Containers and systems for use during external sterilization of drug delivery devices

Abstract

Improved containers and systems are provided for use during external sterilization of drug delivery devices. [Solution] The container may comprise an outer housing and at least one partition enclosed at least partially by the outer housing. The at least one partition may comprise a plurality of first partition plates and a plurality of second partition plates. The at least one partition may also be arranged in an open configuration, in which the plurality of first partition plates and the plurality of second partition plates cooperate with each other to define a plurality of chambers configured to receive at least one of a plurality of drug delivery devices. The at least one partition may also be arranged in a closed configuration, in which the plurality of chambers are substantially completely folded.

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 hereby incorporated by reference in its entirety.

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

Background Art

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

[0004] For both drug integrity and patient safety, it may be desirable to thoroughly sterilize the components of the syringe. Sterilization can be performed at several stages of the assembly process, including pre-filling (e.g., sterilization of empty barrels and / or plungers) and post-filling (e.g., external sterilization of assembled pre-filled syringes). External sterilization is typically performed after the pre-filled syringes have been filled, fully assembled, and placed in at least some of their final packaging (e.g., blister packs). U.S. federal regulations may require external sterilization under specific conditions, parameters, and / or consequences for certain use indications, such as certain ophthalmic indications.

[0005] External sterilization can present design challenges. For example, drugs may be sensitive to sterilization and / or sterilization conditions such as temperature, gas, and / or radiation. More specifically, 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 than possible, while using high temperature and / or high dose suitable for unfilled containers. Therefore, it may be advantageous or desirable to sterilize multiple devices at once to reduce processing time and / or improve efficiency. Another example is that surface interactions between devices, between devices and their packages, and / or between different packages (e.g., between blister packs) may form or promote occluded spaces that may not be effectively and / or completely sterilized during the external sterilization process performed on syringes. Therefore, it is desirable to maintain the integrity of the drug while achieving an appropriate level of sterilization of all relevant devices, packages, and their respective parts.

[0006] This disclosure describes a method that embodies a favorable alternative to existing external sterilization methods and can address one or more of the problems or needs described herein, as well as provide other benefits and advantages. [Overview of the Initiative] [Means for solving the problem]

[0007] A container and system are provided for use during an external sterilization process of multiple drug delivery devices. The container may comprise an outer housing and at least one partition enclosed at least partially by the outer housing. The at least one partition may comprise a plurality of first partition plates and a plurality of second partition plates. The at least one partition may be configurable in an open configuration and a closed configuration. In the open configuration, the plurality of first partition plates and the plurality of second partition plates cooperate to define a plurality of chambers configured to receive at least one of the plurality of drug delivery devices. In the closed configuration, the plurality of chambers are substantially completely folded.

[0008] In some examples, in an open configuration, the first and second partition plates may be positioned substantially perpendicular to each other. In some examples, when at least one partition is positioned in an open configuration, at least one partition has length and width dimensions substantially equal to the length and width dimensions of the outer housing.

[0009] In some configurations, when the partition is positioned in a closed configuration, the partition may have a length and / or width dimension that is less than half the corresponding length and / or width dimension of the outer housing. In some examples, when the partition is positioned in a closed configuration, the partition may have a length and / or width dimension that is less than one-quarter the corresponding length and / or width dimension of the outer housing. In yet another example, when the partition is positioned in a closed configuration, the partition may have a length and / or width dimension that is less than one-eighth the corresponding length and / or width dimension of the outer housing.

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

[0011] According to a second embodiment, a container is provided for use during an external sterilization process of a plurality of drug delivery devices. The container may comprise an outer housing and at least one partition at least partially enclosed by the outer housing. The at least one partition 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] This disclosure will be better understood when the following description is read in conjunction with the accompanying drawings. Some of the drawings are simplified by omitting selected elements in order to more clearly illustrate other elements. Such omissions of elements in some drawings do not necessarily indicate the presence or absence of a particular element in any of the exemplary embodiments, unless expressly described in the corresponding specification. Furthermore, none of the drawings are necessarily shown to exact scale. [Brief explanation of the drawing]

[0013] [Figure 1] An isometric view of an exemplary container for use during an external sterilization process of multiple drug delivery devices, embodying an aspect of the present disclosure, the container comprising five drug delivery devices arranged within the chamber of the container. [Figure 2]Figure 1 is an isometric view of an exemplary partition suitable for use in a container, such as the example container shown, which embodies an aspect of this disclosure, and the partition is arranged in an open configuration. [Figure 3] Figure 2 is an isometric view of an exemplary partition, in which the partition is arranged in a partially closed configuration. [Figure 4A] Figures 2 and 3 are top views of an exemplary partition, in which the partition is arranged in a closed configuration. [Figure 4B] Figure 4A is a side view of an exemplary partition. [Figure 5] An isometric view of an exemplary container for use during an external sterilization process of multiple drug delivery devices, embodying an aspect of the present disclosure, the container comprising a top cover. [Figure 6] This is a top view of an exemplary drug delivery device, more specifically a pre-filled syringe, suitable for use in an exemplary container, embodying an aspect of the present disclosure. [Figure 7] This is a top view of an exemplary drug delivery device, more specifically a pre-filled syringe, placed in a package suitable for use in an exemplary container, embodying an aspect of the present disclosure. [Figure 8] An exemplary method or series of steps for assembling and externally sterilizing a drug delivery device, embodying an aspect of the present disclosure. [Modes for carrying out the invention]

[0014] This disclosure relates to an infusion device that can be safely and reliably used in general for a user to administer a drug or for a patient to self-administer a drug when the user is the user. More specifically, this disclosure relates to a container for use during an external sterilization process of multiple drug delivery devices. As an example, the container can support or hold multiple drug delivery devices during at least several steps of the external sterilization process, i.e., (1) holding or supporting the drug delivery devices when they are transported into the sterilization chamber, (2) holding or supporting the drug delivery devices when they are inside the sterilization chamber during the sterilization process, (3) holding or supporting the drug delivery devices when they are removed from the sterilization chamber after the sterilization process, and / or (4) holding or supporting the drug delivery devices in any other step in which the drug delivery devices are transported or supported. The infusion 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 placed in a primary package, such as a blister pack. By utilizing the containers and systems described herein, as well as their variations, it may be possible to achieve a desired level of microbial elimination while minimizing or avoiding process inefficiencies and / or undesirable effects on the agent.

[0015] As used herein, the term "approximately" means within + / - 10% of the minimum significant figures.

[0016] Referring to the drawings, Figure 1 shows a container 10 for use during the external sterilization process of multiple drug delivery devices 60. The container comprises an outer housing 20 and at least one partition 30 that is at least partially enclosed by the outer housing 20 or located within the outer housing 20. The outer housing 20 shown in Figure 1 is a substantially rectangular parallelepiped (also known as a rectangular prism or cuboid) with four side walls 21, 22, 23, 24 that cooperate to define the internal volume, a bottom wall (not indicated in Figure 1), and a top wall (not shown for illustrative purposes in Figure 1). The outer housing 20 shown in Figure 1 is provided with an opening 25 for allowing and / or facilitating the entry of sterilization gas into the internal volume of the outer housing 20. The opening 25 may also be positioned and sized to function as a handle for the container 10, for example. As a more specific example, the openings 25 shown in Figure 1 are generally spaced apart from each other and facing each other so that each is large enough to accommodate a human hand and acts as a balanced carrying point (for example, on the first side wall 21 and the third side wall 23, or on the second side wall 22 and the fourth side wall 24). The outer housing 20 can be made from any suitable material, such as polypropylene, polycarbonate, polyethylene, acrylonitrile butadiene styrene (ABS), polytetrafluoroethylene (PTFE) / Teflon, other fluoropolymers, other thermoplastic polymers, or other materials or combinations of materials that are relatively lightweight yet provide sufficient structural support and are compatible with the sterilization gas and medical product being used. As a more specific example, the outer housing may be made of HDPE (high-density polyethylene) and / or may include a corrugated design to increase the strength and / or durability of the components.

[0017] Although only two openings 25 are shown in FIG. 1, the outer housing 20 may have more openings of similar or different sizes and shapes arranged along various portions of the outer housing 20, including but not limited to side walls 21, 22, 23, 24, a bottom wall, and / or an upper wall. For example, the outer housing 20 may include about 4 to 60 openings, about 8 to 50 openings, about 12 to 40 openings, about 16 to 36 openings, about 20 to 30 openings, and / or about 24 to 28 openings. The openings may be arranged at substantially equal intervals and spaced apart from each other, or concentrated in a particular portion of the outer housing 20, such as having more on the sides than on the upper and lower portions. The openings 25 are spaced apart from each other and sized to facilitate the distribution of the sterilizing gas while also providing a desired amount of structural stability to the container and / or the drug delivery device 60 disposed therein. The openings 25 may have any suitable size, such as a length of about 2 inches and a width of about 1 / 2 inch. As another example, the openings 25 may be larger, such as having a length of about 2 inches and a width of about 2 inches and a generally circular shape. As yet another example, the openings 25 may have a length of about 2.5 inches and a width of about 2.5 inches. As another example, the openings 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 structure, a collapsible design, or other features that minimize the space when not in use. Additionally or alternatively, the outer housing 20 may have chemical resistance to alkalis, oils, acids, and / or detergents.

[0019] The container 10 comprises at least one partition 30 that is at least partially enclosed by the outer housing 20. For example, the partition 30 shown in Figure 1 is enclosed within the internal volume defined by the outer housing 20. In a more specific example, the partition 30 shown in Figure 1 has length and width dimensions that are slightly smaller than the corresponding length and width dimensions inside the outer housing. In an even more specific example, the outer housing 20 shown in Figure 1 has a length 20a of about 25.1 inches and a width 20b of about 19.6 inches. The partition 30 shown in Figure 1 has a length 30a of about 25 inches and a width 30b of about 19.5 inches. The outer housing 20 and partition 30 may have any other suitable length and width, as long as the partition 39 can be fitted into the outer housing 20. The outer housing 20 may have dimensions corresponding to the size of the sterilization chamber so that the container 10 can be fitted into the chamber without wasted space.

[0020] The container 10 shown in Figure 1 includes a partition 30 comprising a plurality of first partition plates 32, each extending generally in a first direction, and a plurality of second partition plates 34, each extending generally in a second direction substantially perpendicular to the first direction. In a more specific example, the first partition plates 32 extend substantially parallel to the side walls 22, 24, and the second partition plates 34 extend substantially parallel to the side walls 21, 23, however the partition plates 32, 34 may extend at other appropriate angles relative to the outer housing 20. The partition 30 shown in Figure 1 includes a plurality of five first partition plates 32 and a plurality of ten second partition plates, however any other appropriate number of partition plates may be used. For example, the partition 30 may comprise 1 to 20 first partition plates 32 and 1 to 30 second partition plates 34, 2 to 10 first partition plates 32 and 2 to 20 second partition plates 34, 3 to 8 first partition plates 32 and 4 to 16 second partition plates 34, 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 partition plate 32 and the second partition plate 34 cooperate with each other to define a chamber 35 configured to receive the drug delivery device 60. For example, the first partition plate 32 and the second partition plate 34 of the middle partition 30 define 36 chambers, although any other suitable number of chambers 35 may be utilized. For example, the middle partition 30 may define from about 10 to 60 chambers 35, from about 24 to 48 chambers 35, from about 30 to 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 about 5 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 backstop 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 the user to grip the prefilled syringe 50 and / or providing room for components such as the backstop 55. Alternatively or additionally, the prefilled syringe 50 may be extruded or pushed out of the tray through the back surface of the tray.

[0023] The blister pack tray 62 may be combined with a cover 68. In a more specific example, the blister pack tray 62 may be sealed with the cover 68 after the prefilled syringes 50 have been 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 Figure 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. In a more specific example, the cover 68 may have micropores so that it can be gas permeable to facilitate the external sterilization of the prefilled syringes 50 while they remain inside the blister pack 60. In an even more specific example, the blister pack tray 62 may not be gas permeable so that 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 Figure 1 comprises a pre-filled syringe 50 placed in a blister pack 61 (e.g., a tray 62 sealed with a cover 68) so that the drug delivery device 60 is prepared for an external sterilization process. The drug delivery devices 60 are arranged relative to each other (e.g., front-to-back configuration) such that the cover 68 of one device 60 abuts against and / or is adjacent to the blister pack tray 62 of the adjacent device. This configuration helps to facilitate the entry and exit of sterilization gas into and out of the internal chamber defined by the blister pack tray 62 and the cover 68. In a more specific example, if adjacent devices are arranged so that their respective covers 68 abut each other, each cover may block or prevent sterilization gas from entering the internal chamber defined by the blister pack tray 62 and the cover 68.

[0025] Each of the partition plates 32 and 34 shown in Figure 1 is provided with multiple openings 36 to help facilitate the distribution of sterilization gas into the container 10. For example, each of the multiple first partition plates 32 shown in Figure 1 is provided with nine openings 36, and each of the multiple second partition plates 34 shown in Figure 1 is provided with four openings 36. However, the partition plates 32 and 34 may be provided with any other suitable number of openings 36. For example, each of the multiple first partition plates 32 may have about 1 to 20 openings 36 and each of the multiple second partition plates 34 may have about 1 to 10 openings 36; each of the multiple first partition plates 32 may have about 2 to 16 openings 36 and each of the multiple second partition plates 34 may have about 1 to 8 openings 36; each of the multiple first partition plates 32 may have about 4 to 12 openings 36 and each of the multiple second partition plates 34 may have about 2 to 6 openings 36; each of the multiple first partition plates 32 may have about 6 to 10 openings 36 and each of the multiple second partition plates 34 may have about 3 to 5 openings 36. The openings 36 may be spaced apart from each other and of a defined size in order to facilitate the distribution of sterile gas while also providing a desired amount of structural stability to the container and / or the drug delivery device 60 placed therein. For example, the opening 36 may have a length of about 2 inches and a width of about 1 / 2 inch. As another example, the opening 36 may be larger, such as having a length of about 2 inches and a width of about 2 inches and a roughly circular shape. As yet another example, the opening 36 may have a length of about 2.5 inches and a width of about 2.5 inches. As yet another example, the opening 36 may have a length of about 3 inches and a width of about 3 inches.

[0026] As shown in Figure 1, the partition 30 and the outer housing 20 cooperate to define a series of peripheral chambers 38 near the inner periphery of the outer housing 20. More specifically, each peripheral chamber 38 is smaller than the chamber 35 for holding the drug delivery device 60, and the peripheral chambers 38 do not house or hold the drug delivery device 60 but rather act as spacers between the outer housing 20 and the chambers 38 to prevent gas blockage and act as protective barriers to prevent and protect the blister pack 61 from being overloaded. More specifically, the peripheral chambers 38 form a buffer space between the inner wall of the outer housing 20 and the outermost partition plates 32, 34 parallel to the inner wall of the outer housing 20, thereby suppressing or minimizing the amount of gas trapped between them.

[0027] The container 10 may have multiple partitions 30. For example, the container 10 shown in Figure 1 has four partitions stacked vertically from each other and separated by depth partition plates 40. In a more specific example, in Figure 1, the uppermost partition 30c and the second uppermost partition 30d are visible and separated by depth partition plates 40. Partitions 30c, 30d, 30e, and 30f (Figure 5) are similar or identical to each other, and different partition plates 40a, 40b, and 40c (Figure 5) are similar or identical to each other, so that each partition 30c to 30f can support and hold the same number of drug delivery devices 60. In a more specific example, the partition 30c shown in Figure 1 has 36 chambers 35, and each chamber 35 can support and hold 5 drug delivery devices 60, so the partition 30c can support and hold up to 180 drug delivery devices 60. Therefore, each of the subsequent partitions 30d to 30f can support and hold up to 180 drug delivery devices 60 each, for a total of 720 drug delivery devices 60 (e.g., 180 × 4 = 720).

[0028] Each depth partition plate 40 is provided with a plurality of openings 42 that allow and facilitate the distribution of sterilization gas between various partitions 30c to 30f. In a more specific example, each opening 42 shown in Figure 1 substantially extends along the width of the depth partition plate 40 (but not entirely) such that each chamber 35 includes a corresponding portion of the opening 42 to allow and facilitate communication with the upper and / or lower chambers. 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 partition plate 40 may be the same size and shape as the intermediate partition 30, or slightly smaller, in order to enable or facilitate gas distribution between different peripheral chambers 38. The depth partition plates 40 may be made of the same or similar material as the plurality of first partition plates 32 and / or the plurality of second partition plates 34 and / or the outer housing 20.

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

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

[0032] When the partition 30 is placed in the closed configuration 70c, the chamber 35 is configured so that it cannot accept the drug delivery device 60. Also, the chamber 35 may be at or near its minimum volume, meaning it may have no volume at all. In other words, when the partition 30 is placed in the closed configuration 70c, the chamber 35 may be completely closed or minimized. As shown in Figure 4A, when the partition 30 is placed in the closed configuration 70c, the closed length 30g and / or closed width 30h of the partition 30 may differ significantly from these dimensions of the partition 30 in the open configuration 70a. For example, the closed length 30g of the partition 30 when placed in the closed configuration 70c is longer than the length 30a of the partition 30 when placed in the open configuration, due to the fact that the various partition plates 32 are offset from each other in a stepped manner. As another example, when the partition 30 is placed in a closed configuration 70c, its closed width 30h is shorter than the width 30b of the partition 30 when it is placed in an open configuration 70a, because the partition plates 34 are compressed against each other.

[0033] The partition plates 32 and 34 may be provided with interlocking notches 32a and 34a (Figure 3) to facilitate movement between the partition plates 32 and 34. As a more specific example, the upper part of partition plate 34 may have a notch extending from the top down to the middle along the height of partition plate 34, and the lower part of partition plate 32 may have a notch extending from the bottom down to the middle along the height of partition plate 32, or vice versa. Alternative designs for the interface between partition plates 32 and 34 may be used. The notches 32a and 34a may have a thickness that facilitates easy and rapid movement between the various configurations 70a, 70b, and 70c so that the partition 30 has a "quick collapse" design. For example, as shown by arrow 80 in Figure 3, the partition 30 can be folded by applying force to one or more corners of the partition 30.

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

[0035] Referring to Figure 8, an exemplary method for assembling and externally sterilizing a drug delivery device according to one embodiment of the present disclosure is described. During the first step (box 2), at least some individual components of the drug delivery device are often sterilized before being received by the 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. In this step, various known techniques can be used to sterilize various unassembled components of the drug delivery device, including but not limited to those shown in Figures 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 stopper, such as those shown in Figures 2 to 6. At least some of these components may be pre-assembled with each other, but they may also be assembled on the filling line, for example, if the filling process is carried out aseptically. Furthermore, syringes typically have either a tip cap with a Luer lock tip or a detachable (e.g., fixed) needle, rather than having both components. The syringe can also receive any necessary materials or labels in this process. The process then proceeds to an external sterilization step (indicated by dotted box 1). It may be appropriate and / or desirable to use container 10 during some or all of the steps indicated by dotted box 1, or between any additional steps described herein.

[0036] In box 4, the syringe is pre-treated. In processes using nitrogen dioxide (NO2), pre-treatment may include at least some or all of the following steps: taking the sample from storage, adjusting the syringe to equilibrium at room temperature 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 sterile chamber. Pre-treatment may be performed inside or outside the chamber.

[0037] When using ethylene oxide (EtO), the pretreatment step (box 4) may differ slightly from the step described for NO2. For example, syringes may be pretreated inside the sterile chamber (without gas injection) for 360 minutes (or another desired length of time). However, as with the NO2 process, the pretreatment step with EtO may be performed inside or outside the chamber.

[0038] Next, in box 5, the sterilization chamber remains closed (if pretreatment is performed inside the chamber), or container 10 is placed inside the chamber and the chamber is closed. Then, all or substantially all of the air is discharged from the chamber. The air discharge process may be performed in multiple pulses / steps as it may help control the initial humidity inside the chamber. Then, in box 6, the sterilization chamber is humidified to a desired setting such as 75 or 80 (or any desired percentage of relative humidity). In some steps, box 6 and box 7 may 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 there for a desired duration. In recipes using NO2, the gas injection step 7 may include some or all of the following steps: delivering a certain dose of NO2 by creating a vacuum in the chamber for a desired duration, injecting a desired amount (dose concentration) of gas, adjusting the humidity to increase the pressure in the chamber, maintaining this state for a desired duration (i.e., duration) to allow the disinfectant to come into contact with the surface, and then repeating these steps for a desired number of pulses. Once the desired number of pulses is complete, the gas is then finally purged (box 8) and removed from the sterilization chamber. Finally, in box 9, the chamber is vented for a desired number of cycles (also known as "vent exchange") to ensure that all or substantially all of the sterilization gas is flushed from the syringe and package. The steps in boxes 8 and 9 may be combined into a single step so that the sterilization gas is purged via vent exchange. In some examples, the vacuum level may change between these steps. For example, the vacuum during the stay can be minimal, such as approximately 590 Torr.

[0040] This method may include any appropriate parameters relating to steps 7-9, such as the following: - The vacuum level may be approximately 20-500 Torr, approximately 150-400 Torr, approximately 150-300 Torr, or another appropriate vacuum level. - The concentration of the NO2 dose may be approximately 2-20 milligrams per liter, approximately 2-10 milligrams per liter, approximately 2-7 milligrams per liter, or another appropriate dose concentration. - The chamber may have a relative humidity of approximately 70-90 percent, or another suitable humidity level. - The length of stay may be approximately 2-20 minutes, 2-12 minutes, 2-7 minutes, or another appropriate length of stay. - The number of pulses may be approximately 1-24, 1-12, 1-8, 1-4, 1-2, or another appropriate number of pulses. - The process of ventilating the sterile chamber may include ventilating the sterile chamber for approximately 12 to 70 cycles, or for another appropriate number of cycles.

[0041] As a more specific example, Table 1 shows different variables in 10 different exemplary recipes for sterilizing drug delivery devices using nitrogen dioxide (NO2).

[0042] [Table 1]

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

[0044] [Table 2]

[0045] In Tables 1 and 2, the label in the "Vacuum Level (Torr)" column refers to the vacuum force applied to the external sterilization chamber during step 4 in Figure 8. As shown, the vacuum force varies from 20 Torr to 500 Torr, although different vacuum forces may be appropriate. The vacuum force numbers listed are the reciprocals of their strength, with a force of 20 Torr being stronger than a force of 100 Torr, and a force of 100 Torr being stronger than a force of 500 Torr (atmospheric pressure is typically around 760 Torr). Stronger vacuum forces are more likely to result in the elimination of the desired number of contaminating microorganisms. However, if the vacuum force is too high, the process may have undesirable effects on the drug, such as causing the plunger to move undesirably (i.e., move across the sterile barrier, causing sterility to be compromised). 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 in Figure 8. As shown, the doses in Tables 1 and 2 vary from 5 to 20 mg / L, but different doses may be appropriate. Higher doses of NO2 during this process result in faster and more complete sterilization of the drug delivery device. However, if the dose of sterilization gas is too high, the process may have undesirable effects on the drug, such as contamination of the inside of the drug barrel with sterilization gas (i.e., intrusion of sterilization gas and / or discoloration of syringe components). The "Relative Humidity (%RH)" column refers to the relative humidity inside the external sterilization chamber during step 7 in Figure 8. As shown, the relative humidity in each column of Tables 1 and 2 varies from 75% to 80%, but different relative humidity values ​​may be appropriate. Increasing the relative humidity also increases the likelihood of killing the desired number of contaminating microorganisms. The "Dwell Time (minutes:seconds)" 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, "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 has a total stay time of 80 minutes. As shown, the stay times listed in Tables 1 and 2 vary from 5 to 20 minutes, but different stay times may be appropriate. Stay time also increases the likelihood of killing the target number of contaminating microorganisms.However, if the residence time is too long, the process may have undesirable effects on the drug, such as contaminating the inside of the drug barrel with sterile gas and / or having undesirable effects on the function or appearance of the device components. For example, components may undergo undesirable levels of discoloration if the residence time is too long. The “Number of Pulses” column refers to the number of times gas is injected by drawing a vacuum during the NO2 process. As shown, the pulses in each row of Tables 1 and 2 vary from 1 to 24, but different values ​​may be appropriate. A higher number of pulses is more likely to indicate the killing of the desired number of contaminating microorganisms. However, if the number of pulses is too high, the process may have undesirable effects on the drug, such as contaminating the inside of the drug barrel with sterile gas and / or having undesirable effects on the function or appearance of the device components. The “Number of Vents” column refers to the number of times the chamber is ventilated (box 9 in Figure 8) after the gas has been purged from the chamber (box 8 in Figure 8). An exemplary process may use 12, 24, 28, 70, or any desired number of vent exchanges. Up to a certain point, by increasing the number of vents, manufacturers can increase the likelihood that all or substantially all of the sterile gases will be removed from the syringe and packaging (post-purge).

[0046] For each recipe (NO2) in Tables 1 and 2, the steps placed in Box 1 in Figure 8 can be carried out at room temperature (25 degrees Celsius), although other suitable temperatures may be used. However, other temperatures such as approximately 2 to 8 degrees Celsius, or any other desirable temperature that does not have an undesirable effect on the chemicals, may be used.

[0047] Table 3 shows different variables for 10 different exemplary recipes for sterilizing drug delivery devices using NO2.

[0048] [Table 3]

[0049] When using ethylene oxide (EtO), the gas injection step (box 7) may differ slightly. For example, gas injection step 7 may include some or all of the following steps: delivering a certain dose of EtO by creating a vacuum in the chamber for a desired amount of time (i.e., residence time), either before or during the injection of the desired amount (dose concentration) of gas, and then purging the gas. In other words, when using EtO, it may be preferable to perform only one pulse rather than the preferred multiple pulses described above for NO2. For steps 8 (gas purging) and 9 (aeration), the exemplary process using EtO proceeds as described above for NO2.

[0050] External sterilization of injection devices during the manufacturing and / or assembly process may be desirable and / or required by regulations. Furthermore, external sterilization is required for some applications of pre-filled syringes, such as certain ophthalmic applications. For example, 21 CFR 200.50 states that "ophthalmic formulations and dispensers should be sterile." In addition, 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 "generally, SAL values ​​of 10 to 6 are used for final sterilization of health care products." Furthermore, Appendix A of ST67 and EN556-1:2006 states the following: "Sterilization of medical devices - Requirements for medical devices to be marked as "sterile" - Part 1: Requirements for medical devices to be final sterilized"... Section 4.1: "For a medical device to be final sterilized to be marked as "sterile," the theoretical probability of the presence of viable microorganisms on / inside the device is 1 × 10⁻⁶." -6 The following should be the case: Therefore, the number of contaminating microorganisms should be 1 × 10 -6 It is desirable and / or required that the number of contaminating microorganisms be less than 1 × 10⁻⁶ (i.e., less than 1 × 10⁻⁶). Additionally or alternatively, the number of contaminating microorganisms should be 1 × 10⁻⁶. -4 In some cases, it is desirable for the value to be below a certain level, such as 1 × 10⁻⁴.

[0051] Accordingly, the embodiments disclosed herein are particularly advantageous in these types of applications. As used herein, the terms “external sterilization” and / or “to externally sterilize” refer to the sterilization process of an infusion device after it has been assembled. For example, the infusion device shown in Figures 2a–2c, consisting of a syringe 10 (containing the drug in the cavity 13), a plunger rod 16, a return device 20, and a protective cap (not shown), may be externally sterilized after they have all been assembled, labeled, and placed in a blister pack. During the external sterilization process, the infusion device is typically placed in a sterilization chamber and exposed to a sterilization gas such as ethylene oxide (EtO), nitrogen dioxide (NO2), or any other suitable gas for a predetermined time and under other specified conditions (such as temperature, humidity, and pressure). After the sterilization cycle, the sterilization gas is purged from the chamber, and the infusion device remains in the chamber (substantially or completely without the sterilization gas) for another predetermined time and under other specified conditions (such as temperature and pressure).

[0052] The engagement between the retaining device 20 and the syringe 10, as shown in Figures 2a-2c, may prevent the sterilization gas from reaching the occluded or partially occluded space between the retaining device 20 and the syringe 10, thereby failing to completely or adequately sterilize these surfaces. Additionally or alternatively, the sterilization gas may not be effectively purged from these occluded or partially occluded spaces, thereby exposing the drug to the sterilization gas beyond the specified sterilization steps in the chamber. Either and / or both of these situations may be undesirable. As a more specific example, Figure 2d includes various diagrams of the syringe barrel and flange, with their surfaces, particularly those susceptible to occlusion, indicated by dark shading. For example, the upper flange surface 12b and the outer barrel surface 11b may be particularly susceptible to occlusion due to their engagement with the retaining device 20, respectively.

[0053] Figures 3a and 3b show a retaining portion 120 according to an embodiment of the present disclosure. The retaining portion 120 comprises a collar portion 130 that extends distally and annularly with respect to the syringe flange 12. The retaining device 120 also comprises a body portion 132 that defines an opening 134 and engages with the upper surface of the flange 12. The retaining portion 120 also comprises a plurality of protrusions 150 that engage with the syringe 10 such that the inner surface of the collar 130a is spaced apart from the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. In Figures 3a and 3b, three protrusions 150 are spaced apart from each other around the inner surface of the collar 130a, and more preferably spaced substantially equally apart from each other to form a three-point engagement between the retaining device 120 and the syringe 10. The raised portion 150 may be integrally formed with the inner surface 130a of the collar of the retaining device 120, or the raised portion 150 may be a separate component attached to the inner surface 130a of the collar. In either case, the raised portion 150 cooperates to enable a relatively tight fit between the retaining device 120 and the syringe 10 while minimizing the occluded space between the inner surface 130a of the collar and the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. For example, in one embodiment, only the raised portion 150 is the portion where the inner surface 130a of the collar engages with the outer surface 12a of the flange 12. For example, in another embodiment, only the raised portion 150 is the portion where the inner surface 130a of the collar engages with the outer surface of the syringe barrel 11.

[0054] The raised portion 150 shown in Figures 3a and 3b may instead have any suitable configuration that provides a gap between the syringe 10 and the inner surface 130a of the collar. For example, in one embodiment, the raised portion 150 may be replaced with a substantially circular projection or a line of projections.

[0055] Figures 4a and 4b show a retaining portion 220 according to another embodiment of the present disclosure. The retaining portion 220 comprises a collar portion 230 that extends distally and annularly with respect to the syringe flange 12. The retaining device 220 also comprises a body portion 232 that defines an opening 234 and engages with the upper surface of the flange 12. The retaining portion 220 also comprises a plurality of protrusions 250 that engage with the syringe such that the inner surface of the collar 230a is spaced apart from the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. In Figures 4a and 4b, five protrusions 250 are spaced apart from each other around the inner surface of the collar 230a, and more preferably spaced substantially equally apart from each other to form a five-point engagement between the retaining device 220 and the syringe 10. The raised portion 250 may be integrally formed with the inner surface 230a of the collar of the retaining device 220, or the raised portion 250 may be a separate component attached to the inner surface 230a of the collar. In either case, the raised portion 250 cooperates to enable a relatively tight fit between the retaining device 220 and the syringe 10 while minimizing the occluded space between the inner surface 230a of the collar and the outer surface 12a of the flange 12 and / or the outer surface of the barrel 11. For example, in one embodiment, only the raised portion 250 is the portion in which the inner surface 230a of the collar engages with the outer surface 12a of the flange 12. For example, in another embodiment, only the raised portion 250 is the portion in which the inner surface 230a of the collar engages with the outer surface of the syringe barrel 11.

[0056] The raised portion 250 shown in Figures 4a and 4b may instead have any suitable configuration that provides a gap between the syringe 10 and the inner surface of the collar 230a. For example, in one embodiment, the raised portion 250 may be replaced with a substantially circular projection or a line of projections.

[0057] Lethal tests were performed on different stopper sections 20, 120, and 220 shown in Figures 2 to 4. For example, before the sterilization cycle, 1 × 10^6 to 6 × 10^6 CFU (e.g., 1,000,000 to 6,000,000 CFU) of Geobacillus stearothermophilus were "added" to the pre-filled syringe. As a more specific example, 1 to 6 × 10^6 CFU of Geobacillus stearothermophilus were added to the stopper and barrel sections of the pre-filled syringe. As used herein, the term "CFU" refers to a "colony-forming unit." A "colony-forming unit" is a unit used to estimate the number of viable bacterial or fungal cells in a sample ("viability" means the ability to grow by binary fission under controlled conditions). Geobacillus stearothermophilus (formerly Bacillus stearothermophilus) is a rod-shaped, Gram-positive bacterium belonging to the phylum Firmicutes. This bacterium is thermophilic and widely distributed in soil, hot springs, and marine sediments, and can cause food spoilage. Therefore, pre-filled syringes with added biological indicators were sterilized using various sterilization parameters, the lethality of the sterilization process was measured, and the level of sterility assurance (SAL) was assessed. Biological indicators were added to or directly inoculated into the pre-filled syringes, as described in more detail below.

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

[0059] [Table 4]

[0060] For each recipe number, five samples (or at least five test sites for one or more samples) were tested. Table 4 shows, in the "Added Rebound Agent" and "Added Barrel" columns, how many of the five samples for each recipe reached the target lethality. For example, the target lethality for this test was a sterility assurance level (SAL) of 1 × 10⁻⁶. In other words, the target lethality for this test was a 6-log reduction in the number of bacteria present (before sterilization vs. after sterilization). As a more specific example, for recipe number 1, in the rebound agent area (the row corresponding to recipe number 1 in the "Added Rebound Agent" column), one of the five samples tested reached this target lethality, while in the barrel area (the row corresponding to recipe number 1 in the "Added Barrel" column), all five samples tested reached this target lethality. Note that the test results for the added stopper in recipes 1-4 (using stopper 20 shown in Figure 2) were obtained by direct inoculation, while the test results for the added stopper in recipes 5-14 (using stopper 120 or stopper 220 shown in Figures 3-4) were obtained by biological indicators. Also note that the "-" symbol indicates that data has not been reported for these parameters / samples. Apart from the differences in testing methods, samples tested with stoppers 120 and 220 achieved the target lethality at a higher rate than samples tested with stopper 20. As described above, the raised portions 150 and 250 minimize and / or block the occluded space, instead allowing the bactericide to reach various components of the prefilled syringe, particularly the stopper region and flange region, completely or substantially.

[0061] Intrusion studies were also conducted for different sterilization parameters. As mentioned above, it is desirable to achieve the target lethality during external sterilization, but it is also desirable to reduce, minimize, and / or substantially prevent the intrusion of sterilization gases into the drug product chamber. However, the two objectives (achieving lethality and minimizing intrusion) may be conflicting or canceling interests. For example, some sterilization parameters that may improve the likelihood of achieving a higher lethality rate may increase the likelihood of higher sterilization gas intrusion. Table 5 and Figure 7 below show the results of intrusion studies evaluating the effects of different NO2-based sterilization recipes on drug product chambers.

[0062] [Table 5]

[0063] The last four columns on the right (collectively labeled "NO2 Content in Product (PPM)") refer to the amount of NO2 that entered the drug product container, more specifically, the amount of NO2 that entered the drug container, more specifically, the NO2 level measured as parts per million nitrates in the liquid. Within this group, the first three columns labeled "Day 1," "Day 14," and "Day 30" refer to the entry rates measured at different times after the sterilization process. Within this group, the last column labeled "Control" refers to the baseline levels of NO2 and nitrates (NO3), which are the product of the sample (water for injection). The "unexposed" control sample provides a fundamental difference between the exposed sample and the control when compared to the "exposed" sample, such as on Day 1. For example, for test number 5, the entry rate on Day 1 is 0.342, and the control is 0.336, so the difference between the exposed and unexposed samples may 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 is desirable to minimize or substantially or completely prevent intrusion, but it is also desirable to avoid exceeding intrusion levels 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 to use “adjusted” 30-day values ​​adjusted based on control values. As shown in Table 5 and Figure 7 above, almost all intrusion values ​​are below the 1 PPM threshold (the only exception being the 30-day measurement for sample 11). Also, as shown in Table 5 and Figure 7 above, different vacuum forces, pulse numbers, and aeration rates have different effects on intrusion measurements. These parameters and trends can be used to determine sterilization parameters that achieve the target lethality while maintaining below the desired intrusion level.

[0065] As should be understood, the devices and methods of this disclosure may have one or more advantages over the prior art, and one or more of these advantages may be present in particular embodiments according to the features of this disclosure included in those embodiments. Other advantages not specifically mentioned herein may also be understood in the same way.

[0066] Preferably, pre-filled syringes do not have an internal coating. Syringes may also have an external coating that comes into 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 distance from the rear end to the opening where the needle is attached (but not including the needle, if present).

[0068] Syringe barrels can have an inner diameter of 4 to 6.5 mm. If the syringe has a nominal maximum filling 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 filling volume of 0.5 ml, the inner diameter of the syringe barrel may be 4 to 5 mm.

[0069] The walls of the syringe barrel may have a thickness of at least 1 mm, approximately 1–3 mm, approximately 1.5–3 mm, or approximately 2.4–2.8 mm. The wall thickness limits or prevents sterile gas from entering the inside of the syringe, thereby minimizing or preventing contact with the liquid formulation contained in the pre-filled syringe.

[0070] The above description relates to various devices, assemblies, components, subsystems, and methods of use associated with drug delivery devices. Devices, assemblies, components, subsystems, methods, or drug delivery devices may further include, or be used in conjunction with, the drugs specified below, and their generic and biosimilar equivalents, but not limited to those drugs. As used herein, the term "drug" is interchangeable with other similar terms and may be used to refer to any type of drug or therapeutic substance, including traditional and non-traditional medicines, dietary supplements, supplements, biological preparations, biological activators and compositions, large molecules, biosimilars, bioequivalents, therapeutic antibodies, polypeptides, proteins, small molecules, and generic drugs. Non-therapeutic injectable materials are also included. 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 restrictive.

[0071] The drug is contained within a reservoir. In some cases, the reservoir is a pre-filled syringe. The pre-filled syringe may have a maximum filling volume, i.e., the maximum volume that can be 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 more than the amount actually administered to the patient to account for any dead space in the syringe and needle, as well as losses incurred by preparing the syringe for injection. Therefore, the amount actually administered to the patient may be 0.01 ml to 1 ml, 0.02 ml to 0.5 ml, 0.025 ml 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, angiogenesis, and / or vascular permeability activity. VEGF inhibitors are intended to include both anti-VEGF antibodies and their antigen-binding fragments, as well as non-antibody VEGF inhibitors. Non-antibody VEGF inhibitors include aflibercept, pegaptanib, and antibody mimetic drugs. Preferably, the non-antibody VEGF inhibitor is aflibercept. Aflibercept, currently marketed under the name Eylea® and also known as a VEGF trap, is a recombinant human soluble VEGF receptor fusion protein in which a portion of the extracellular domains of human VEGF receptors 1 and 2 is fused to the Fc portion of human IgGl (Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99(17):11393-11398, International Publication No. 00 / 75319(A1) brochure).

[0073] In some embodiments, the reservoir of the drug delivery device may be filled with colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF), or the device may be used with such factors. Such G-CSF agents include, but are not limited to, Neulasta® (pegfilgrastim, PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF) and Neupogen® (filgrastim, G-CSF, hu-MetG-CSF). In other embodiments, the drug delivery device may contain, or be used with, an erythropoiesis-stimulating agent (ESA), which may be in liquid or lyophilized form. An ESA is any molecule that stimulates erythropoiesis. In some embodiments, the ESA is an erythropoiesis-stimulating protein. As used herein, “erythropoiesis-stimulating protein” means any protein that directly or indirectly activates an erythropoietin receptor, for example, by binding to the receptor and causing its dimerization. Examples of red blood cell production stimulating proteins include erythropoietin and its variants, analogs, or derivatives, which bind to and activate the erythropoietin receptor; antibodies that bind to and activate the erythropoietin receptor; or peptides that bind to and activate the erythropoietin receptor.Examples of red blood cell production 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), and Binocrit® (epoetin alfa). Examples include, but are not limited to, epoetin alpha Hexal, Abseamed® (epoetin alpha), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alpha, epoetin beta, epoetin iota, epoetin omega, epoetin delta, epoetin zeta, epoetin theta, and epoetin delta, PEGylated erythropoietin, carbamylated erythropoietin, and their molecules, variants, or analogues.

[0074] Among certain exemplary proteins, there are specific proteins described below, including their fusions, fragments, analogues, variants, or derivatives: fully humanized and human OPGL-specific antibodies, in particular fully humanized monoclonal antibodies, OPGL-specific antibodies, peptide bodies, and related proteins (also referred to as RANKL-specific antibodies, peptide bodies, etc.); myostatin-specific peptide bodies, myostatin-binding proteins, peptide bodies, and related proteins; in particular, those targeting IL-4 and / or IL-13 receptors. IL-4 receptor-specific antibodies, peptide bodies, and related proteins that inhibit binding-mediated activity; interleukin-1 receptor 1 ("IL1-R1")-specific antibodies, peptide bodies, and related proteins; Ang2-specific antibodies, peptide bodies, and related proteins; NGF-specific antibodies, peptide bodies, and related proteins; CD22-specific antibodies, peptide bodies, and related proteins, 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 human CD22-specific IgG antibodies such as epratuzumab (CAS registry number 501423-23-0), human CD22-specific fully humanized antibodies, humanized and fully human monoclonal antibodies, humanized and fully human antibodies, etc.; IGF-1 receptor-specific antibodies, peptide bodies, and related proteins, including but not limited to anti-IGF-1R antibodies; B7RP-specific fully human monoclonal IgG2 This includes, but is not limited to, antibodies, including, but not limited to, fully human IgG2 monoclonal antibodies that bind to the epitope of the initial immunoglobulin-like domain of B7RP-1, and including, but not limited to, those that inhibit the interaction between B7RP-1 and its native receptor ICOS on activated T cells, such as B-7-related protein 1 specific antibodies, peptide bodies, and related proteins (also referred to as "B7RP-1" as well as B7H2, ICOSL, B7h, and CD275); e.g., 146B7, HuMaxIL-15 specific antibodies, peptide bodies, and related proteins, including but not limited to IL-15 antibodies and related proteins, particularly humanized monoclonal antibodies; IFN gamma specific antibodies, peptide bodies, and related proteins, including but not limited to human IFN gamma specific antibodies and fully human anti-IFN gamma antibodies; TALL-1 specific antibodies, peptide bodies, and related proteins, as well as other TALL-specific binding proteins; parathyroid hormone ("PTH") specific antibodies, peptide bodies, and related proteins. Proteins, etc.; thrombopoietic receptor ("TPO-R") specific antibodies, peptide bodies, related proteins, etc.; hepatocyte growth factor ("HGF") specific antibodies, peptide bodies, related proteins, etc., including those targeting the HGF / SF:cMet axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / dispersion factor (HGF / SF); TRAIL-R2 specific antibodies, peptide bodies, related proteins, etc.; activin A specific antibodies, peptide bodies, proteins, etc.; TGF-β specific antibodies, peptide bodies, Related proteins, etc.; amyloid-beta protein-specific antibodies, peptide bodies, related proteins, etc.; c-Kit-specific antibodies, peptide bodies, related proteins, etc., including but not limited to proteins that bind to c-Kit and / or other stem cell factor receptors; OX40L-specific antibodies, peptide bodies, 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® (dalbepowder). Ethin alfa), Epogen® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon β-1a), Bexxar® (tositumomab, anti-CD22 monoclonal antibody), Betaseron® (interferon-β), Campath® (alemtuzumab, anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-α4β7)mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Humatrope® (somatropin, human growth hormone), Humira® (adalimumab), Vectibix® (panitumumab), Xgeva( (Registered Trademark) (Denosumab), Prolia (Registered Trademark) (Denosumab), Enbrel (Registered Trademark) (Etanercept, TNF receptor / Fc fusion protein, TNF blocker), Nplate (Registered Trademark) (Romiplostim), Rilotumumab, Ganitumumab, Conatumumab, Brodalumab, Insulin in Solution, Infergen (Registered Trademark) (Interferon alfacon-1), Natrecor (Registered Trademark) (Nesiritide, Recombinant Human Type B Natriuretic Peptide (hBNP)), Kineret (Registered Trademark) (Anakinra), Leukine (Registered Trademark) (Sargamostim, rhuGM-CSF), LymphoCide (Registered Trademark) (Epratuzumab, Anti-CD22 mAb), Benlysta (trademark) (lymphostat B, belimumab, anti-BlyS mAb), 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, CDP 870), Soliris (trademark) (eculizumab), pexerizumab (anti-complement C5), Numax (registered trademark) (MEDI-524), Lucentis (registered trademark) (ranibizumab), Panorex (registered trademark) (17-1A, edrecolomab), Trabio (registered trademark) (reldelimumab), TheraCimhR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem (registered trademark) (IDM-1), OvaRex (registered trademark) (B43.13), Nuvion (registered trademark) (vizilizumab), cantuzumab meltansine (huC242-DM1), NeoRecormon (registered trademark) (epoetin beta), Neumega (registered trademark) (oprelbequin, human interleukin-11), Orthoclone OKT3 (registered trademark) (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit (registered trademark) (epoetin alfa), Remicade (registered trademark) (infliximab, anti-TNFα monoclonal antibody), Reopro (registered trademark) (absiximab, anti-GP) (Ib / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanorimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon α-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®, Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor co-protein)), VEGF trap (IgG1 VEGFR1 Ig domain fused with Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimabe), 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 (saltumumab), M200 (boroxiximab, 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 mAb 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 fibrogen for idiopathic pulmonary fibrosis stage 1 (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), and in other embodiments, a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9). Examples of 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, trevananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the drug delivery device reservoir may be filled with IMLYGIC® (Tarimogene Laharpa Lepbec) or other oncolytic HSVs for the treatment of melanoma or other cancers, including but not limited to OncoVEXGALV / CD;OrienX010;G207, 1716;NV1020;NV12023;NV1034; and NV1042, or the device may be used in conjunction with them. In some embodiments, the drug delivery device may contain or be used in conjunction with endogenous tissue inhibitors (TIMPs) of metalloproteinases, such as but not limited to TIMP-3. Antagonistic antibodies of the human calcitonin gene-related peptide (CGRP) receptor, such as erenumab and bispecific antibody molecules targeting the CGRP receptor and other headache targets, may also be delivered using the drug delivery device of this disclosure. In addition, bispecific T cell induction (BiTE®) antibodies, such as but not limited to BLINCYTO® (blinatumomab), may be used in or with the drug delivery device of this disclosure. In some embodiments, the drug delivery device may contain or be used with APJ macromolecule agonists, such as but not limited to apelin or its analogues.In some embodiments, a therapeutically effective amount of anti-thymocrine interstitial lymphocyte generating factor (TSLP) or TSLP receptor antibody is used in or in conjunction with the drug delivery device of the present disclosure.

[0076] While drug delivery devices, assemblies, components, subsystems, and methods have been described in terms of exemplary embodiments, they are not limited to such exemplary embodiments. This detailed description should be construed as illustrative only and does not describe all possible embodiments of the Disclosure. Many alternative embodiments can be carried out using either the current art or art developed after the filing date of this patent, but such embodiments would still fall within the scope of the claims defining the invention disclosed herein.

[0077] Those skilled in the art will understand that various modifications, changes, and combinations of the above embodiments can be made without departing from the spirit and scope of the invention disclosed herein, and that such modifications, changes, and combinations should be interpreted as falling within the scope of the concept of the invention.

Claims

1. A container for use during the external sterilization process of multiple drug delivery devices, Outer housing and At least one partition enclosed at least partially by the outer housing, the at least one partition comprising a plurality of first partition plates and a plurality of second partition plates, the at least one partition being configurable in an open configuration and a closed configuration, in the open configuration the plurality of first partition plates and the plurality of second partition 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 completely folded by the at least one partition and A container equipped with [the necessary features / features].

2. The container according to claim 1, wherein when the at least one partition is arranged in the open configuration, each of the plurality of first partition plates is arranged substantially perpendicular to each of the plurality of second partition plates.

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

4. The container according to any one of claims 1 to 3, wherein when the at least one partition is positioned in the closed configuration, the at least one partition has a length and / or width dimension that is substantially less than the length and / or width dimension of the outer housing.

5. The container according to any one of claims 1 to 4, wherein when the at least one partition is positioned in the closed configuration, the at least one partition has a length and / or width dimension that is less than half of the corresponding length and / or width dimension of the outer housing.

6. The container according to any one of claims 1 to 4, wherein when the at least one partition is positioned in the closed configuration, the at least one partition has a length and / or width dimension that is less than one-quarter of the corresponding length and / or width dimension of the outer housing.

7. The container according to any one of claims 1 to 4, wherein when the at least one partition is positioned in the closed configuration, the at least one partition has a length and / or width dimension that is less than 1 / 8 of the corresponding length and / or width dimension of the outer housing.

8. The container according to any one of claims 1 to 7, wherein each of the plurality of drug delivery devices comprises a pre-filled syringe contained in a blister pack.

9. The container according to any one of claims 1 to 8, wherein each of the plurality of chambers defines a chamber volume, the chamber volume is non-zero when the at least one partition is arranged in the open configuration, and the chamber volume is 0 when the at least one partition is arranged in the closed configuration.

10. A container for use during the external sterilization process of multiple drug delivery devices, Outer housing and At least one partition enclosed at least partially by the outer housing, wherein the at least one partition defines a plurality of chambers, and each of the plurality of chambers is configured to receive at least two of the plurality of drug delivery devices in a front-to-back configuration. A container equipped with [the necessary features / features].

11. The container according to claim 10, wherein the at least one partition 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. The container according to claim 10, wherein the at least one partition 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. The container according to claim 10, wherein the at least one partition 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 according to any one of claims 10 to 13, wherein each of the at least one partition is configured to accept at least 180 drug delivery devices.

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

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

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

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

19. The container according to claim 18, wherein the container is configured to accept at least 720 drug delivery devices.

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

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