationalization of the manufacturing process of the drug delivery device 10.

[0061] After the sterilization process is completed, the first housing portion can be connected to the second housing portion to seal the pre-assembled configuration of the drug container 14, the septum 40, and the stopper 34 filled with the drug and / or other components (e.g., the insertion mechanism 12, the fluid path assembly 22, the drive mechanism 24, the controller 26, etc.) within the sterilized internal space of the drug delivery device 10. Thus, the sealing process can result in a pre-loaded and pre-filled type drug delivery device 10. In some embodiments, the connection between the first housing portion and the second housing portion can seal the interior of the drug delivery 10 and prevent or block the entry of contaminants. Further, in some embodiments, the first housing portion and the second housing portion can be hermetically connected within the same environment or chamber that has undergone a gas sterilization process.

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

Example

[0063] The following describes the results of experimental tests comparing a composite septum constructed in accordance with the principles of the present disclosure to a conventional septum made entirely of a gas-impermeable material. Both the composite septum and the conventional septum had approximately 10 at the base end surface of their flanges. 6Individual challenge microorganisms were inoculated. Then, each septum was crimped onto the tip surface of the drug container. This process was repeated to create 30 samples using the composite septum and 30 samples using the conventional septum. Next, the samples were exposed to gaseous sterilization treatment. In this treatment, EtO was used as the gaseous sterilant. After 18 hours of EtO sterilization, no microbial growth was observed at the interface between the composite septum and the drug container in all 30 samples. Some of the composite septum samples showed no microbial growth after only 8 hours of EtO sterilization. In comparison, after 30 hours of EtO sterilization, only 15 out of 30 samples using the conventional septum showed no microbial growth at the interface with the drug container. Therefore, it was experimentally shown that the amount of time required to sterilize the interface between the composite septum and the container disclosed herein is significantly less than the amount of time required to sterilize the interface between the conventional septum and the container.

[0064] Drug information As described above, the container can be filled with a drug. This drug can be any one or combination of the drugs listed below, provided that the following list should not be considered as encompassing all or limiting all.

[0065] For example, a syringe can be filled with a colony-stimulating factor such as granulocyte colony-stimulating factor (G-CSF). Examples of such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the syringe can be used with various pharmaceuticals such as erythropoiesis-stimulating agents (ESAs), which can be in liquid or lyophilized form.ESA refers to any molecule that stimulates erythropoiesis, such as 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® (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, and the entirety of each of the following patents or patent applications incorporated herein by reference: U.S. Patent No. 4,703,008, U.S. Patent No. 5,441,868, U.S. Patent No. 5,547,933, U.S. Patent No. 5,618,698, U.S. Patent No. 5,621,080, U.S. Patent No. 5,756,349, U.S. Patent No. 5,767,078, U.S. Patent No. 5,773,569, U.S. Patent No. 5,955,422, U.S. Patent No. 5,986,047, U.S. Patent No. 6,583,272, U.S. Patent No. 7,084,245, and U.S. Patent No. 7,271,689, and the molecules disclosed in PCT International 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] ESA can be an erythropoiesis-stimulating protein. As used in the present invention, "erythropoiesis-stimulating protein" means, for example, any protein that binds to a receptor and directly or indirectly causes activation of the erythropoietin receptor by causing dimerization of the receptor. Examples of erythropoiesis-stimulating proteins include erythropoietin and its variants, analogs or derivatives that bind to and activate the erythropoietin receptor, antibodies that bind to and activate the erythropoietin receptor, and peptides that bind to and activate the erythropoietin receptor. Examples of erythropoiesis-stimulating proteins include, but are not limited to, epoetin α, epoetin β, epoetin δ, epoetin ω, epoetin ι, epoetin ζ and their analogs, PEGylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1 / hematide), and mimetic antibodies. Exemplary erythropoiesis-stimulating proteins include erythropoietin, darbepoetin, erythropoietin agonist variants and peptides or antibodies that bind to and activate the erythropoietin receptor (and compounds reported in US Patent Application Publication No. 2003 / 0215444 and US Patent Application Publication No. 2006 / 0040858, the entire contents of each disclosure of which are incorporated herein by reference), and the following patents or patent applications, the entire contents of each disclosure of which are incorporated herein by reference: US Patent No. 4,703,008, US Patent No. 5,441,868, US Patent No. 5,547,933, US Patent No. 5,618,698, US Patent No. 5,621,080, US Patent No. 5,756,349, US Patent No. 5,767,078, US Patent No. 5,773,569, US Patent No. 5,955,422, US Patent No. 5,830,851, US Patent No. 5,856,298, US Patent No. 5,986,047, US Patent No. 6,030,086, US Patent No. 6,310,078, US Patent No. 6,391,633, US Patent No. 6,583,272, US Patent No. 6,586,398, US Patent No. 6,900,292, US 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, U.S. Patent Application Publication No. 2004 / 0143857, U.S. Patent Application Publication No. 2004 / 0157293, U.S. Patent Application Publication No. 2004 / 0175379, U.S. Patent Application Publication No. 2004 / 0175824, U.S. Patent Application Publication No. 2004 / 0229318, U.S. Patent Application Publication No. 2004 / 0248815, U.S. Patent Application Publication No. 2004 / 0266690, U.S. Patent Application Publication No. 2005 / 0019914, U.S. Patent Application Publication No. 2005 / 0026834, 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 / 0244409U.S. Patent Application Publication No. 2006 / 0088906, U.S. Patent Application Publication No. 2006 / 0111279, and PCT International Publication No. 91 / 05867 Pamphlet, International Publication No. 95 / 05465 Pamphlet, International Publication No. 99 / 66054 Pamphlet, International Publication No. 00 / 24893 Pamphlet, International Publication No. 01 / 81405 Pamphlet, International Publication No. 00 / 61637 Pamphlet, International Publication No. 01 / 36489 Pamphlet, International Publication No. 02 / 014356 Pamphlet, International Publication No. 02 / 19963 Pamphlet, International Publication No. 02 / 20034 Pamphlet, International Publication No. 02 / 49673 Pamphlet, International Publication No. 02 / 085940 Pamphlet, International Publication No. 03 / 029291 Pamphlet, International Publication No. 2003 / 055526 Pamphlet, International Publication No. 2003 / 084477 Pamphlet, International Publication No. 2003 / 094858 Pamphlet, International Publication No. 2004 / 002417 Pamphlet, International Publication No. 2004 / 002424 Pamphlet, International Publication No. 2004 / 009627 Pamphlet, International Publication No. 2004 / 024761 Pamphlet, International Publication No. 2004 / 033651 Pamphlet, International Publication No. 2004 / 035603 Pamphlet, International Publication No. 2004 / 043382 Pamphlet, International Publication No. 2004 / 101600 Pamphlet, International Publication No. 2004 / 101606 Pamphlet, International Publication No. 2004 / 101611 Pamphlet, International Publication No. 2004 / 106373 Pamphlet, International Publication No. 2004 / 018667 Pamphlet, International Publication No. 2005 / 001025 Pamphlet, International Publication No. 2005 / 001136 Pamphlet, 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,Examples include erythropoietin molecules or variants or analogs thereof disclosed in International Publication No. WO 2005 / 100403 Pamphlet, International Publication No. WO 2005 / 092369 Pamphlet, International Publication No. WO 2006 / 50959 Pamphlet, International Publication No. WO 2006 / 02646 Pamphlet, and International Publication No. WO 2006 / 29094 Pamphlet.

[0067] Examples of other pharmaceuticals for use with this device can include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva® (denosumab), and Prolia® (denosumab), Enbrel® (etanercept, a TNF receptor / Fc fusion protein, a TNF blocker), Neulasta® (pegfilgrastim, pegylated filgrastim, pegylated G-CSF, pegylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), and Nplate® (romiplostim), other biological agents such as Sensipar® (cinacalcet), and small molecule drugs. This device can be used with therapeutic antibodies, polypeptides, proteins, or other chemicals such as iron, for example ferumoxytol, iron dextran, ferrous glyconate, and iron sucrose. The pharmaceuticals can be in liquid form or can be reconstituted from a lyophilized form.

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

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

[0070] Peptibodies of the mTN8-19 family, including TN8-19-1 to TN8-19-40, TN8-19 con1 and TN8-19 con2, those of SEQ ID NOs: 305 to 351, peptibodies of the mL2 family of SEQ ID NOs: 357 to 383, peptibodies of the mL15 family of SEQ ID NOs: 384 to 409, peptibodies of the mL17 family of SEQ ID NOs: 410 to 438, peptibodies of the mL20 family of SEQ ID NOs: 439 to 446, peptibodies of the mL21 family of SEQ ID NOs: 447 to 452, peptibodies of the mL24 family of SEQ ID NOs: 453 to 454 and peptibodies of SEQ ID NOs: 615 to 631, as disclosed in the following publication and each of which is incorporated herein by reference in its entirety, individually and specifically, including, but not limited thereto, myostatin-specific peptibodies, myostatin-binding proteins, peptibodies and related proteins, etc., particularly those related in part to myostatin-specific peptibodies and described in U.S. Patent Application Publication No. 2004 / 0181033 and PCT International Publication No. 2004 / 058988 pamphlet which are incorporated herein by reference in their entirety.

[0071] As disclosed in the following publications, 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, although not limited thereto, IL-4 receptor-specific antibodies, such as antibodies as described in the following publications, in particular those shown in the following publications, are in particular partially related to those shown in PCT International Publication No. 2005 / 047331 pamphlet or International Application PCT / US Patent Application Publication No. 2004 / 37242 specification and US Patent Application Publication No. 2005 / 112694 specification, the entireties of which are incorporated herein by reference, including those that suppress activities mediated by binding to the receptors of IL-4 and / or IL-13, such as IL-4 receptor-specific antibodies, peptibodies, and related proteins.

[0072] As disclosed in the following publications, those shown in the following publications, namely 15CA, 26F5, 27F2, 24E12, and 10H7, although not limited thereto, are partially IL1-R1 specific binding proteins, in particular those related to monoclonal antibodies, and are incorporated herein by reference in their entireties, including but not limited to those described in US Patent Application Publication No. 2004 / 097712 specification, such as interleukin 1-receptor 1 ("IL1-R1") specific antibodies, peptibodies, and related proteins.

[0073] As disclosed in the following publications, each of which is hereby incorporated by reference in its entirety into this specification individually and specifically, particularly those of the sequences described in the following publications, including but not limited to 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 1K, Con4-L1(N), Con4-L1C, TN-12-9(N), C17(N), TN8-8(N), TN8-14(N), Con1(N), Ang2-specific antibodies, peptibodies, etc. Each of the PCT International Publication No. 03 / 057134 pamphlet and the US Patent Application Publication No. 2003 / 0229023 specification, which are particularly partially related thereto, is hereby incorporated by reference in its entirety into this specification. Also, regarding anti-Ang2 antibodies and formulations, including but not limited to anti-Ang2 antibodies and formulations such as those described in the PCT International Publication No. 2003 / 030833 pamphlet, which are related to various permutations of Ab526, Ab528, Ab531, Ab533, Ab535, Ab536, Ab537, Ab540, Ab543, Ab544, Ab545, Ab546, A551, Ab553, Ab555, Ab558, Ab559, Ab565, AbF1, AbFD, AbFE, AbFJ, AbFK, AbG1D4, AbGC1E8, AbH1C12, AblA1, AblF, AblK, AblP and AblP, and each of which is hereby incorporated by reference in its entirety into this specification.

[0074] As disclosed in the following publications, the entireties of which are hereby incorporated by reference in their entireties individually and specifically into this specification, specifically including, but not limited to, the NGF-specific antibodies 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11 shown in the following publications, the NGF-specific antibodies 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, the entireties of which are hereby incorporated by reference into this specification, including but not limited to NGF-specific antibodies, peptibodies and related proteins, etc.

[0075] For example, including but not limited to the human CD22-specific fully humanized antibody of epratuzumab (CAS registration number 501423-23-0), such as the dimer of human-mouse monoclonal hLL2 γ-chain disulfide bound to the human-mouse monoclonal hLL2 κ-chain, in particular including but not limited to human CD22-specific IgG antibodies, including but not limited to humanized and fully human monoclonal antibodies, including but not limited to humanized and fully human antibodies, etc., but not limited thereto. Specifically, CD22-specific antibodies, peptibodies and related proteins, etc., such as those described in U.S. Patent No. 5,789,554, the entirety of which is hereby incorporated by reference into this specification, which are CD22-specific antibodies.

[0076] The IGF-1 specific antibodies L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52 and IGF-1R-binding fragments and derivatives thereof, including but not limited to, IGF-1 receptor specific antibodies, peptides, and related proteins as described in PCT International Publication No. 06 / 069202 pamphlet, the entire contents of which are hereby incorporated by reference in their entirety.

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

[0078] (i) 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), U.S. Patent Application Publication No. 2004 / 0228859 (published November 18, 2004), including but not limited to, for example, antibody 1A (DSMZ deposit number DSM ACC 2586), antibody 8 (DSMZ deposit number DSM ACC 2589), antibody 23 (DSMZ deposit number DSM ACC 2588), and antibody 18.

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

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

[0081] (iv) antibodies 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 US Patent Application Publication No. US 2005 / 0084906 (published on April 21, 2005).

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

[0083] (vi) Each of the antibodies produced by hybridomas having ATCC accession numbers PTA - 2792, PTA - 2788, PTA - 2790, PTA - 2791, PTA - 2789, PTA - 2793 and antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2 and 4.17.3, including but not limited to, for example, antibody CP - 751,871, as described in U.S. Patent 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.

[0084] (vii) 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 an antibody comprising a heavy chain encoded by a polynucleotide of plasmid 15H12 / 19D12 HCA(γ4) deposited with ATCC under accession number PTA - 5214 and a light chain encoded by a polynucleotide of plasmid 15H12 / 19D12 LCF(κ) deposited with ATCC under accession number PTA - 5220, including but not limited to these.

[0085] (viii) Regarding the aforementioned antibodies, peptibodies, related proteins, etc. that specifically target the IGF-1 receptor, the entire content of each is incorporated herein by reference in U.S. Patent Application Publication No. 2004 / 0202655 (published on October 14, 2004), 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.

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

[0087] For example, 146B7, etc., in particular including, but not limited to, peptibodies including, for example, HuMax IL-15 antibodies and related proteins. With respect to IL-15 specific antibodies and related proteins, the entireties of which are hereby incorporated by reference into this specification, those disclosed in U.S. Patent Application Publication No. 2003 / 0138421, U.S. Patent Application Publication No. 2003 / 023586, U.S. Patent Application Publication No. 2004 / 0071702 and U.S. Patent No. 7,153,507, etc., in particular IL-15 specific antibodies such as antibodies, specifically humanized monoclonal antibodies, peptibodies and related proteins, etc.

[0088] Fully human anti-IFNγ antibodies such as IFNγ-specific antibodies, peptibodies, and related proteins, particularly human IFNγ-specific antibodies, particularly, for example, IFNγ-specific antibodies, particularly, for example, the antibodies shown as 1118, 1118*, 1119, 1121, and 1121* in the following patent publications, the entire content of which is incorporated herein by reference in its entirety, as described in U.S. Patent Application Publication No. 2005 / 0004353. The entire sequences of the heavy and light chains of each of these antibodies, as well as the sequences of their heavy and light chain variable regions and complementarity-determining regions, are each specifically incorporated herein in their entirety by reference, as disclosed in the aforementioned publication and Thakur et al. (1999), Mol. Immunol. 36:1107-1115. In addition, the descriptions of the characteristics of these antibodies described in the aforementioned publication are also incorporated herein by reference in their entirety. Specific antibodies include those having the heavy chain of SEQ ID NO: 17 and the light chain of SEQ ID NO: 18, those having the heavy chain variable region of SEQ ID NO: 6 and the light chain variable region of SEQ ID NO: 8, those having the heavy chain of SEQ ID NO: 19 and the light chain of SEQ ID NO: 20, those having the heavy chain variable region of SEQ ID NO: 10 and the light chain variable region of SEQ ID NO: 12, those having the heavy chain of SEQ ID NO: 32 and the light chain of SEQ ID NO: 20, those having the heavy chain variable region of SEQ ID NO: 30 and the light chain variable region of SEQ ID NO: 12, those having the heavy chain sequence of SEQ ID NO: 21 and the light chain sequence of SEQ ID NO: 22, those having the heavy chain variable region of SEQ ID NO: 14 and the light chain variable region of SEQ ID NO: 16, those having the heavy chain of SEQ ID NO: 21 and the light chain of SEQ ID NO: 33, and those having the heavy chain variable region of SEQ ID NO: 14 and the light chain variable region of SEQ ID NO: 31. The specific antibody contemplated is antibody 1119 disclosed in the aforementioned U.S. Patent Application Publication, which has the complete heavy chain of SEQ ID NO: 17 disclosed in the aforementioned U.S. Patent Application Publication and the 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 hereby incorporated by reference in its entirety and specifically and individually herein: U.S. Patent Application Publication No. 2003 / 0195156 and U.S. Patent Application Publication No. 2006 / 0135431, which are incorporated by reference in their entirety herein with respect to the TALL-1 binding proteins, particularly the molecules of Tables 4 and 5B, etc.; TALL-1 specific antibodies, peptibodies and related proteins, etc.; and other TALL specific binding proteins.

[0090] As described in U.S. Patent No. 6,756,480, which is incorporated by reference in its entirety herein particularly with respect to the proteins that bind to PTH, etc.; parathyroid hormone (「PTH」) specific antibodies, peptibodies and related proteins, etc.

[0091] As described in U.S. Patent No. 6,835,809, which is incorporated by reference in its entirety herein particularly with respect to the proteins that bind to TPO-R, etc.; thrombopoietin receptor (「TPO-R」) specific antibodies, peptibodies and related proteins, etc.

[0092] Hepatocyte growth factor (「HGF」) specific antibodies, peptibodies and related proteins, etc., including those targeting the HGF / SF:cMet axis (HGF / SF:c-Met) such as complete human monoclonal antibodies that neutralize hepatocyte growth factor / scatter factor (HGF / SF) described in U.S. Patent Application Publication No. 2005 / 0118643 and PCT International Publication No. 2005 / 017107 pamphlet, huL2G7 described in U.S. Patent No. 7,220,410, OA-5d5 described in U.S. Patent Nos. 5,686,292 and 6,468,529 and PCT International Publication No. 96 / 38557 pamphlet, each of which is incorporated by reference in its entirety herein particularly with respect to the proteins that bind to HGF.

[0093] TRAIL-R2-specific antibodies, peptibodies, related proteins, etc., such as those described in U.S. Patent No. 7,521,048, which is incorporated herein by reference in its entirety in particular with respect to proteins that bind to TRAIL-R2.

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

[0095] TGF-β-specific antibodies, peptibodies, related proteins, etc., including but not limited to those described in U.S. Patent No. 6,803,453 and U.S. Patent Application Publication No. 2007 / 0110747, which are incorporated herein by reference in their entireties respectively in particular with respect to proteins that bind to TGF-β.

[0096] Amyloid β-protein-specific antibodies, peptibodies, related proteins, etc., including but not limited to those described in PCT International Publication No. 2006 / 081171, which is incorporated herein by reference in its entirety in particular with respect to proteins that bind to amyloid β-protein. One contemplated antibody is an antibody having a heavy chain variable region containing 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, etc., including but not limited to those described in U.S. Patent Application Publication No. 2007 / 0253951, which is incorporated herein by reference in its entirety in particular with respect to proteins that bind to c-Kit and / or other stem cell factor receptors.

[0098] Including, but not limited to, OX40L-specific antibodies, peptibodies, related proteins, etc., as described in U.S. Patent Application Publication No. 2006 / 0002929, which is hereby incorporated by reference in its entirety, particularly in part related to proteins that bind to OX40L and / or other ligands of the OX40 receptor.

[0099] Activase (registered trademark) (alteplase, tPA), Aranesp (registered trademark) (darbepoetin alfa), Epogen (registered trademark) (epoetin alfa or erythropoietin), GLP-1, Avonex (registered trademark) (interferon beta-1a), Bexxar (registered trademark) (tositumomab, anti-CD22 monoclonal antibody), Betaseron (registered trademark) (interferon-β), Campath (registered trademark) (alemtuzumab, anti-CD52 monoclonal antibody), Dynepo (registered trademark) (epoetin delta), Velcade (registered trademark) (bortezomib), MLN0002 (anti-α4β7 mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel (registered trademark) (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex (registered trademark) (epoetin alfa), Erbitux (registered trademark) (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin (registered trademark) (somatropin, human growth hormone), Herceptin (registered trademark) (trastuzumab, anti-HER2 / neu (erbB2) receptor mAb), Humatrope (registered trademark) (somatropin, human growth hormone), Humira (registered trademark) (adalimumab), insulin in solution, Infergen (registered trademark) (interferon alfa con-1), Natrecor (registered trademark) (nesiritide, recombinant human B-type natriuretic peptide (hBNP), Kineret (registered trademark) (anakinra), Leukine (registered trademark) (sargramostim, rhuGM-CSF), LymphoCide (registered trademark) (epratuzumab, anti-CD22 mAb), Benlysta (trademark) (lynphosphostat B, belimumab, anti-BlySmAb), Metalyse (registered trademark) (tenecteplase, t-PA analog), Mircera (registered trademark) (methoxypolyethylene glycol-epoetin beta), Mylotarg (registered trademark) (gemtuzumab ozogamicin), Raptiva (registered trademark) (efalizumab), Cimzia (registered trademark) (certolizumab pegol, CDP870), Soliris (trademark) (eculizumab), pexelizumab (anti-complement C5), Numax (registered trademark) (MEDI-524), Lucentis (registered trademark) (ranibizumab), Panorex (registered trademark) (17-1A, edrecolomab), Trabio (registered trademark) (lerdelimumab), TheraCim hR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem (registered trademark) (IDM-1), OvaRex (registered trademark) (B43.13), Nuvion (registered trademark) (visilizumab), canzumab mertansine (huC242-DM1), NeoRecormon (registered trademark) (epoetin beta), Neumega (registered trademark) (oprelvekin, human interleukin-11), Neulasta (registered trademark) (PEGylated filgrastim, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen (registered trademark) (filgrastim, G-CSF, hu-MetG-CSF), Orthoclone OKT3 (registered trademark) (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit (registered trademark) (epoetin alpha), Remicade (registered trademark) (infliximab, anti-TNFα monoclonal antibody), Reopro (registered trademark) (abciximab, anti-GPlIb / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanilimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alfa-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Patent No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax™, Vectibix® (panitumumab), Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)), VEGF trap (Ig domain of VEGFR1 fused to IgG1 Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimibe), Orencia® (abatacept, 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 (mapatumumab, 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 B C 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] Examples include, but are not limited to, romosozumab, blosozumab, or BPS804 (Novartis), and sclerostin antibodies may also be included. Further therapeutic agents that may be included are rilonacept, vixarelimab, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX, or XGEVA. Additionally, a monoclonal antibody (IgG) that binds to human protein convertase subtilisin / kexin type 9 (PCSK9) can be included in the device. Such PCSK9-specific antibodies include the following patents or patent applications, each of which is hereby incorporated by reference in its entirety for all purposes: U.S. Patent No. 8,030,547, U.S. Patent No. 8,563,698, U.S. Patent No. 8,829,165, U.S. Patent No. 8,859,741, U.S. Patent No. 8,871,913, U.S. Patent No. 8,871,914, U.S. Patent No. 8,883,983, U.S. Patent No. 8,889,834, U.S. Patent No. 8,981,064, U.S. Patent No. 9,056,915, U.S. Patent No. 8,168,762, U.S. Patent No. 9,045,547, U.S. Patent No. 8,030,457, U.S. Patent No. 8,030,457, U.S. Patent No. 8,829,165, U.S. Patent No. 8,981,064, U.S. Patent No. 8,030,Specification of Patent No. 457, US Patent Application Publication No. 2013 / 0064825, US Patent Application Publication No. 2012 / 0093818, US Patent Application Publication No. 2013 / 0079502, US Patent Application Publication No. 2014 / 0357850, US Patent Application Publication No. 2011 / 0027287, US Patent Application Publication No. 2014 / 0357851, US Patent Application Publication No. 2014 / 0357854, 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. 2013 / 0052201, US Patent Application Publication No. 2012 / 0027765, US Patent Application Publication No. 2015 / 0087819, US Patent Application Publication No. 2011 / 0117011, US Patent Application Publication No. 2015 / 0004174, Provisional Patent Application No. 60 / 957,668 of the United States, Provisional Patent Application No. 61 / 008,965 of the United States, Provisional Patent Application No. 61 / 010,630 of the United States, Provisional Patent Application No. 61 / 086,133 of the United States, Provisional Patent Application No. 61 / 125,304 of the United States, Provisional Patent Application No. 61 / 798,970 of the United States, Provisional Patent Application No. 61 / 841,039 of the United States, Provisional Patent Application No. 62 / 002,623 of the United States, Provisional Patent Application No. 62 / 024,399 of the United States, Provisional Patent Application No. 62 / 019,729 of the United States, Provisional Patent Application No. 62 / 067,637 of the United States, US Patent Application No. 14 / 777,Repatha (registered trademark) (evolocumab), Praluent (registered trademark) (alirocumab), and their molecules, variants, analogs or derivatives, such as those disclosed in U.S. Patent No. 371, International Application Publication No. PCT / US2013 / 048714, International Application Publication No. PCT / US2015 / 040211, International Application Publication No. PCT / US2015 / 056972, International Publication Pamphlet No. WO2008 / 057457, International Publication Pamphlet No. WO2008 / 057458, International Publication Pamphlet No. WO2008 / 057459, International Publication Pamphlet No. WO2008 / 063382, International Publication Pamphlet No. WO2008 / 133647, International Publication Pamphlet No. WO2009 / 100297, International Publication Pamphlet No. WO2009 / 100318, International Publication Pamphlet No. WO2011 / 037791, International Publication Pamphlet No. WO2011 / 053759, International Publication Pamphlet No. WO2011 / 053783, International Publication Pamphlet No. WO2008 / 125623, International Publication Pamphlet No. WO2011 / 072263, International Publication Pamphlet No. WO2009 / 055783, International Publication Pamphlet No. WO2012 / 0544438, International Publication Pamphlet No. WO2010 / 029513, International Publication Pamphlet No. WO2011 / 111007, International Publication Pamphlet No. WO2010 / 077854, International Publication Pamphlet No. WO2012 / 088313, International Publication Pamphlet No. WO2012 / 101251, International Publication Pamphlet No. WO2012 / 101252, International Publication Pamphlet No. WO2012 / 101253, International Publication Pamphlet No. WO2012 / 109530, International Publication Pamphlet No. WO2001 / 031007, International Publication Pamphlet No. WO2009 / 026558, International Publication Pamphlet No. WO2009 / 131740, International Publication Pamphlet No. WO2013 / 166448, and International Publication Pamphlet No. WO2014 / 150983, but are not limited thereto.,

[0101] Talimogene laherparepvec or another oncolytic HSV, including for the treatment of melanoma or other cancers, can also be included. Examples of oncolytic HSVs include Talimogene laherparepvec (U.S. Patent Nos. 7,223,593 and 7,537,924), OncoVEX GALV / CD (U.S. Patent No. 7,981,669), OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143), G207, 1716, NV1020, NV12023, NV1034, and NV1042 (Vargehes et al. (2002), Cancer Gene Ther., 9(12):967-978), but are not limited thereto.

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

[0103] Antagonistic antibodies to the human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecules targeting the CGRP receptor and other headache targets are also included. Further information regarding these molecules can be found in PCT International Publication No. 2010 / 075238 pamphlet.

[0104] In addition, bispecific T cell engager antibodies (BiTe), such as blinatumomab, can be used in the device. Alternatively, an APJ macromolecule agonist, such as apelin or an analog thereof, can be included in the device. Information regarding such molecules can be found in PCT International Publication No. WO 2014 / 099984 pamphlet.

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

[0106] Although 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 fall within the known and customary practice within the art to which the disclosure pertains, including departures from the disclosure, in accordance with the principles of the disclosure.

[0107] It should be noted that the structures and configurations of the drug delivery devices and their various components and assemblies, as shown in the various exemplary embodiments, are merely exemplary. In this disclosure, although only a few embodiments of the subject matter in question are described in detail, those skilled in the art who consider this disclosure will be able to make many modifications (e.g., variations in the size, dimensions, structure, shape and proportions of the various elements, the values of the parameters, the mounting configurations, the use of materials, the color, the orientation, etc.) without substantially departing from the novel teachings and advantages of the subject matter disclosed herein. For example, elements shown as being integrally formed can be composed of multiple parts or elements, and vice versa. Also, the positions of the elements can be reversed or otherwise changed, and the nature or number of separate elements or positions can be partially modified or varied. Accordingly, all such modifications are intended to be included within the scope of this disclosure as defined by the appended claims. Further, the order or sequence of any process or method steps can be changed or rearranged according to alternative embodiments. Without departing from the scope of this disclosure, other substitutions, modifications, variations and omissions can be made in the design, operating conditions and arrangements of the various exemplary embodiments.

Claims

1. Housing and a container disposed within the housing and having an interior volume and an end surface, an opening formed in the end surface and communicating 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 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 and at least a portion of the distal end being made of a second material, the first material being permeable to a gas sterilant; 13. A drug delivery device comprising:

2. The drug delivery device of claim 1 , wherein a proximal facing surface of the end portion of the flange sealingly engages the end 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, the second material being less permeable than the first 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 according to any one of claims 4 to 6, wherein the length of the end portion of the flange is shorter than the total length of the flange, and the width of the end portion of the flange is equal to the total width of the flange.

8. The drug delivery device of any one of claims 1 to 3, wherein a portion of the tip of the septum located distal to the flange is made of a second material, the second material being less permeable than the first 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 according to any one of claims 8 to 10, wherein the length of the end portion of the flange is shorter than the total length of the flange, and the width of the end portion of the flange is equal to the total width of the flange.

12. A drug delivery device according to any one of claims 2 to 11, 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 end 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. A drug delivery device according to any one of claims 1 to 16, comprising 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 actuation of the drug delivery device.

19. 1. A method of assembling a drug delivery device, comprising: a container having an interior volume and an end surface, an opening formed in the end surface and communicating 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, 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; providing a container assembly comprising: sterilizing the container assembly with a gaseous sterilant such that the gaseous sterilant diffuses through the first material to sterilize the end 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 a second material, the second material being less permeable than the first 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. The method of any one of claims 19 to 21, wherein the tip of the septum is made entirely of the first material.

24. 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 to the flange is made of a second material, the second material being less permeable than the first material.

25. 21. The method of claim 19 or 20, wherein the septum is made entirely of the first material.

26. 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.

27. a container having an interior volume and an end surface, an opening formed in the end surface and communicating with the interior volume; a septum including a proximal end and a distal end, the proximal end being insertable into the interior volume of the container through the opening, the distal end including a flange disposed outside the proximal end, at least an end portion of the flange being made from a first material and at least a portion of the distal end being made from a second material, the first material being permeable to a gas sterilant; 14. A container assembly comprising:

28. 30. The container assembly of claim 27, wherein the gas sterilant comprises at least one of ethylene oxide or steam.

29. 30. The container assembly of claim 27 or 28, wherein the proximal end of the septum is made of the second material, the second material being less permeable than the first material.

30. 30. The container assembly of claim 29, wherein the tip of the septum is made entirely of the second material, except for the end portion of the flange.

31. 29. The container assembly of claim 27 or 28, 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 to the flange is made of a second material, the second material being less permeable than the first material.

32. 32. The container assembly of any one of claims 27 to 31, comprising a stopper slidably disposed within the interior volume of the container, and a drug disposed between the stopper and the septum.

33. 33. A container assembly according to any one of claims 27 to 32, comprising a fluoropolymer film completely covering the septum except for a proximal facing surface of the end portion of the flange and an outer peripheral surface of the end portion of the flange.

34. 34. The container assembly of claim 27, 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 end surface of the container, the fastener being permeable to the gas sterilant.

35. a container having an interior volume and an end surface, an opening formed in the end surface and communicating with the interior volume; a septum including a proximal end and a distal end, the proximal end being insertable into the interior volume of the container through the opening, the distal end including a flange disposed outside the proximal end; an annular sealing member disposed between the flange and the end surface of the container, the annular sealing member being made of a first material, the first material being permeable to a gas sterilant; 14. A container assembly comprising:

36. 36. The container assembly of claim 35, wherein the gas sterilant comprises at least one of ethylene oxide or steam.

37. 37. The container assembly of claim 35 or 36, wherein at least a portion of the septum is made of a second material, the second material being less permeable than the first material.

38. 38. The container assembly of claim 35, further comprising a fastener that engages a distal facing surface of the septum and an exterior surface of the container to secure the annular sealing member between the flange and the end surface of the container, the fastener being permeable to the gas sterilant.

39. 40. The container assembly of claim 38, wherein the fastener has at least one opening configured to allow the gas sterilant to pass through the fastener.

40. 1. A septum for a medication container, comprising: A longitudinal axis; a proximal end portion insertable into the medication container; a distal portion including a flange disposed radially outward of the proximal portion, the flange including an outer peripheral surface and a proximal facing surface; and At least an end portion of the flange is made of a first material and at least a portion of the tip is made of a second material, the first material being 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.

41. 41. The septum of claim 40, wherein the gas sterilant comprises at least one of ethylene oxide or steam.

42. 42. The septum of claim 40 or 41, wherein the proximal end of the septum is made of the second material, the second material being less permeable than the first material.

43. 43. The septum of claim 42, wherein the tip of the septum is made entirely of the second material, except for the end portion of the flange.

44. 42. The septum of claim 40 or 41, wherein the proximal end of the septum is made of the first material and a portion of the distal end of the septum disposed distal to the flange is made of a second material, the second material being less permeable than the first material.

45. 42. The septum of claim 40 or 41, made entirely of the first material.

46. 46. ​​The septum of claims 40 or 45, including a fluoropolymer film completely covering the septum except for the proximal facing surface of the flange and a portion of the exterior peripheral surface of the end portion of the flange.

47. Housing and a container disposed within the housing and having an interior volume and an end surface, an opening formed in the end surface and communicating 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, the flange being disposed outside the proximal end and contacting the end surface of the container, the entire septum being made of a material that is permeable to a gas sterilant; 13. A drug delivery device comprising:

48. 48. The drug delivery device of claim 47, wherein the proximal facing surface of the flange sealingly engages the end surface of the container to prevent ingress of contaminants.

49. 49. The drug delivery device of claim 47 or 48, wherein the gas sterilant comprises at least one of ethylene oxide or steam.

50. 50. A drug delivery device according to any one of claims 47 to 49, comprising a fluoropolymer film completely covering the septum except for the proximal facing surface of the flange and a portion of the outer peripheral surface of the flange (47).

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