Container and system for use during external sterilization of drug delivery devices

Abstract

A container and system for use during an external sterilization process of multiple drug delivery devices are provided. The container may include an outer housing and at least one divider at least partially surrounded by the outer housing. The at least one divider may include a plurality of first dividers and a plurality of second dividers. The at least one divider may also be arranged in an open configuration, in which the plurality of first dividers and the plurality of second dividers cooperate with each other to define a plurality of chambers configured to receive at least one of the multiple drug delivery devices. The at least one divider may also be arranged in a closed configuration, in which the plurality of chambers are substantially completely collapsed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 62 / 980,898, filed February 24, 2020. This priority application is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to drug delivery devices. More particularly, the present disclosure relates generally to containers and systems for use during external sterilization of drug delivery devices. [Background technology]

[0003] As is well known in the art, a syringe is a medical delivery device used to administer medication to a patient. Syringes are often commercially available either in a pre-filled form, in which a set dose or amount of medication can be provided, or in an empty form, which is intended to be filled by the end user from a vial or other medication source when medication administration is desired. In either case, the syringe often includes a barrel portion adapted to hold the medication, a conventional piercing element such as a needle, a plunger rod, an elastomeric or rubber-like stopper element that fits substantially fluid-tight inside the barrel, and a flange around the open proximal end of the syringe barrel as a form of finger rest to facilitate user manipulation of the device.

[0004] For both the integrity of the drug and patient safety, it may be desirable to thoroughly sterilize the components of the syringe. Sterilization can occur at several stages of the assembly process, including pre-filling (e.g., sterilization of the empty barrel and / or plunger) and post-filling (e.g., external sterilization of the assembled pre-filled syringe). External sterilization typically occurs after the pre-filled syringe has been filled, fully assembled, and placed in at least some parts of its final package (e.g., a blister pack). Federal regulations may require external sterilization under specific conditions, parameters, and / or results for some indications of use, such as certain ophthalmic indications.

[0005] External sterilization can present design challenges. For example, the drug may be sensitive to sterilization and / or the conditions of sterilization, such as temperature, gas, and / or radiation. As a more specific example, it may be desirable, advantageous, or necessary for external sterilization to be performed under relatively time-consuming conditions, such as performing one or more of the sterilization steps for a longer period of time than would be possible while operating at a high temperature and / or high volume appropriate for the unfilled container. Therefore, it may be advantageous or desirable to sterilize multiple devices at once to reduce processing time and / or improve efficiency. As another example, surface interactions between devices, between devices and their packaging, and / or between various packages (e.g., between blister packs) may create or promote occlusions that may not be effectively and / or completely sterilized during the external sterilization step performed on syringes. Therefore, it is desirable to maintain the integrity of the drug while achieving an appropriate level of sterilization of all associated devices, packaging, and their respective parts.

[0006] The present disclosure describes methods that embody advantageous alternatives to existing external sterilization methods and that may address one or more of the problems or needs described herein, as well as provide other benefits and advantages. Summary of the Invention [Means for solving the problem]

[0007] A container and system for use during an external sterilization process of multiple drug delivery devices are provided. The container may include an outer housing and at least one divider at least partially surrounded by the outer housing. The at least one divider may include a plurality of first dividers and a plurality of second dividers. The at least one divider may be disposable in an open configuration and a closed configuration. In the open configuration, the plurality of first dividers and the plurality of second dividers cooperate to define a plurality of chambers configured to receive at least one of the multiple drug delivery devices. In the closed configuration, the plurality of chambers are substantially fully collapsed.

[0008] In some examples, in the open configuration, the first divider and the second divider can be disposed substantially perpendicular to one another. In some examples, when the at least one divider is disposed in the open configuration, the at least one divider has length and width dimensions that are substantially equal to the length and width dimensions of the outer housing.

[0009] In some forms, when the divider is disposed in the closed configuration, the divider can have length and / or width dimensions that are less than ½ of the corresponding length and / or width dimensions of the outer housing. In some examples, when the divider is disposed in the closed configuration, the divider can have length and / or width dimensions that are less than ¼ of the corresponding length and / or width dimensions of the outer housing. In yet other examples, when the divider is disposed in the closed configuration, the divider can have length and / or width dimensions that are less than ⅛ of the corresponding length and / or width dimensions of the outer housing.

[0010] In some examples, each of the plurality of drug delivery devices includes a pre-filled syringe in a blister pack. In some examples, each of the plurality of chambers can define a chamber volume. When at least one partition is arranged in an open configuration, the chamber volume can be a non-zero value, and when at least one partition is arranged in a closed configuration, the chamber volume can be 0.

[0011] According to a second aspect, there is provided a container for use during an external sterilization process of a plurality of drug delivery devices. The container may include an outer housing and at least one divider at least partially surrounded by the outer housing. The at least one divider may define a plurality of chambers, each configured to receive at least two of the plurality of drug delivery devices in a front-to-back configuration. The container may be configured to receive at least 180 drug delivery devices, at least 360 drug delivery devices, at least 540 drug delivery devices, or at least 720 drug delivery devices.

[0012] The present disclosure will be more fully 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 drawings does not necessarily indicate the presence or absence of the particular element in any of the illustrative embodiments, unless expressly described in the corresponding specification. Additionally, none of the drawings are necessarily drawn to scale. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is an isometric view of an exemplary container for use during an external sterilization process for multiple drug delivery devices, embodying aspects of the present disclosure, the container including five drug delivery devices disposed within a chamber of the container. [Figure 2]2 is an isometric view of an exemplary divider suitable for use in a container such as the exemplary container shown in FIG. 1 , embodying aspects of the present disclosure, the divider positioned in an open configuration. [Figure 3] 3 is an isometric view of the exemplary divider shown in FIG. 2, the divider being positioned in a partially closed configuration. [Figure 4A] FIG. 4 is a top view of the exemplary divider shown in FIGS. 2 and 3, the divider being positioned in a closed configuration. [Figure 4B] FIG. 4B is a side view of the exemplary divider shown in FIG. 4A. [Figure 5] 1 is an isometric view of an exemplary container for use during an external sterilization process of multiple drug delivery devices, the container including a top cover, embodying aspects of the present disclosure. [Figure 6] FIG. 1 is a top view of an exemplary drug delivery device, more specifically a pre-filled syringe, suitable for use with an exemplary container, embodying aspects of the present disclosure. [Figure 7] FIG. 1 is a top view of an exemplary drug delivery device disposed within a package suitable for use with an exemplary container, more specifically, a pre-filled syringe disposed within a blister pack, embodying aspects of the present disclosure. [Figure 8] 1 is an exemplary method or sequence of steps for assembling and externally sterilizing a drug delivery device embodying aspects of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0014] The present disclosure generally relates to an injection device that can be safely and reliably utilized by a user to administer a drug or for self-administration of a drug by a patient. More specifically, the present disclosure generally relates to a container for use during an external sterilization process for multiple drug delivery devices. As an example, the container can support or hold multiple drug delivery devices during at least some steps of the external sterilization process, i.e., (1) hold or support the drug delivery devices when they are transported to a sterilization chamber, (2) hold or support the drug delivery devices when they are in the sterilization chamber during the sterilization process, (3) hold or support the drug delivery devices when they are removed from the sterilization chamber after the sterilization process, and / or (4) hold or support the drug delivery devices during any other steps in which the drug delivery devices are transported or supported. The injection device may be in the form of a syringe, such as a pre-filled syringe, and / or in the form of a pre-filled syringe disposed in a primary package, such as a blister pack. Utilizing the vessels and systems described herein and variations thereof may enable the utilization of desired bioburden kill levels while minimizing or avoiding process inefficiencies and / or undesirable effects on chemicals.

[0015] As used herein, the term "about" means + / - 10% of the least significant figure.

[0016] Referring to the drawings, FIG. 1 shows a container 10 for use during an external sterilization process of multiple drug delivery devices 60. The container comprises an outer housing 20 and at least one divider 30 at least partially surrounded by or disposed within the outer housing 20. The outer housing 20 shown in FIG. 1 is generally rectangular prism-shaped (also known as a rectangular prism or cuboid) having four side walls 21, 22, 23, and 24, a bottom wall (not labeled in FIG. 1 ), and a top wall (not shown in FIG. 1 for illustrative purposes) that cooperate to define an interior volume. The outer housing 20 shown in FIG. 1 includes an opening 25 for allowing and / or facilitating the entry of sterilization gas into the interior volume of the outer housing 20. The opening 25 may also be positioned and sized to function as a handle for the container 10, or the like. 1 are each large enough to accommodate a human hand and are generally spaced apart and positioned opposite one another (e.g., on first and third side walls 21 and 23, or on second and fourth side walls 22 and 24) to serve as balancing carrying points. Outer housing 20 may be made from any suitable material, such as polypropylene, polycarbonate, polyethylene, acrylonitrile butadiene styrene (ABS), polytetrafluoroethylene (PTFE) / Teflon, other fluoropolymers, other thermoplastic polymers, or another material or combination of materials that is relatively lightweight yet provides sufficient structural support while being compatible with the sterilization gas and medical products utilized. As a more specific example, outer housing 20 may be made from HDPE (high density polyethylene) and / or may include a corrugated design to enhance the strength and / or durability of the component.

[0017] Although only two openings 25 are shown in FIG. 1 , the outer housing 20 may have many more openings of similar or different sizes and shapes located along various portions of the outer housing 20, including, but not limited to, the sidewalls 21, 22, 23, 24, the bottom wall, and / or the top wall. For example, the outer housing 20 may include about 4-60 openings, about 8-50 openings, about 12-40 openings, about 16-36 openings, about 20-30 openings, and / or about 24-28 openings. The openings may be spaced apart from one another at approximately equal intervals or may be concentrated in certain portions of the outer housing 20, such as having more openings on the sides than on the top and bottom. The openings 25 may be spaced apart and sized to facilitate distribution of sterilizing gas while also providing a desired amount of structural stability to the container and / or drug delivery device 60 disposed therein. Opening 25 may have any suitable size, such as about 2 inches long and about ½ inch wide. As another example, opening 25 may be larger, such as about 2 inches long and about 2 inches wide and generally circular in shape. As yet another example, opening 25 may have a length of about 2.5 inches and a width of about 2.5 inches. As another example, opening 25 may have a length of about 3 inches and a width of about 3 inches.

[0018] The outer housing 20 may also include features that allow for nesting of additional outer housings when not in use, such as a tapered configuration, a collapsible design, or other features that minimize space when not in use. Additionally or alternatively, the outer housing 20 may be chemically resistant to alkalis, oils, acids, and / or cleaning agents.

[0019] The container 10 includes at least one divider 30 at least partially enclosed by the outer housing 20. For example, the divider 30 shown in FIG. 1 is enclosed within an interior volume defined by the outer housing 20. As a more specific example, the divider 30 shown in FIG. 1 has length and width dimensions that are slightly smaller than the corresponding length and width dimensions of the interior of the outer housing. As an even more specific example, the outer housing 20 shown in FIG. 1 has a length 20a of approximately 25.1 inches and a width 20b of approximately 19.6 inches. The divider 30 shown in FIG. 1 has a length 30a of approximately 25 inches and a width 30b of approximately 19.5 inches. The outer housing 20 and divider 30 may have any other suitable length and width, so long as the divider 39 can fit within the outer housing 20. The outer housing 20 may have dimensions that correspond to the size of a sterilization chamber so that the container 10 can fit within the chamber without wasted space.

[0020] 1 includes a middle divider 30 including a plurality of first dividers 32, each extending generally in a first direction, and a plurality of second dividers 34, each extending generally in a second direction substantially perpendicular to the first direction. As a more specific example, the first dividers 32 extend generally parallel to the side walls 22, 24, and the second dividers 34 extend generally parallel to the side walls 21, 23, although the dividers 32, 34 may extend at other suitable angles relative to the outer housing 20. The middle divider 30 shown in FIG. 1 includes a plurality of five first dividers 32 and a plurality of ten second dividers, although any other suitable number of dividers may be utilized. For example, the middle partition 30 may include a plurality of 1 to 20 first partition plates 32 and 1 to 30 second partition plates 34, a plurality of 2 to 10 first partition plates 32 and 2 to 20 second partition plates 34, a plurality of 3 to 8 first partition plates 32 and 4 to 16 second partition plates 34, a plurality of 4 to 6 first partition plates 32 and 6 to 12 second partition plates 34, or any other suitable number of partition plates.

[0021] The first and second dividers 32, 34 cooperate with one another to define chambers 35 configured to receive the drug delivery device 60. For example, the first and second dividers 32, 34 of the middle divider 30 define 36 chambers, although any other suitable number of chambers 35 may be utilized. For example, the middle divider 30 may define approximately 10-60 chambers 35, approximately 24-48 chambers 35, approximately 30-42 chambers 35, or any other suitable number of chambers 35.

[0022] In the container 10 shown in FIG. 1, each chamber 35 is configured to receive approximately five drug delivery devices 60. As a more specific example, each of the drug delivery devices 60 shown in FIG. 1 includes a prefilled syringe 50 within a blister pack 61 (FIGS. 6-7). As an example, the prefilled syringe 50 includes a barrel 51, a plunger rod 52, a stopper 53, a luer lock cap 54, and a detent 55. As an example, the blister pack 61 generally includes a tray 62 and a cover 68. As a more specific example, the blister pack 61 may include two pairs of flanges 63, 64, such as snap-fit ​​flanges, for supporting and / or holding the prefilled syringe barrel 51, and chambers 65, 66, 67 for allowing a user to grip the prefilled syringe 50 and / or for providing room for components such as the detent 55. Alternatively or additionally, the pre-filled syringe 50 may be squeezed or pushed out of the tray through the underside of the tray.

[0023] The blister pack tray 62 may be coupled with a cover 68. As a more specific example, the blister pack tray 62 may be sealed with the cover 68 after the prefilled syringe 50 is filled and assembled. The blister pack tray 62 may be made of any suitable material, such as polyethylene terephthalate glycol copolymer (PETG), and the cover 68 may be made of any suitable material, such as Tyvek or any suitable medical paper. The cover 68 shown in FIG. 7 is gas permeable to allow sterilization gas to enter (and exit) the internal chamber defined by the blister pack tray 62 and the cover 68 during the external sterilization process. As a more specific example, the cover 68 includes micropores such that the cover 68 can be gas permeable to facilitate external sterilization of the prefilled syringe 50 while it remains within the blister pack 60. As an even more specific example, the blister pack tray 62 need not be gas permeable so that the sterilization gas passes through the cover 68 but not through the blister pack tray 62.

[0024] As described above, the drug delivery device 60 shown in FIG. 1 includes a prefilled syringe 50 disposed within a blister pack 61 (e.g., a tray 62 sealed with a cover 68) such that the drug delivery device 60 is prepared for a step of external sterilization. The drug delivery devices 60 are positioned relative to one another (e.g., a front-to-back configuration) such that the cover 68 of one device 60 abuts and / or is adjacent to the blister pack tray 62 of an adjacent device. This configuration helps facilitate the passage of sterilizing gas into and out of the internal chamber defined by the blister pack tray 62 and cover 68. As a more specific example, when adjacent devices are positioned such that their respective covers 68 abut one another, the respective covers may block or prevent sterilizing gas from entering the internal chamber defined by the blister pack tray 62 and cover 68.

[0025] Each of the dividers 32, 34 shown in Figure 1 includes a plurality of openings 36 to help facilitate distribution of sterilizing gas into the container 10. For example, each of the first plurality of dividers 32 shown in Figure 1 includes nine openings 36, and each of the second plurality of dividers 34 shown in Figure 1 includes four openings 36. However, the dividers 32, 34 may include any other suitable number of openings 36. For example, each of the plurality of first partition plates 32 may include about 1-20 openings 36, each of the plurality of second partition plates 34 may include about 1-10 openings 36, each of the plurality of first partition plates 32 may include about 2-16 openings 36, each of the plurality of second partition plates 34 may include about 1-8 openings 36, each of the plurality of first partition plates 32 may include about 4-12 openings 36, each of the plurality of second partition plates 34 may include about 2-6 openings 36, each of the plurality of first partition plates 32 may include about 6-10 openings 36, and each of the plurality of second partition plates 34 may include about 3-5 openings 36. The openings 36 may be spaced and sized to facilitate distribution of sterilizing gas while also providing a desired amount of structural stability to the container and / or drug delivery device 60 disposed therein, for example. For example, opening 36 may have a length of about 2 inches and a width of about ½ inch. As another example, opening 36 may be larger, such as about 2 inches long and about 2 inches wide and generally circular in shape. As yet another example, opening 36 may have a length of about 2.5 inches and a width of about 2.5 inches. As another example, opening 36 may have a length of about 3 inches and a width of about 3 inches.

[0026] 1 , the divider 30 and the outer housing 20 cooperate to define a series of peripheral chambers 38 around the periphery of the inner wall of the outer housing 20. More specifically, each of the peripheral chambers 38 is smaller than the chamber 35 for holding the drug delivery device 60, and instead of containing or holding the drug delivery device 60, the peripheral chambers 38 act as spacers between the outer housing 20 and the chambers 38 to prevent gas blockage and act as a protective barrier to prevent and protect the blister pack 61. More specifically, the peripheral chambers 38 form a buffer space between the inner wall of the outer housing 20 and the outermost dividers 32, 34 parallel to the inner wall of the outer housing 20, thereby reducing or minimizing the amount of gas trapped therebetween.

[0027] The container 10 may include multiple dividers 30. For example, the container 10 shown in FIG. 1 includes four dividers stacked vertically and separated by depth dividers 40. As a more specific example, the topmost divider 30c and the second-highest divider 30d are visible in FIG. 1 and are separated by the depth dividers 40. The dividers 30c, 30d, 30e, and 30f (FIG. 5) are similar or identical to each other, and the different dividers 40a, 40b, and 40c (FIG. 5) are similar or identical to each other, such that each divider 30c-30f can support and hold the same number of drug delivery devices 60. As a more specific example, the divider 30c shown in FIG. 1 includes 36 chambers 35, each capable of supporting and holding five drug delivery devices 60, allowing the divider 30c to support and hold a maximum of 180 drug delivery devices 60. Therefore, each of the subsequent partitions 30d to 30f can also support and hold up to 180 drug delivery devices 60 each, for a total of 720 drug delivery devices 60 (eg, 180×4=720).

[0028] Each depth divider 40 includes a plurality of openings 42 that allow and facilitate distribution of sterilizing gas among the various middle dividers 30c-30f. As a more specific example, each of the openings 42 shown in FIG. 1 extends substantially (but not completely) along the width of the depth divider 40, such that each chamber 35 includes a corresponding portion of an opening 42 to allow and facilitate communication with the chamber above and / or below. As an alternative or additional example, the openings may extend along the length (e.g., along lines 30a and 20a) rather than along the width (e.g., along lines 30b and 20b). As a further alternative or additional example, each opening may be an individual opening rather than extending along the length or width of the plurality of chambers 35.

[0029] Each depth divider 40 may be sized and shaped similarly to or slightly smaller than the middle dividers 30 to enable or facilitate gas distribution between the different peripheral chambers 38. The depth dividers 40 may be made of the same or similar materials as the plurality of first dividers 32 and / or the plurality of second dividers 34 and / or the outer housing 20.

[0030] Each divider 30 may be positionable between an open configuration 70a (FIGS. 1-2) and a closed configuration 70c (FIGS. 4A and 4B), and potentially an intermediate configuration 70b (FIG. 3). For example, the divider 30 may be positioned in the open configuration 70a when the divider 30 is being placed in the container 10 or when the container 10 is about to be loaded. As another example, the divider 30 may be positioned in the closed configuration 70c when the divider 30 is not in use or is in storage / non-use.

[0031] When the divider 30 is disposed in the open configuration 70a, the chamber 35 is configured to receive an intended number of drug delivery devices 60, such as the five shown in FIG. 1. As another example, when the divider 30 is disposed in the open configuration 70a, the chamber 35 may have its maximum volume or another volume substantially equal to the maximum volume. In other words, when the divider 30 is disposed in the open configuration 70a, the chamber 35 may be in a fully open or fully deployed state.

[0032] When the divider 30 is disposed in the closed configuration 70c, the chamber 35 is configured so as not to receive the drug delivery device 60. The chamber 35 may also be at or near a minimum volume, i.e., have no volume. In other words, when the divider 30 is disposed in the closed configuration 70c, the chamber 35 may be fully closed or minimized. As shown in FIG. 4A , when the divider 30 is disposed in the closed configuration 70c, the closed length 30g and / or closed width 30h of the divider 30 may be significantly different from these dimensions of the divider 30 in the open configuration 70a. For example, the closed length 30g of the divider 30 when disposed in the closed configuration 70c is longer than the length 30a of the divider 30 when disposed in the open configuration due to the fact that the various divider plates 32 are offset from one another in a stepped manner. As another example, the closed width 30h of the divider 30 when disposed in the closed configuration 70c is less than the width 30b of the divider 30 when disposed in the open configuration 70a because the divider plates 34 are compressed together.

[0033] The dividers 32, 34 may include mating notches 32a, 34a ( FIG. 3 ) that facilitate movement between the respective dividers 32, 34. As a more specific example, the top of the divider 34 may include a notch extending from the top to the middle along the height of the divider 34, and the bottom of the divider 32 may include a notch extending from the bottom to the middle along the height of the divider 32, or vice versa. Alternative designs of the interface between the dividers 32, 34 may be utilized. The notches 32a, 34a may have a thickness that facilitates easy and rapid movement between the various configurations 70a, 70b, 70c, such that the divider 30 has a “quick collapse” design. For example, as shown by arrow 80 in FIG. 3 , the divider 30 may be collapsed by applying force to one or more corners of the divider 30.

[0034] The closed configuration 70c of the divider 30 may be suitable for facilitating quick assembly of the container 10 while reducing footprint / space requirements for shipping or storage.

[0035] Referring to FIG. 8, an exemplary method for assembling and externally sterilizing a drug delivery device according to one embodiment of the present disclosure will be described. During the first step (Box 2), at least some individual components of the drug delivery device are often sterilized before being received by a manufacturing facility. For example, the syringe barrel and plunger stopper and any other components that may come into direct contact with the drug product may be sterilized during this step. This step can use various known techniques for sterilizing various unassembled components of a drug delivery device, including, but not limited to, the components shown in FIGS. 6 and 7. During the second step (Box 3), the barrel is filled and the stopper (also known as the "plunger stopper") is assembled with the barrel. The assembly step may also include adding at least some of the following: a plunger rod, a flange extender, a tip cap with a luer lock, a needle, a rigid needle shield, and / or a detent, such as those shown in FIGS. 2-6. While at least some of these components may be pre-assembled with each other, they may also be assembled at the filling line, for example, if the filling process is performed aseptically. Also, the syringe typically has either a tip cap, luer lock tip, or an attached (e.g., fixed) needle, rather than having both components. The syringe may also receive any necessary or indicative material at this stage. It then proceeds to an external sterilization stage (indicated by dotted box 1). It may be appropriate and / or desirable to utilize container 10 during some or all of the steps indicated by dotted box 1, or during additional steps described herein.

[0036] In Box 4, the syringe is pre-treated. For processes using nitrogen dioxide (NO), pre-treatment may include at least some or all of the following steps: removing the sample from storage, allowing the syringe to equilibrate at room conditions for a desired amount of time (e.g., 30 minutes, 90 minutes, 2 hours, or any desired amount of time), and placing the syringe in a sterilization chamber. Pre-treatment can occur inside or outside the chamber.

[0037] When using ethylene oxide (EtO), the pretreatment step (Box 4) may differ slightly from that described for NO. For example, syringes may be pretreated inside the sterilization chamber (without gas injection) for 360 minutes (or another desired length of time). However, as with the NO process, the pretreatment step with EtO may be performed inside or outside the chamber.

[0038] Next, for box 5, the sterilization chamber remains closed (if pre-treatment is performed inside the chamber), or the container 10 is placed inside the chamber and the chamber is closed. All or substantially all of the air is then evacuated from the chamber. The air evacuation step can be performed in multiple pulses / steps, as this can help control the initial humidity level in the chamber. Then, in box 6, the sterilization chamber is humidified to a desired setting, such as 75 or 80 (or any desired amount of relative humidity percentage). In some steps, boxes 6 and 7 can be swapped to inject sterilization gas before increasing the humidity.

[0039] Next, in Box 7, the desired sterilization gas is injected into the chamber and held for the desired dwell time. For recipes using NO2, gas injection step 7 may include some or all of the following steps: drawing a vacuum in the chamber for a desired amount of time, then injecting a desired amount (dose concentration) of gas and adjusting humidity to increase chamber pressure to deliver a dose of NO2; holding this condition for a desired amount of time (i.e., dwell time) to allow the sterilant to contact the surface; and then repeating these steps for a desired number of pulses. After the desired number of pulses is completed, the gas is finally purged (Box 8), and the gas is removed from the sterilization chamber. Finally, in Box 9, the chamber is vented (also known as a "vent exchange") for a desired number of cycles to ensure all or substantially all of the sterilization gas is flushed from the syringe and package. The steps of Box 8 and Box 9 may be combined into a single step, such that the sterilization gas is purged via the vent exchange. In some instances, the vacuum level may be changed during these steps. For example, the vacuum during the residence time may be minimal, such as about 590 Torr.

[0040] The method may include any suitable parameters for steps 7-9, such as: The vacuum level can be about 20-500 Torr, about 150-400 Torr, about 150-300 Torr, or another suitable vacuum level. The NO2 dose concentration can be about 2-20 milligrams per liter, about 2-10 milligrams per liter, about 2-7 milligrams per liter, or another suitable dose concentration. The chamber may have a relative humidity of about 70 to 90 percent, or another suitable humidity. The residence time may be about 2 to 20 minutes, about 2 to 12 minutes, about 2 to 7 minutes, or another suitable residence time. The number of pulses can be about 1 to 24, about 1 to 12, about 1 to 8, about 1 to 4, about 1 to 2, or another suitable number of pulses. The step of venting the sterilization chamber may include venting the sterilization chamber for about 12 to 70 cycles, or another suitable number of cycles.

[0041] As a more specific example, Table 1 shows the different variables of ten different exemplary recipes for sterilizing drug delivery devices using nitrogen dioxide (NO2).

[0042] [Table 1]

[0043] As another example, Table 2 shows different variables for six different exemplary recipes for sterilizing drug delivery devices using NO2.

[0044] [Table 2]

[0045] In Tables 1 and 2, the labels in the "Vacuum Level (Torr)" column refer to the vacuum force applied to the external sterilization chamber during step 4 of Figure 8. As shown, the vacuum force varies from 20 Torr to 500 Torr, although different vacuum forces may be appropriate. The listed vacuum force numbers are the inverse of their strength, with 20 Torr being stronger than 100 Torr, which is stronger than 500 Torr (atmospheric pressure is typically about 760 Torr). The stronger the vacuum force, the more likely it is to demonstrate kill of the desired bioburden. However, if the vacuum force becomes too high, the process may have undesirable effects on the drug, such as undesirably displacing the plunger (i.e., displacing it across the sterile barrier, causing a breach of sterility). The "NO2 Dose (mg / L)" column refers to the NO2 concentration (mg) per liter of air introduced into the external sterilization chamber during step 7 of Figure 8. As shown, the doses in Tables 1 and 2 vary from 5 to 20 mg / L, although different doses may be appropriate. The higher the NO2 dose during this step, the more rapidly and completely the drug delivery device will be sterilized. However, if the sterilization gas dose is too high, the process may have undesirable effects on the drug, such as contaminating the interior of the drug barrel with sterilization gas (i.e., sterilization gas infiltration and / or discoloration of syringe components). The "Relative Humidity (%RH)" column refers to the relative humidity within the external sterilization chamber during step 7 in Figure 8. As shown, the relative humidity in each column in Tables 1 and 2 varies from 75% to 80%, although different relative humidity values ​​may be appropriate. Increasing the relative humidity also increases the likelihood of demonstrating kill of the desired bioburden. The "Dwell Time (min:sec)" column refers to the amount of time the drug delivery device is in the sterilization chamber while sterilization gas is present. For Tables 1 and 2, the "Total Dwell Time" is equal to the "Dwell Time" column multiplied by the "Number of Pulses" column. For example, for the first row in Table 1, the sample will have a total residence time of 80 minutes. As indicated, the residence times listed in Tables 1 and 2 vary from 5 to 20 minutes, although different residence times may be appropriate. Residence time also increases the likelihood of demonstrating kill of the desired bioburden.However, if the residence time becomes too long, the process may have undesirable effects on the drug, such as contaminating the interior of the drug barrel with sterilizing gas and / or undesirably affecting the function or appearance of device components. As an example, components may experience undesirable levels of discoloration if the residence time becomes too long. The "Number of Pulses" column refers to the number of times gas is injected by pulling a vacuum during the NO process. As shown, the pulses in each row of Tables 1 and 2 vary from 1 to 24, although different values ​​may be appropriate. A higher number of pulses is more likely to demonstrate kill of the desired bioburden. However, if the number of pulses becomes too high, the process may have undesirable effects on the drug, such as contaminating the interior of the drug barrel with sterilizing gas and / or undesirably affecting the function or appearance of device components. The "Number of Vents" column refers to the number of times the chamber is vented (Box 9 in Figure 8) after gas is purged from the chamber (Box 8 in Figure 8). Exemplary processes may use 12, 24, 28, 70, or any desired number of vent exchanges. Up to a point, by increasing the number of vents, a manufacturer can increase the likelihood that all or substantially all of the sterilizing gas will be removed from the syringe and package (post-purging).

[0046] For each recipe (NO2) in Tables 1 and 2, the steps enclosed in Box 1 of Figure 8 may be performed at room temperature (25 degrees Celsius), although other suitable temperatures may be used. However, other temperatures may be used, such as from about 2 degrees Celsius to about 8 degrees Celsius, or any other desired temperature that does not have an undesirable effect on the drug.

[0047] Table 3 shows the different variables of ten different exemplary recipes for sterilizing drug delivery devices with NO2.

[0048] [Table 3]

[0049] When using ethylene oxide (EtO), the gas injection step (Box 7) may be slightly different. For example, gas injection step 7 may include some or all of the following steps: delivering a dose of EtO by drawing a vacuum in the chamber for a desired amount of time (i.e., dwell time), either before or while injecting the desired amount (dose concentration) of gas, and then purging the gas. In other words, when using EtO, it may be desirable to perform only a single pulse rather than the preferred multiple pulses described above for NO. For steps 8 (gas purging) and 9 (venting), an exemplary process using EtO proceeds as described above for NO.

[0050] External sterilization of injection devices during the manufacturing and / or assembly process may be desirable and / or required by regulation. Furthermore, some uses of prefilled syringes (e.g., certain ophthalmic applications) require external sterilization. For example, 21 CFR 200.50 indicates that "ophthalmic preparations and dispensers should be sterile." Furthermore, ANSI / AAMI ST67:2011 / (R)2017, "Sterilization of Health Care Products—Requirements and Guidance for Selecting a Sterility Assurance Level (SAL) for Products Labeled 'Sterile,'" states in section 4.1.1 that "SAL values ​​of 10-6 are generally used for terminal sterilization of health care products." Furthermore, Appendix A of ST67 and EN556-1:2006 states: "Sterilization of medical devices - Requirements for medical devices to be designated "sterile" - Part 1: Requirements for terminally sterilized medical devices"...Section 4.1: "For a terminally sterilized medical device to be designated "sterile," the theoretical probability of viable microorganisms being present on / in the device must be greater than 1 x 10 -6 Therefore, the microbial contamination should be 1 x 10 -6 (i.e., 1 x 10^-6). Additionally or alternatively, the bioburden may be less than 1 x 10 -4 In some cases, it may be desirable to be below another level, such as 1x10^-4.

[0051] Thus, the embodiments disclosed herein are particularly advantageous in these types of applications. As used herein, the terms "external sterilization" and / or "externally sterilizing" refer to a sterilization process for an injection device after it has been assembled. For example, the injection device shown in FIGS. 2a-2c can be externally sterilized after the syringe 10 (with the drug in cavity 13), plunger rod 16, detent device 20, and protective cap (not shown) are all assembled, labeled, and placed in a blister pack. During the external sterilization process, the injection device is typically placed in a sterilization chamber and exposed to a sterilizing gas, such as ethylene oxide (EtO), nitrogen dioxide (NO), or any other suitable gas, for a predetermined length of time and under other specified conditions (e.g., temperature, humidity, and pressure). After the sterilization cycle, the sterilizing gas is purged from the chamber, and the injection device remains in the chamber (substantially or completely free of the sterilizing gas) for another predetermined length of time and under other specified conditions (e.g., temperature and pressure).

[0052] Due to the engagement between the detent device 20 and the syringe 10 shown in FIGS. 2a-2c, sterilization gas may not be able to reach the enclosed or partially enclosed spaces between the detent device 20 and the syringe 10, thereby failing to fully or adequately sterilize these surfaces. Additionally or alternatively, sterilization gas may not be effectively purged from these enclosed or partially enclosed spaces, thereby exposing the medication to sterilization gas beyond the designated sterilization step in the chamber. Either and / or both of these situations may be undesirable. As a more specific example, FIG. 2d includes various views of a syringe barrel and flange, with surfaces particularly susceptible to clogging indicated by dark shading. For example, the flange top surface 12b and the barrel exterior surface 11b may be particularly susceptible to clogging due to their respective engagement with the detent device 20.

[0053] 3a and 3b illustrate a detent 120 according to an embodiment of the present disclosure. The detent 120 includes a collar portion 130 extending annularly and distally relative to the syringe flange 12. The detent device 120 also includes a body portion 132 defining an opening 134 and engaging the upper surface of the flange 12. The detent 120 also includes a plurality of ridges 150 that engage the syringe 10 such that the inner collar surface 130a is spaced apart from the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. In FIGS. 3a and 3b, three ridges 150 are spaced apart from one another around the inner collar surface 130a, more preferably spaced apart at approximately equal intervals from one another to form a three-point engagement between the detent device 120 and the syringe 10. The ridges 150 may be integrally formed with the inner collar surface 130a of the detent device 120, or the ridges 150 may be separate components attached to the inner collar surface 130a. In either case, the ridges 150 cooperate to facilitate a relatively secure fit between the detent device 120 and the syringe 10 while minimizing obstruction space between the inner collar surface 130a and the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. For example, in one embodiment, the ridges 150 are the only portion of the inner collar surface 130a that engages the outer surface 12a of the flange 12. For example, in another embodiment, the ridges 150 are the only portion of the inner collar surface 130a that engages the outer surface of the syringe barrel 11.

[0054] 3a-3b may alternatively have any suitable configuration that spaces the collar inner surface 130a from the syringe 10. For example, in one embodiment, the ridge 150 may be replaced with a generally circular protrusion or line of protrusions.

[0055] 4a and 4b illustrate a detent 220 according to another embodiment of the present disclosure. The detent 220 includes a collar portion 230 extending annularly and distally relative to the syringe flange 12. The detent device 220 also includes a body portion 232 defining an opening 234 and engaging the upper surface of the flange 12. The detent 220 also includes a plurality of ridges 250 for engaging the syringe such that the inner collar surface 230a is spaced apart from the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. In FIGS. 4a and 4b, five ridges 250 are spaced apart from one another around the inner collar surface 230a, more preferably spaced apart at approximately equal intervals from one another to form a five-point engagement between the detent device 220 and the syringe 10. The ridges 250 may be integrally formed with the inner collar surface 230a of the detent device 220, or the ridges 250 may be separate components attached to the inner collar surface 230a. In either case, the ridges 250 cooperate to facilitate a relatively secure fit between the detent device 220 and the syringe 10 while minimizing obstruction space between the inner collar surface 230a and the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. For example, in one embodiment, the ridges 250 are the only portion of the inner collar surface 230a that engages the outer surface 12a of the flange 12. For example, in another embodiment, the ridges 250 are the only portion of the inner collar surface 230a that engages the outer surface of the syringe barrel 11.

[0056] 4a-4b may alternatively have any suitable configuration that spaces the collar inner surface 230a from the syringe 10. For example, in one embodiment, the ridge 250 may be replaced with a generally circular protrusion or line of protrusions.

[0057] Lethality tests were conducted on the different detents 20, 120, and 220 shown in Figures 2-4. For example, prefilled syringes were "spiked" with 1 x 10^6 to 6 x 10^6 CFU (e.g., 1,000,000 to 6,000,000 CFU) of Geobacillus stearothermophilus prior to a sterilization cycle. As a more specific example, 1 to 6 x 10^6 CFU of Geobacillus stearothermophilus were spiked into the detents and barrels of the prefilled syringes. As used herein, the term "CFU" refers to "colony-forming units." "Colony-forming units" are units used to estimate the number of viable bacterial or fungal cells in a sample ("viability" is the ability to grow by binary fission under controlled conditions). Geobacillus stearothermophilus (formerly Bacillus stearothermophilus) is a rod-shaped, Gram-positive bacterium and a member of the phylum Firmicutes. This bacterium is thermophilic, widely distributed in soil, hot springs, and marine sediments, and can cause food spoilage. Therefore, spiked pre-filled syringes were sterilized using various sterilization parameters to measure the lethality of the sterilization process and evaluate the Sterility Assurance Level (SAL). The pre-filled syringes were spiked or directly inoculated with a biological indicator, as described in more detail below.

[0058] In particular, lethality tests were conducted on different detents disclosed herein, such as detents 20, 120, 220. Table 4 shows the results of lethality tests evaluating the effectiveness of NO2-based sterilization on various pre-filled syringes having different detents 20, 120, 220.

[0059] [Table 4]

[0060] For each recipe number, five samples (or at least five test positions for one or more samples) were tested. Table 4 shows how many of the five samples for each recipe achieved the target lethality in the "Detents Added" and "Barrel Added" columns. For example, the target lethality for this test was a Sterility Assurance Level (SAL) of 1 x 10^-6. In other words, the target lethality for this test was a 6-log reduction in the number of bacteria present (pre-sterilization vs. post-sterilization). As a more specific example, for Recipe No. 1, for the detent region (row corresponding to Recipe No. 1 in the "Detents Added" column), one of the five samples tested achieved this target lethality, while for the barrel region (row corresponding to Recipe No. 1 in the "Barrel Added" column), all five of the samples tested achieved this target lethality. It should be noted that the test results for the added detents of recipes Nos. 1-4 (using detent 20 shown in FIG. 2) were tested by direct inoculation, while the test results for the added detents of recipes Nos. 5-14 (using detent 120 or detent 220 shown in FIGS. 3-4) were tested by biological indicator. Also, note that the "-" symbol indicates that no data is reported for these parameters / samples. Aside from the differences in test methodology, samples tested using detents 120, 220 achieved a higher percentage of the target lethality compared to samples using detent 20. As mentioned above, ridges 150, 250 minimize and / or prevent occlusion spaces and instead allow the disinfectant to fully or substantially reach various components of the pre-filled syringe, particularly the detent and flange areas.

[0061] Different sterilization parameters were also tested for intrusion studies. As noted above, while it is desirable to achieve a target lethality during external sterilization, it is also desirable to reduce, minimize, and / or substantially prevent the intrusion of sterilization gas into the drug product chamber. However, the two goals (achieving lethality and minimizing intrusion) may be conflicting or offsetting concerns. For example, some sterilization parameters that may improve the likelihood of achieving a higher lethality rate may increase the likelihood of high sterilization gas intrusion. Table 5 below and Figure 7 show the results of intrusion studies evaluating the effect of different recipes of NO2-based sterilization on the drug product chamber.

[0062] [Table 5]

[0063] The last four columns on the right (collectively labeled "NO2 Content in Product (PPM)") refer to the NO2 content that invaded the drug product container, more specifically the NO2 levels measured as parts per million of nitrate in the liquid. The first three columns within this group, labeled "Day 1," "Day 14," and "Day 30," refer to intrusion rates measured at different times after the sterilization process. The final column within this group, labeled "Control," refers to the baseline levels of NO2 and the product (water for injection) nitrate (NO3) of the sample. When compared to an "exposed" sample, such as Day 1, the "unexposed" control sample provides a baseline difference between the exposed sample and the control. For example, for Test No. 5, the intrusion rate on Day 1 was 0.342 and the control was 0.336, so the difference between the exposed and unexposed samples would be 0.006 PPM. Another potentially relevant parameter is that the test method may have an error rate of + / - 0.1 PPM.

[0064] In general, it may be desirable to minimize or substantially or completely prevent intrusion, but to avoid exceeding an intrusion level of 3 PPM, 1 PPM, or another appropriate limit. It may be desirable to use "raw" 30-day values, such as those listed in the columns of Table 5 above, or "corrected" 30-day values ​​adjusted based on the control values. As shown in Table 5 above and Figure 7, nearly all intrusion values ​​are below the 1 PPM threshold (the only exception is the 30-day measurement for Sample 11). Also, as shown in Table 5 above and Figure 7, different vacuum forces, pulse numbers, and venting rates have different effects on intrusion measurements. These parameters and trends may be used to determine sterilization parameters that achieve target lethality while maintaining below desired intrusion levels.

[0065] As will be understood, devices and methods according to the present disclosure may have one or more advantages over the prior art, any one or more of which may be present in a particular embodiment according to the features of the present disclosure included in that embodiment. Other advantages not specifically recited herein may be understood as well.

[0066] Preferably, the pre-filled syringe does not include an internal coating. The syringe may also include a coating on the exterior surface of the syringe that is in contact with the environment, such as an oxygen barrier coating.

[0067] The syringe barrel may have a length of 45-85 mm, 60-65 mm, or another suitable length. The length of the syringe barrel is the length between the rear end and the outlet where the needle is attached (but does not include the needle, if present).

[0068] The syringe barrel may have an inner diameter of 4 to 6.5 mm. If the syringe has a nominal maximum fill volume of 1 ml, the inner diameter of the syringe barrel may be 5.5 to 6.5 mm. If the syringe has a nominal maximum fill volume of 0.5 ml, the inner diameter of the syringe barrel may be 4 to 5 mm.

[0069] The wall of the syringe barrel may have a thickness of at least 1 mm, about 1 to 3 mm, about 1.5 to 3 mm, or about 2.4 to 2.8 mm. The wall thickness limits or prevents sterilizing gas from entering the interior of the syringe, thereby minimizing or preventing contact with the liquid formulation contained within the pre-filled syringe.

[0070] The above description describes various devices, assemblies, components, subsystems, and methods of use related to drug delivery devices. The devices, assemblies, components, subsystems, methods, or drug delivery devices may further include or be used in conjunction with drugs, including, but not limited to, the drugs identified below and their generic and biosimilar equivalents. As used herein, the term drug may be used interchangeably with other similar terms and may be used to refer to any type of pharmaceutical or therapeutic substance, including traditional and non-traditional medicines, nutraceuticals, supplements, biologics, biologically active agents and compositions, large molecules, biosimilars, bioequivalents, therapeutic antibodies, polypeptides, proteins, small molecules, and generic drugs. Non-therapeutic injectable materials are also encompassed. Drugs may be in liquid form, lyophilized form, or reconstituted from lyophilized form. The following list of exemplary drugs should not be considered exhaustive or limiting.

[0071] The drug is contained in a reservoir. Optionally, the reservoir is a prefilled syringe. The prefilled syringe may have a maximum filling volume, i.e., the volume that can be maximally occupied by the syringe, of 0.3 ml to 1.5 ml, preferably 0.5 ml to 1.0 ml. The amount of liquid composition filled into the syringe may be about 0.05 ml to 1.0 ml, about 0.1 ml to 0.5 ml, about 0.14 ml to 0.3 ml, or about 0.15 ml to 0.2 ml. The syringe is usually filled with an amount greater than the amount actually administered to the patient to account for any dead space in the syringe and needle and losses due to preparing the syringe for injection. Therefore, the amount actually administered to the patient may be 0.01 ml to 1 ml, 0.02 to 0.5 ml, 0.025 to 0.5 ml, 0.03 ml to 0.05 ml, or 0.05 ml.

[0072] In some embodiments, the reservoir of the pre-filled syringe contains a VEGF inhibitor. The term "VEGF inhibitor" refers to a molecule that specifically interacts with VEGF and inhibits one or more of its biological activities, such as its mitogenic activity, angiogenic activity, and / or vascular permeability activity. VEGF inhibitors are intended to include both anti-VEGF antibodies and their antigen-binding fragments, and non-antibody VEGF inhibitors. Non-antibody VEGF inhibitors include aflibercept, pegaptanib, and antibody mimetics. Preferably, the non-antibody VEGF inhibitor is aflibercept. Aflibercept, also known as VEGF trap and currently marketed under the name Eylea®, is a recombinant human soluble VEGF receptor fusion protein in which portions of the extracellular domains of human VEGF receptors 1 and 2 are fused to the Fc portion of human IgG1 (Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99(17):11393-11398; WO 00 / 75319(A1)).

[0073] In some embodiments, the reservoir of the drug delivery device may be loaded with, or the device may be used in conjunction with, a colony-stimulating factor, such as granulocyte colony-stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neulasta® (pegfilgrastim, PEGylated filgastim, PEGylated G-CSF, PEGylated hu-Met-G-CSF) and Neupogen® (filgrastim, G-CSF, hu-Met-G-CSF). In other embodiments, the drug delivery device may contain, or be used in conjunction with, an erythropoiesis-stimulating agent (ESA), which may be in liquid or lyophilized form. An ESA is any molecule that stimulates red blood cell production. In some embodiments, the ESA is an erythropoiesis-stimulating protein. As used herein, "erythropoiesis-stimulating protein" refers to any protein that directly or indirectly activates the erythropoietin receptor, for example, by binding to the receptor and causing its dimerization. Erythropoiesis-stimulating proteins include erythropoietin and variants, analogs, or derivatives thereof that bind to and activate the erythropoietin receptor, antibodies that bind to and activate the erythropoietin receptor, or peptides that bind to and activate the erythropoietin receptor.Erythropoiesis-stimulating proteins include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methoxypolyethylene glycol-epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), Epoetin alpha, epoetin beta, epoetin iota, epoetin omega, epoetin delta, epoetin zeta, epoetin theta, and epoetin delta, PEGylated erythropoietin, carbamylated erythropoietin, and molecules or variants or analogs thereof.

[0074] Among certain exemplary proteins are the specific proteins described below, including fusions, fragments, analogs, variants, or derivatives thereof: OPGL-specific antibodies (also referred to as RANKL-specific antibodies, peptibodies, etc.), peptibodies, related proteins, etc., including fully humanized and human OPGL-specific antibodies, particularly fully humanized monoclonal antibodies; myostatin-binding proteins, peptibodies, related proteins, etc., including myostatin-specific peptibodies; and antibodies directed against receptors for IL-4 and / or IL-13, particularly those directed against receptors for IL-4 and / or IL-13. IL-4 receptor-specific antibodies, peptibodies, related proteins, etc., which inhibit binding-mediated activity; interleukin 1-receptor 1 ("IL1-R1")-specific antibodies, peptibodies, related proteins, etc.; Ang2-specific antibodies, peptibodies, related proteins, etc.; NGF-specific antibodies, peptibodies, related proteins, etc.; CD22-specific antibodies, peptibodies, related proteins, etc., particularly dimers of human-mouse monoclonal hLL2 gamma chain disulfide bound to human-mouse monoclonal hLL2 kappa chain. human CD22-specific antibodies, including, but not limited to, humanized and fully human monoclonal antibodies, particularly including, but not limited to, human CD22-specific IgG antibodies, such as the human CD22-specific fully humanized antibody epratuzumab (CAS Registry Number 501423-23-0); IGF-1 receptor-specific antibodies, peptibodies, and related proteins, including, but not limited to, anti-IGF-1R antibodies; B7RP-specific fully human monoclonal IgG2 antibodies, including but not limited to, B-7 related protein 1-specific antibodies, peptibodies, related proteins, and the like (also referred to as "B7RP-1" and B7H2, ICOSL, B7h, and CD275), including but not limited to, fully human IgG2 monoclonal antibodies that bind to an epitope in the first immunoglobulin-like domain of B7RP-1, and those that inhibit the interaction of B7RP-1 with its natural receptor, ICOS, on activated T cells; HuMax, e.g., 146B7;IL-15 specific antibodies, peptibodies, related proteins, and the like, including but not limited to IL-15 antibodies and related proteins, particularly humanized monoclonal antibodies; IFN gamma specific antibodies, peptibodies, related proteins, and the like, including but not limited to human IFN gamma specific antibodies and fully human anti-IFN gamma antibodies; TALL-1 specific antibodies, peptibodies, related proteins, and the like, as well as other TALL specific binding proteins; parathyroid hormone ("PTH") specific antibodies, peptibodies, related proteins, and the like. thrombopoietin receptor ("TPO-R")-specific antibodies, peptibodies, related proteins, etc.; hepatocyte growth factor ("HGF")-specific antibodies, peptibodies, related proteins, etc., including those targeting the HGF / SF:c-Met axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / scatter factor (HGF / SF); TRAIL-R2-specific antibodies, peptibodies, related proteins, etc.; activin A-specific antibodies, peptibodies, proteins, etc.; TGF-β-specific antibodies, peptibodies, amyloid beta protein-specific antibodies, peptibodies, related proteins, etc.; c-Kit-specific antibodies, peptibodies, related proteins, etc., including but not limited to proteins that bind to c-Kit and / or other stem cell factor receptors; OX40L-specific antibodies, peptibodies, related proteins, etc., including but not limited to proteins that bind to OX40L and / or other ligands of the OX40 receptor; Activase® (alteplase, tPA), Aranesp® (Darbepox), etin alfa), Epogen® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon-beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-alpha4beta7mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Humatrope® (somatropin, human growth hormone), Humira® (adalimumab), Vectibix® (panitumumab), Xgeva® (denosumab), Prolia® (denosumab), Enbrel® (etanercept, TNF-receptor / Fc fusion protein, TNF blocker), Nplate® (romiplostim), rilotumumab, ganitumab, conatumumab, brodalumab, insulin in solution, Infergen® (interferon alfacon-1), Natrecor® (nesiritide, recombinant human B-type natriuretic peptide (hBNP)), Kineret® (anakinra), Leukine® (sargamostim, rhuGM-CSF), LymphoCide® (epratuzumab, anti-CD22 mAb), Benlysta™ (lymphostat B, belimumab, anti-BlyS mAb), Metalyse® (tenecteplase, t-PA analog), Mircera® (methoxypolyethylene glycol-epoetin beta), Mylotarg® (gemtuzumab ozogamicin), Raptiva® (efalizumab), Cimzia® (certolizumab pegol, CDP 870), Soliris™ (eculizumab), pexelizumab (anti-complement C5), Numax® (MEDI-524), Lucentis® (ranibizumab), Panorex® (17-1A, edrecolomab), Trabio® (lerdelimumab), TheraCimhR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem® (IDM-1), OvaRex® (B43.13), Nuvion® (vigilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GP IL6 receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alpha-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Pat. No. 7,153,507), Tysabri® (natalizumab, anti-alpha4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax™, Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)), VEGF trap (IgG1 Ig domain of VEGFR1 fused to Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimibe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist), CNTO 148 (golimumab, anti-TNFα mAb), HGS-ETR1 (mapatuzumab, human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (zalutumumab), M200 (volociximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb, and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. difficile toxin A and toxin BC mAbs MDX-066 (CDA-1) and MDX-1388), anti-CD22 dsFv-PE38 conjugate (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 stage 1 fibrogen (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 (CNTO 1275), anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-integrin receptor mAb (MDX-018, CNTO 95), anti-IP10 ulcerative colitis mAb (MDX-1100), 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-TGFβmAb(GC-1008), TRAIL-2 mAb (HGS-ETR2), TWEAK mAb, VEGFR / Flt-1 mAb, ZP3 mAb (HuMax-ZP3)

[0075] In some embodiments, the drug delivery device may contain or be used in conjunction with a sclerostin antibody, such as, but not limited to, romosozumab, brosozumab, or BPS 804 (Novartis), or in other embodiments, a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9). Such PCSK9-specific antibodies include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab). In other embodiments, the drug delivery device may contain or be used in conjunction with rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the reservoir of the drug delivery device may be loaded with, or the device may be used in conjunction with, IMLYGIC® (talimogene laherparepvec) or another oncolytic HSV for the treatment of melanoma or other cancers, including but not limited to, OncoVEX GALV / CD; OrienX010; G207, 1716; NV1020; NV12023; NV1034; and NV1042. In some embodiments, the drug delivery device may contain, or be used in conjunction with, an endogenous tissue inhibitor of metalloproteinase (TIMP), such as, but not limited to, TIMP-3. Antagonistic antibodies of the human calcitonin gene-related peptide (CGRP) receptor, such as, but not limited to, erenumab, and bispecific antibody molecules targeting the CGRP receptor and other headache targets, may also be delivered using the drug delivery devices of the present disclosure. Additionally, bispecific T cell-engaging (BiTE®) antibodies, such as, but not limited to, BLINCYTO® (blinatumomab), can be used in or with the drug delivery devices of the present disclosure. In some embodiments, the drug delivery devices may contain or be used with APJ large molecule agonists, such as, but not limited to, apelin or analogs thereof.In some embodiments, a therapeutically effective amount of anti-thymic stromal lymphopoietin (TSLP) or a TSLP receptor antibody is used in or with the drug delivery device of the present disclosure.

[0076] Although the drug delivery devices, assemblies, components, subsystems, and methods have been described in terms of exemplary embodiments, they are not limited to the exemplary embodiments. This detailed description should be construed as exemplary only and does not describe every possible embodiment of the present disclosure. Many alternative embodiments can be implemented using either current technology or technology developed after the filing date of this patent, and such embodiments would still fall within the scope of the claims that define the invention disclosed herein.

[0077] Those skilled in the art will understand that various modifications, variations and combinations can be made to the above-described embodiments without departing from the spirit and scope of the present invention disclosed herein, and that such modifications, variations and combinations should be construed as being within the scope of the present invention.

Claims

1. 1. A container for use during an external sterilization process for a plurality of drug delivery devices, comprising: An outer housing; at least one divider at least partially enclosed by the outer housing, the at least one divider comprising a plurality of first divider plates and a plurality of second divider plates, the plurality of first divider plates including a first plurality of notches extending along a height of the first divider plates, the plurality of second divider plates including a second plurality of notches extending along a height of the second divider plates, the first plurality of notches and the second plurality of notches interlocking with each other to facilitate movement between the plurality of first divider plates and the plurality of second divider plates, whereby the at least one divider is disposable in an open configuration and a closed configuration, wherein in the open configuration the plurality of first divider plates and the plurality of second divider plates cooperate to define a plurality of chambers configured to receive at least one of the plurality of drug delivery devices, and in the closed configuration the plurality of chambers are substantially fully collapsed; A container comprising:

2. 2. The container of claim 1, wherein each of the plurality of first dividers is disposed substantially perpendicular to each of the plurality of second dividers when the at least one divider is disposed in the open configuration.

3. 3. The container of claim 1 or 2, wherein the at least one divider has length and width dimensions substantially equal to length and width dimensions of the outer housing when the at least one divider is disposed in the open configuration.

4. 4. A container according to any one of claims 1 to 3, wherein the at least one divider has length and / or width dimensions that are substantially less than length and / or width dimensions of the outer housing when the at least one divider is arranged in the closed configuration.

5. 5. The container of claim 1, wherein the at least one divider has a length and / or width dimension that is less than half of a corresponding length and / or width dimension of the outer housing when the at least one divider is disposed in the closed configuration.

6. 5. The container of claim 1, wherein the at least one divider has a length and / or width dimension that is less than 1 / 4 of a corresponding length and / or width dimension of the outer housing when the at least one divider is disposed in the closed configuration.

7. 5. The container of claim 1, wherein the at least one divider has a length and / or width dimension that is less than 1 / 8 of a corresponding length and / or width dimension of the outer housing when the at least one divider is disposed in the closed configuration.

8. 8. The container of claim 1, wherein each of the plurality of drug delivery devices comprises a pre-filled syringe located within a blister pack.

9. 9. The container of claim 1, wherein each of the plurality of chambers defines a chamber volume, the chamber volume being a non-zero value when the at least one divider is disposed in the open configuration, and the chamber volume being zero when the at least one divider is disposed in the closed configuration.

10. 1. A container for use during an external sterilization process for a plurality of drug delivery devices, comprising: An outer housing; at least one divider at least partially surrounded by the outer housing, the at least one divider defining a plurality of chambers, each of the plurality of drug delivery devices including a package having a tray and a cover, each of the plurality of chambers configured to receive at least two of the plurality of drug delivery devices in a front-to-back configuration such that a cover of one of the plurality of drug delivery devices is adjacent to one of the trays of an adjacent one of the plurality of drug delivery devices; A container comprising:

11. 11. The container of claim 10, wherein the at least one divider defines a plurality of chambers each configured to receive at least three of the plurality of drug delivery devices in a front-to-back configuration.

12. 11. The container of claim 10, wherein the at least one divider defines a plurality of chambers each configured to receive at least four of the plurality of drug delivery devices in a front-to-back configuration.

13. 11. The container of claim 10, wherein the at least one divider defines a plurality of chambers each configured to receive at least five of the plurality of drug delivery devices in a front-to-back configuration.

14. The container of any one of claims 10 to 13, wherein each of the at least one compartment is configured to receive at least 180 drug delivery devices.

15. Container according to any one of claims 10 to 14, wherein the container comprises at least two dividers.

16. 16. The container of claim 15, wherein the container is configured to receive at least 360 drug delivery devices.

17. Container according to any one of claims 10 to 14, wherein the container comprises at least four compartments.

18. 18. The container of claim 17, wherein the container is configured to receive at least 540 drug delivery devices.

19. 20. The container of claim 18, wherein the container is configured to receive at least 720 drug delivery devices.

20. 20. The container of any one of claims 10 to 19, wherein the plurality of drug delivery devices each comprise a pre-filled syringe within a blister pack.

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