Method for external sterilization of drug delivery device

Abstract

To provide a method of externally sterilizing a drug delivery device utilizing nitrogen dioxide (NO2).SOLUTION: The method includes placing the drug delivery device in a sterilization chamber, introducing into the chamber a dose of NO2 having a concentration of about 2-20 milligrams per liter by applying a vacuum level of about 10-600 Torr and holding the vacuum level for a dwell time of about 2-20 minutes, repeating the step of introducing into the chamber a dose of NO2 for about 1-24 pulses, purging the sterilization chamber of at least substantially all of the NO2, and aerating the sterilization chamber.SELECTED DRAWING: Figure 2E

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 62 / 901,179, filed September 16, 2019, U.S. Patent Application No. 62 / 905,341, filed September 24, 2019, and U.S. Patent Application No. 62 / 942,382, filed December 2, 2019. These priority applications are incorporated herein by reference in their entireties.

[0002] The present disclosure relates generally to infusion devices for drug delivery. More particularly, the present disclosure relates generally to methods for 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 pre-filled, with a set dose of medication already provided therein, or empty, to be filled by the end user from a vial or other source of medication when administration of the medication is desired.

[0004] Syringes often include a barrel portion adapted to hold a medicament. The distal end of the barrel is often configured to include and / or mate with a conventional piercing element, such as a pointed needle cannula or a cannula with a blunt end, to deliver the medicament contained within the barrel. The piercing element may be made of steel, plastic, or any other suitable material. A plunger rod may be inserted through the open proximal end of the syringe barrel, and engagement of the plunger rod with an elastomeric or rubber stopper element mounted in a substantially fluid-tight manner within the interior of the barrel allows a user to apply manual force to the plunger and deliver the medicament through the piercing element. A flange is also often provided around the open distal end of the syringe barrel as a form of finger rest to facilitate user manipulation of the device. In some examples, syringes may also include a detent or a component coupled or connected to the flange (also known as a "detent") to improve the grip, usability, and / or ergonomic design of the syringe. As a more specific example, the detent may have a radial length greater than the length of the flange, thereby effectively extending the length of the gripping surface. Also or alternatively, the detent and / or plunger rod may reduce or prevent inadvertent movement of the plunger rod and / or stopper component. As a more specific example, the detent and / or plunger rod may have components that engage with each other to define a maximum point in the retraction direction to which the plunger rod may travel.

[0005] For both drug integrity 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. U.S. federal regulations may require external sterilization under specific conditions, parameters, and / or results for some use applications, such as certain ophthalmic applications.

[0006] External sterilization can present design challenges. For example, medications may be sensitive to sterilization and / or conditions such as temperature, gas, and radiation. Furthermore, achieving a desired or necessary level of sterilization of a syringe and / or its components can be difficult, particularly in light of medication sensitivity. As a more specific example, surface interactions between various components of the syringe and the detent device and / or between the syringe and the packaging can create or contribute to occlusions that may not be effectively and / or completely sterilized during the external sterilization step performed on the syringe. As a more specific example, surface interactions between the syringe and the detent and / or between the syringe and the packaging can create or contribute to occlusions. If occlusions prevent or impede effective levels of sterilizing gas from reaching an area, the area may not be effectively sterilized. If occlusions prevent or impede sterilizing gas from purging an area, a patient, such as a patient who is already visually immunocompromised prior to treatment, may develop a more serious condition, such as a superficial eye infection or endophthalmitis. Therefore, it is desirable to maintain the integrity of the drug while achieving an appropriate level of sterilization of all relevant parts and components of the syringe. Furthermore, some sterilization gases can be absorbed by many types of plastics and rubbers, which can have adverse and / or undesirable effects on the drug product therein and, in turn, can adversely affect the efficacy, quality, and / or safety of the drug product. Other sterilization gases can cause discoloration of the syringe surface, which can be undesirable for a variety of reasons.

[0007] The present disclosure describes an approach that embodies an advantageous alternative to existing external sterilization approaches 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]

[0008] A method for externally sterilizing a drug delivery device using nitrogen dioxide (NO2) is provided, comprising the steps of placing the drug delivery device in a sterilization chamber; introducing a dose of NO2 having a concentration of about 2 to 20 milligrams per liter into the chamber by applying a vacuum level of about 10 to 600 Torr and maintaining the vacuum level for a dwell time of about 2 to 20 minutes; repeating the step of introducing the NO2 dose into the chamber for a number of pulses of about 1 to 24; purging at least substantially all of the NO2 from the sterilization chamber; and venting the sterilization chamber.

[0009] The drug delivery device to be sterilized may be a pre-filled syringe including a barrel, a stopper, a plunger rod, and a detent. The barrel of the pre-filled syringe may contain a drug such as a VEGF inhibitor. The barrel may be a plastic barrel.

[0010] The vacuum level can be about 100-500 Torr, about 150-400 Torr, about 150-300 Torr, or another suitable vacuum level.

[0011] The NO2 dose concentration can be about 2-10 milligrams per liter, about 2-7 milligrams per liter, or another suitable dose concentration.

[0012] The chamber may have a relative humidity of about 70 to 90 percent or another suitable humidity.

[0013] The residence time can be about 2 to 12 minutes, about 2 to 7 minutes, or another suitable residence time.

[0014] The number of pulses can be about 1 to 12, about 1 to 8, about 1 to 4, about 1 to 2, or another suitable number of pulses.

[0015] Venting the sterilization chamber may include venting the sterilization chamber for about 12 to 70 cycles, or another suitable number of cycles, to at least substantially prevent discoloration of the drug delivery device.

[0016] The method of external sterilization of a drug delivery device may achieve at least a 2 log reduction in microorganisms, may achieve at least a 3 log reduction in microorganisms, may achieve at least a 4 log reduction in microorganisms, may achieve at least a 5 log reduction in microorganisms, may achieve at least a 6 log reduction in microorganisms, or may achieve another suitable reduction in microorganisms.

[0017] The present disclosure will be more fully understood from the following description taken in conjunction with the accompanying drawings. Some of the drawings may be simplified by omitting selected elements to more clearly show other elements. The omission of such elements in some of the drawings does not necessarily indicate the presence or absence of the particular element in any of the illustrative embodiments, unless expressly described in the corresponding written specification. Additionally, none of the drawings are necessarily drawn to scale. [Brief explanation of the drawings]

[0018] [Figure 1] FIG. 1 is a perspective view of an exemplary injection device having a syringe with a barrel, a flange (partially shown), a plunger, and a detent, according to aspects of the present disclosure. [Figure 2A] FIG. 10 is a perspective view of another exemplary injection device having a barrel, a flange, and a detent, according to aspects of the present disclosure. [Figure 2B] 2B is an exploded perspective view of the device shown in FIG. 2A according to various embodiments of the present disclosure. [Figure 2C] FIG. 2B is a front view of the device shown in FIG. 2A showing the barrel (partial view) and detent according to various embodiments of the present disclosure. [Figure 2D] 2B is a bottom view of the detent and syringe shown in FIG. 2A according to various embodiments of the present disclosure. [Figure 2E] 2C is a perspective view of the detent shown in FIG. 2B according to various embodiments of the present disclosure. [Figure 2F] FIG. 2C is a front view of the detent shown in FIG. 2B according to various embodiments of the present disclosure. [Figure 2G] 2C is a top view of the detent shown in FIG. 2B according to various embodiments of the present disclosure. [Figure 2H] 2C is a bottom view of the detent shown in FIG. 2B according to various embodiments of the present disclosure. [Figure 3A] FIG. 1 is a perspective top view of an exemplary package according to an aspect of the present disclosure that may be used to secure and / or hold an injection device, for example, during external sterilization of the injection device. [Figure 3B] FIG. 3B is a perspective bottom view of the package shown in FIG. 3A. [Figure 3C] FIG. 11 is a perspective top view of the package shown in FIG. 10 with an exemplary injection device. [Figure 4] FIG. 10 is a perspective top view of another exemplary package according to an aspect of the present disclosure that may be used to secure and / or hold an injection device, for example, during external sterilization of the injection device. [Figure 5A] FIG. 10 is a top view of another exemplary package according to an aspect of the present disclosure with a top protective cover removed, which may be used to secure and / or hold an injection device, for example, during external sterilization of the injection device. [Figure 5B] FIG. 12B is a top view of the exemplary package shown in FIG. 12A with the top protective cover in place. [Figure 6A] 2A-2C illustrate various perspective views of the syringe of FIG. 1 highlighting areas of the syringe that may be particularly susceptible to gas blockage during and after an external sterilization process, according to various embodiments of the present disclosure. [Figure 6B] 2A-2C illustrate various perspective views of the syringe of FIG. 1 highlighting areas of the syringe that may be particularly susceptible to gas blockage during and after an external sterilization process, according to various embodiments of the present disclosure. [Figure 6C] 2A-2C illustrate various perspective views of the syringe of FIG. 1 highlighting areas of the syringe that may be particularly susceptible to gas blockage during and after an external sterilization process, according to various embodiments of the present disclosure. [Figure 7]1 is a flowchart of a method for assembling and externally sterilizing a drug delivery device according to various embodiments of the present disclosure. [Figure 8] 10 shows a graph of sterilization gas penetration rate measurements for various sterilization parameters at different times in accordance with various embodiments of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0019] The present disclosure generally relates to an injection device that can be safely and reliably activated by a user to administer a drug or, if the user is a patient, to self-administer the drug. More specifically, the present disclosure generally relates to a technique for external sterilization of a drug delivery device, which in some examples includes a syringe and a detent and / or package configured to receive and / or support the syringe. The injection device may be a syringe, such as a pre-filled syringe, containing a medication. The techniques and / or "recipes" described herein and variations thereof may allow a user to utilize a desired bioburden kill level while minimizing or avoiding undesirable effects on the medication. As used herein, the term "about" is intended to mean + / - 10% of the smallest significant figure.

[0020] FIG. 1 is a perspective view of an injection device 10, such as a syringe 10, generally having a barrel 11 with a proximal open end 11a, a distal end 11b (FIGS. 2A, 2B, 5A, and 5B), a cavity 13, a flange portion 12, a plunger rod 16, a stopper component 18 (FIGS. 5A and 5B), and a detent 20.

[0021] In some instances, engagement between the detents and the syringe may prevent sterilization gas from reaching the enclosed or partially enclosed spaces between each detent and the syringe, 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 the 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, FIGS. 6A-6C include various views of a syringe barrel and flange, the surfaces of which may be particularly susceptible to clogging being designated by reference numeral 11c (proximal section of barrel 11) and reference numeral 12c (proximal section of flange 12). For example, flange top surface 12c and barrel exterior surface 11c may be particularly susceptible to clogging due to their respective engagement with detents as is known in the art.

[0022] The syringe barrel distal end 11b may include and / or support a needle or other suitable component for completing a fluid path to a patient. For example, the syringe barrel distal end may include a luer lock component 17 (FIGS. 2A and 2B) and / or a protective cap 19 (FIG. 5A) covering the luer lock component 17. Prior to use, the protective cap 19 may be removed to allow the luer lock component 17 to receive a needle. The syringe barrel proximal end 11a (see FIG. 2A) may receive a plunger rod 16 for pushing a stopper component 18 in a distal direction 15 to expel a medication from the syringe 10. For example, the stopper component 18 may form a fluid-tight relationship with the cavity 13 while also moving in the distal direction 15 along the cavity 13 to push the medication out of the distal end of the syringe 10. Plunger rod 16 may include plunger rod end 14 having a larger diameter than the main body portion of plunger rod 16 to limit the distance plunger rod 16 travels in distal direction 15 and / or to make it easier for a user to push plunger rod 16. Plunger rod 16 may be a one-way component, in that the plunger rod is not fixedly connected to a stopper, so that stopper 18 does not move with plunger rod 16 when plunger rod 16 moves in the proximal direction (opposite distal direction 15).

[0023] 5A and 5B show syringes 10 (collectively, packaged syringes 8) disposed within a package 9, such as a blister pack 9. The package 9 includes a base portion 9a and a cover 9b (FIG. 5B), such as a Tyvek cover 9b, that extends substantially or completely across and / or is sealed to the base portion 9a. The Tyvek cover 9b may extend outside the perimeter of the base portion 9a in at least one portion, such as one side, to facilitate easier removal of the Tyvek cover 9b. Additionally or alternatively, the base portion 9a may include a tab portion 9c that is not sealed by the Tyvek cover 9b to facilitate easy removal.

[0024] Syringe barrel 11 may be made of plastic, glass, or any suitable material. As a more specific example, syringe barrel 11 may be made of a plastic material including at least one of the following materials: specific grades of polypropylene (homopolymer and / or copolymer polypropylene), cycloolefin copolymer (COC), cycloolefin polymer (COP), or other suitable materials. As a more specific example, syringe barrel 11 may be made of cycloolefin polymer (COP).

[0025] The detent 20 may be coupled or connected to the syringe 10 to improve the grip, usability, and / or ergonomic design of the syringe. The flange 12 may include a diameter larger than the diameter of the syringe barrel 11 and may serve as a finger rest to allow a user to manipulate the syringe 10 during use. For example, a user can rest two or more of their fingers on the flange 12 while using their thumb to press the plunger rod end 14. As a more specific example, the detent 20 may be coupled to the flange 12 to effectively extend the flange, thereby increasing the length of the grip surface. As an even more specific example, particularly in certain syringe applications, such as ophthalmic applications, it may be desirable for a user to have a larger effective grip surface to improve the grip, usability, and / or ergonomic design of the syringe. However, due to space constraints during manufacturing and shipping, and the advantages of scale using a standard syringe / flange configuration, it may not be desirable to increase the size of the flange 12. Additionally, syringes are commonly used in autoinjectors that have geometries that cannot accommodate syringes with enlarged flange sizes. Therefore, it may be desirable to have additional components, such as detent components, that can be attached and / or coupled to the syringe at the time of the manufacturing process.

[0026] The detents may be manufactured from any suitable material. For example, the detents may be molded from polypropylene ("PP") or acrylonitrile butadiene styrene ("ABS"). ABS may have the advantage of being harder than PP and other materials, allowing the detents to be lighter. As a more specific example, if the detents are made from PP, they may have a minimum wall thickness of 1.5 mm, while if the detents are made from ABS, they may have a minimum wall thickness of 1 mm.

[0027] The detent 20 may also be used to limit, restrict, reduce, or prevent inadvertent movement of the stopper component 18 relative to the syringe 10. For example, the detent 20 may fit onto the flange 12 to reduce or prevent inadvertent movement of the plunger rod 16. For example, as shown in FIG. 1 , the detent 20 may have a locking surface 34 that engages the plunger rod 16 to limit or prevent relative movement between the two components in the distal direction 15. As a more specific example, the plunger rod 16 may have a locking ring 16a that has a larger diameter than the rest of the plunger rod 16 but a smaller diameter than the cavity, and the locking surface 34 of the detent 20 may have a smaller diameter than the locking ring 16a such that the locking ring 16a cannot move proximally past the detent 20. This configuration would function to limit proximal movement of the plunger rod 16.

[0028] For the reasons stated above and possibly others, users generally do not remove detent 20 before using syringe 10.

[0029] External sterilization of injection devices during the manufacturing and / or assembly process may be desirable and / or required by regulation. Furthermore, external sterilization is required for some uses of prefilled syringes (e.g., certain ophthalmic applications). 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 the following: "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 on / in the device should be 1x10-6 or less." Therefore, a bioburden of 1x10-6 (e.g., 1x10 -6 ) may be desirable and / or required.

[0030] 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 the figures may be externally sterilized after the syringe 10 (with the drug in cavity 13), plunger rod 16, detent 20, and protective cap (not shown) are all assembled. 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), vaporized hydrogen peroxide (VHP), carbon dioxide (CO), chlorine dioxide, or any other suitable gas, for a predetermined length of time and under other specified conditions (e.g., temperature and pressure). Then, 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).

[0031] 2A-2H illustrate another exemplary detent 120 that may be used with a syringe 10 such as that shown in Figures 2A-2C. The detent 120 may generally include a collar portion 130 that extends around at least a portion of the syringe 10, an external gripping portion 140 for handling and / or gripping by a user, at least one protrusion such as a ridge 150 that helps to allow or promote airflow through the space between the detent and the syringe, a cavity 160 for receiving at least a portion of the syringe flange 12, and an opening 170 that allows the plunger rod 16 to extend through the detent 120.

[0032] The collar portion 130, as best shown in FIGS. 2D-2H, defines an inner surface 132 that extends around at least a portion of the syringe 10. As a more specific example, the inner surface 132 is a generally annular surface that extends around most of the circumference of the barrel 11 of the syringe 10. As an even more specific example, the inner surface 132 extends around most of the circumference of the distal portion 11c of the barrel 11, as described in more detail in FIGS. 13A-13C. The inner surface 132 may have generally the same curvature as the barrel 11 and may extend around the barrel 11 over the length of the inner surface 132. As shown in FIG. 2D, the inner surface 132 may extend around the inner surface of the collar 130 in a generally circular / annular manner except where the collar 130 and inner surface 132 terminate over an opening 134 in the collar 130, which allows the detent 120 to mate with the syringe 10. As a more specific example, the opening 134 allows the detent 120 to accept the syringe 10 by sliding the syringe 10 toward the detent 120 (or vice versa) until the syringe 10 contacts the detent 120 in a snap-fit ​​configuration. As another example, the inner surface 132 extends approximately 270 degrees around the circumference of the barrel 11. The axial length of the collar 130 (measured along the axis of the barrel 11) is approximately 5 millimeters, but may have other suitable lengths. As the axial length of the collar 130 increases, the connection between the syringe 10 and the detent 120 may be more secure. Also, or alternatively, as the axial length of the collar 130 increases, the center of gravity may be further away from the midpoint of the axial length, thereby making it easier to orient the detent 120 during manufacturing. As a more specific example, it may be desirable to use a "shaker" or "feeder" receptacle, such as a pan or bowl, to automatically assemble syringes and similarly orient multiple detent components in a shaking tray to simplify the manufacturing process. The feeder bowl may have, for example, a central receptacle with a spiral track along the sidewall of the receptacle, which carries parts up through the sidewall toward the top edge of the receptacle where they can be fed to an assembly station.In many cases, feeder bowls are more reliable and / or effective when the center of gravity of the components is at least some distance away from the midpoint of the axial length of the components, thereby causing all or substantially all components to tip toward the "heavier" side of the components. The center of gravity of detent 120 is shown in FIG. 2F by reference numeral 136. Furthermore, feeders are often more reliable when parts have some asymmetrical feature (along at least one or two axes), and the feeder has a track edge or pattern that can force improperly oriented parts back into the bowl. In this case, the track edge or pattern feature acts as a gate; that is, if the part is correctly oriented, the part does not interact with the feature, but if the part is incorrectly oriented, the part interacts with the feature and falls back into the bowl.

[0033] As noted above, detent 120 provides a user with a larger gripping surface than flange 12 of syringe 10. As a more specific example, flange portion 12 shown in FIGS. 2A and 2B has a generally oval or elliptical configuration with a maximum width 12a of approximately 13 millimeters and a barrel 11 diameter of approximately 9.5 millimeters. Thus, flange portion 12 has an effective gripping surface of approximately 2 millimeters on each side of flange portion 12. In comparison, detent 120 has a maximum width 120a of approximately 34 millimeters and a collar width 130b (FIGS. 2D and 2H) of approximately 12 millimeters. Thus, outer gripping portion 140 of detent 120 has an effective gripping surface of approximately 11 millimeters on each side of collar 130.

[0034] The external gripping portion 140 has an angle 142 (FIG. 2C) of approximately minus 25 degrees relative to the top surface 144 of the detent 120. Thus, the external gripping portion 140 has an angle of 115 degrees relative to the syringe axis 11d. It may be desirable for the angle of the external gripping portion 140 relative to the syringe axis 11d to be closer to 90 degrees than 180 degrees (i.e., 135 degrees or less) to allow the user to have an adequate grip on the external gripping portion 140. It may be more desirable for the external gripping portion 140 to have a smaller angle relative to the syringe axis 11d, such as 125 degrees or less, or 120 degrees or less, or 115 degrees or less. The external gripping portion 140 may also include anti-slip or grip-enhancing features, such as ribs or a material with a relatively high coefficient of friction.

[0035] As mentioned above, detent 120 may also include at least one protrusion, such as at least one ridge 150, that engages syringe 10 to move collar inner surface 132 away from syringe 10. As a more specific example, detent inner surface 132 may include at least one protrusion 150 that extends away from inner surface 132 and engages flange 12 and / or barrel 11 and is configured to allow or promote air flow through space 152 between inner surface 132 and syringe 10. 2A-2H, the detent includes five ridges 150a, 150b, 150c, 150d, and 150e that are generally spaced apart from one another around the inner collar surface 132, and more preferably are generally equally spaced apart from one another, to form a five-point engagement between the detent 120 and the syringe 10. However, any suitable number of ridges may be used, such as one, two, three, four, five, six, seven, eight, nine, or ten or more. The ridges 150 may be integrally formed with the inner collar surface 132 of the detent 120, or the ridges 150 may be separate components attached to the inner collar surface 132. In either case, the ridges 150 may cooperate to provide a space 152 between the inner surface 132 and the syringe 10 while still allowing for a relatively secure fit between the detent 120 and the syringe 10. For example, the ridges 150 may engage the barrel 11 in a snap-fit ​​relationship. While the ridges 150a, 150b, 150c, 150d, and 150e are shown generally parallel to the syringe axis 11d, they may have other configurations. The ridges 150a, 150b, 150c, 150d, and 150e shown in the figures may extend along the entire height 138 of the collar 130, as shown in FIG. 2E, or the ridges 150a, 150b, 150c, 150d, and 150e may extend along only a portion of the height of the collar 130.

[0036] By allowing air flow through the space 152 (FIG. 2D) between the inner surface 132 and the syringe 10, the detent 120 and syringe 10 cooperate to minimize or eliminate any occlusion area between the collar inner surface 132 and the barrel or flange. For example, in one embodiment, the ridge 150 is only present where the collar inner surface 132 engages the barrel 11.

[0037] 2A-2H may have any suitable configuration that allows airflow through the space 152 between the inner surface 132 and the syringe 10. For example, in one embodiment, the protrusions may be replaced with generally circular lumps, bumps, or other non-linear protrusions. As a more specific example, the protrusions of the detent 120 may be disposed on the collar 130 instead of within a cavity.

[0038] As mentioned above, the detent 120 includes a cavity 160 for receiving at least a portion of the syringe flange 12. As a more specific example, the cavity is defined by opposing surfaces 162, 164 (FIGS. 2E and 2F). As shown in FIG. 2C, the distance between opposing surfaces 162, 164 may be greater than the axial height of the flange 12 such that a gap 166 exists between at least one of the opposing surfaces 162, 164 and the upper and lower surfaces of the flange 12. As a more specific example, the gap 166 shown in FIG. 2C is between the lower opposing surface 162 and the lower surface of the flange 12, but in other configurations, a similar gap may exist between the upper opposing surface 164 and the top surface of the flange or on both sides (top and bottom) of the flange 12. Gap 166 and other similar gaps described herein may be advantageous to allow or encourage airflow and / or to prevent or reduce occlusions.

[0039] Cavity 160 is preferably shaped and sized to receive the entire flange 12 to promote secure engagement between collar 130 and barrel 11. Cavity 160 may also be shaped and sized to receive flange 12 in any orientation to simplify and / or improve manufacturing. For example, cavity 160 may be shaped and sized to receive flange 12 having its maximum width in any orientation. As a more specific example, the minimum width of cavity 160 may be at least slightly larger than the maximum width of flange 12 to allow the flange to be inserted in any orientation and / or to allow flange 12 to rotate freely within detent 120.

[0040] As mentioned above, opening 170 allows plunger rod 16 to extend through detent 120. Opening 170 may be sized to allow free movement of plunger rod 16 except when locking ring 16a abuts or engages a surface defining opening 170. As a more specific example, opening 170 may have a diameter or width that is at least slightly larger than the diameter or width of the portion of plunger rod designated by reference numeral 16 in FIG. 1 (i.e., the section of plunger rod having a plus-shaped cross-section), but the diameter or width of opening 170 is at least slightly smaller than the diameter or width of locking ring 16a, thereby preventing or limiting proximal movement of plunger rod 16 beyond the point shown in FIG. 1.

[0041] Referring to FIG. 7, 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. Various known techniques can be used to sterilize the various unassembled components of the drug delivery device, including but not limited to the components shown in FIGS. 1-6C. 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. 1-6C. While at least some of these components may be pre-assembled together, they may also be assembled at the filling line, for example, if the filling process is performed aseptically. Also, syringes typically have either a tip cap luer lock tip or an attached (e.g., fixed) needle, rather than having both components. They then proceed to an external sterilization step (indicated by dotted box 1).

[0042] In box 4, the syringe is primed. For processes using nitrogen dioxide (NO), priming 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. Priming can occur inside or outside the chamber.

[0043] When using ethylene oxide (EtO), the priming process may differ slightly from that described for NO. For example, the syringe may be priming inside the sterilization chamber (without gas injection) for 360 minutes (or another desired length of time). However, as with the NO process, the priming process with EtO may be performed inside or outside the chamber.

[0044] The sterilization chamber is then closed and all or substantially all of the air is evacuated from the chamber in box 5. The sterilization chamber is then humidified to a desired setting, such as 75 or 80 (or any desired amount of percentage relative humidity).

[0045] Next, in box 7, the desired sterilization gas is injected and held in the chamber for the desired dwell time. For recipes using NO2, gas injection step 7 may include some or all of the following steps: delivering a dose of NO2 by pulling a vacuum in the chamber for a desired amount of time (i.e., dwell time) while injecting the desired amount of gas (dose concentration); purging the gas and releasing the vacuum; and then repeating these steps for the desired number of pulses. Once the desired number of pulses is complete, the gas is then finally purged (in 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 the desired number of cycles to ensure all or substantially all of the sterilization gas is flushed from the syringe and package. In some instances, the vacuum level may vary during these steps. For example, the vacuum during the dwell time may be a minimum, such as about 590 Torr.

[0046] The method may include any suitable parameters for steps 7-9, such as: The vacuum level can be about 100-500 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 35 cycles or another suitable number of cycles.

[0047] As a more specific example, Table 1 shows the different variables of ten different exemplary recipes for sterilizing drug delivery devices with nitrogen dioxide (NO2).

[0048] [Table 1]

[0049] As another example, Table 2 shows different variables for six different exemplary recipes for sterilizing drug delivery devices using NO2.

[0050] [Table 2]

[0051] 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 1. 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 inversely proportional to 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 and 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 7. 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 7. 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 would have a total residence time of 80 minutes. As shown, the residence times listed in Tables 1 and 2 vary from 5 to 20 minutes, although different residence times may be appropriate. Residence times also increase the likelihood of demonstrating kill of the desired bioburden.However, if the residence time becomes too high, the process may have undesirable effects on the drug, such as contaminating the interior of the drug barrel with sterilizing gas. The "Number of Pulses" column refers to the number of times gas is injected by pulling a vacuum during the NO2 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 pulse number is more likely to demonstrate kill of the desired bioburden. However, if the pulse number becomes too high, the process may have undesirable effects on the drug, such as contaminating the interior of the drug barrel with sterilizing gas. The column referring to "Number of Vents" refers to the number of times the chamber is vented (Box 9 in Figure 7) after gas is purged from the chamber (Box 8 in Figure 7). 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, manufacturers can increase the likelihood that all or substantially all of the sterilizing gas is removed from the syringe and package (post-purge).

[0052] For each recipe (NO2) in Tables 1 and 2, the steps enclosed within Box 1 in Figure 1 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.

[0053] Table 3 shows the different variables of ten different exemplary recipes for sterilizing drug delivery devices with NO2.

[0054] [Table 3]

[0055] When using ethylene oxide (EtO), the gas injection step (Box 7) is 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) while injecting a desired amount (dose concentration) of gas, followed by 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.

[0056] At least some of the detents shown in the figure were subjected to lethality testing. For example, before the sterilization cycle, the pre-filled syringe was "spiked" with 1x10^6 to 6x10^6 CFU (e.g., 1,000,000 to 6,000,000 CFU) of Geobacillus stearothermophilus. As a more specific example, 1 to 6x10^6 CFU of Geobacillus stearothermophilus was spiked into the detents and barrel of the pre-filled syringe. 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.

[0057] In particular, lethality tests were conducted on different detents, such as the detent 20 disclosed herein. Table 4 shows the results of lethality tests evaluating the effectiveness of NO2-based sterilization on various pre-filled syringes having detent 20.

[0058] [Table 4]

[0059] 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 reached 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 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 reached 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 reached this target lethality. Note that the test results for the added detents in recipes 1-4 (which used the detent 20 shown in Figures 2A-2H) were tested by direct inoculation, while the test results for the added detents in recipes 5-14 (which used the alternative detent 120) were tested by biological indicator. Also, note that the "-" symbol indicates that no data is reported for these parameters / samples. Aside from differences in testing methodology, samples tested using the detents with protrusions achieved a higher percentage of the target lethality compared to samples using detents without protrusions. As noted above, the protrusions minimize and / or prevent occlusion spaces, instead allowing the disinfectant to fully or substantially reach various components of the pre-filled syringe, particularly the detent and flange areas.

[0060] 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 also increase the likelihood of high sterilization gas intrusion. Table 5 below and Figure 8 show the results of intrusion studies evaluating the effect of different recipes of NO2-based sterilization on the drug product chamber.

[0061] [Table 5]

[0062] 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.

[0063] 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 FIG. 8, 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 FIG. 8, 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.

[0064] While nitrogen dioxide (NO) offers many advantages as a sterilizing gas, in some instances, the sterilization process may cause discoloration of the surfaces of the injection device and / or its components. For example, discoloration may occur in one or more of the following components: the syringe, syringe barrel, detent device, stopper, plunger rod, and / or protective cap. As another example, the packaging of the injection device, such as the peel-off cover of a blister pack, may also discolor. Discoloration is generally undesirable for aesthetic and other reasons.

[0065] The type of material may be relevant to reducing, mitigating, and / or preventing discoloration due to external sterilization processes. For example, some plastic materials may more effectively inhibit and / or hide discoloration than other plastic materials. As a more specific example, polypropylene may provide reduced discoloration (e.g., reduced yellowing) compared to other materials, such as polycarbonate. Even more specifically, certain polypropylene blends may be more effective at inhibiting and / or hiding discoloration than others. As another example, polyethylene is another material that may more effectively inhibit and / or hide discoloration than other materials. As yet another example, polyesters such as polyethylene terephthalate (PET) and polyethylene terephthalate glycol (PETG) may more effectively inhibit and / or hide discoloration than other materials. As another example, polystyrenes such as polystyrene (PS) or acrylonitrile styrene acrylate (ASA) may also more effectively inhibit and / or hide discoloration than other materials. Polystyrene may be resistant to oxidation reactions, including those that occur during interaction with NO. Acrylonitrile butadiene styrene (ABS) may be preferred for certain components of the injection device and / or packaging because it is a white, rather than clear, styrene-based resin, which may prevent and / or hide discoloration. Blister packs may be made from any suitable material, such as polyethylene terephthalate glycol (PETG).

[0066] The color of a material may also be relevant to reducing, mitigating, and / or preventing discoloration due to an external sterilization process. For example, as noted above with respect to ABS, some materials may naturally possess particular colors, pigments, or shades that make them better suited to reducing, mitigating, and / or preventing discoloration. Additionally or alternatively, adding a tint to the materials used to form the injection device components and / or packaging can counteract discoloration and / or its effects. As a more specific example, a blue or gray shade may be particularly suitable for this purpose. The blue or gray shade may be added, for example, from a mixture of titanium dioxide (generally to obtain a white pigment) and / or carbon black (generally to obtain a black pigment).

[0067] Additives and / or stabilizers may also be used to reduce, mitigate, and / or prevent discoloration due to external sterilization processes. For example, increasing the levels of resin additives and stabilizers, including but not limited to antioxidants, may be beneficial in reducing the appearance of discoloration. As discussed above, at least some of the discoloration due to NO sterilization may be related to the oxidation process, and therefore minimizing or reducing the effects of oxidation can reduce discoloration. While such additives are currently added to standard resins, customized resins with increased amounts of additives may be beneficial in reducing, mitigate, and / or prevent discoloration.

[0068] As yet another example, post-sterilization processes may also be used to reduce, mitigate, and / or prevent discoloration due to external sterilization processes. For example, bubbling with NO gas can reduce the effects of discoloration. As a more specific example, immediate and / or aeration processes or other processes involving exposure to fresh air can reduce and / or mitigate the effects of discoloration. Aeration processes are described in more detail below.

[0069] As another example, differences in part thickness, surface finish, whether the polypropylene is a homopolymer or copolymer, average molecular weight, and relative proportions of additives can be parameters that affect the amount of discoloration a component undergoes or is perceived by the user.

[0070] 3A-3C show an injection device package 200 according to another embodiment of the present disclosure. The package 200 includes a support wall 210 for receiving and supporting an injection device, such as the syringe 10 shown in FIGS. 2A-2H. The package 200 may be used during various steps in the life cycle of the injection device, including at least one of the following steps: external sterilization, transportation to a user, storage before use by a user, preparation of the injection device and injection site for use, and storage after injection. For example, at a manufacturing site, a manufacturer can place an assembled pre-filled syringe (e.g., syringe barrel, detent, stopper, plunger rod, medication, and protective cap) within the package such that the assembled pre-filled syringe is supported by the package 200 with a snap-fit ​​connection between the support wall 210 and the syringe barrel. The manufacturer can perform an external sterilization step on the assembled pre-filled syringe while the assembled pre-filled syringe is supported by the package 200. The manufacturer may then also add a protective coating (not shown) onto the top wall 212 of the package to define a chamber 214 within the package 200 that forms an airtight seal and protects the assembled pre-filled syringe from outside air and / or contaminants. The protective coating may be a clear plastic layer bonded to the package 200 by any suitable means, such as an adhesive and / or a heat sealing process. During another step in the life of the injection device, the user may peel back the protective coating to gain access to the pre-filled syringe.

[0071] The package 200 may include protrusions or spacers to limit surface area contact between the tray and the injection device, thereby reducing or preventing occlusions between them. For example, the package 200 may include protrusions 220 that extend outward from the support wall 210 of the package 200 and create a gap between the injection device and the package 200, thereby minimizing or preventing occlusions between the injection device and the package 200. The protrusions or spacers thereby enable an effective connection between the package and the injection device while allowing sterilization gas to flow between the components during the external sterilization process. The protrusions or spacers may also improve (reduce time and / or improve effectiveness of) venting of the sterilization gas after the external sterilization process. While the package 200 shown in FIGS. 3A-3C includes two protrusions 220, any suitable number may be used. Also, while the protrusions 220 shown in FIGS. 3A-3C have a generally pyramidal shape, they may have any suitable shape. As another example, package 200 may not include a snap-fit ​​arrangement with the syringe, but instead may allow the syringe to rest within package 200 and allow sterilizing gas to flow between the components during an external sterilization process. In such a design, the gap between support walls 210 is larger than the diameter of the syringe to provide space between support walls 210 and the syringe. Also, in such a design, a Tyvek cover preferably prevents the syringe from exiting the package.

[0072] The package 200 includes a hollow center section 240 (between the two snap-fit ​​regions 110) that is wider than other known center sections. For example, the distance 244 shown in FIG. 3C is preferably at least 1.5 centimeters to provide a user with space to grip the syringe 10 when removing it from the package 200. Even more preferably, the distance 244 shown in FIG. 3C is preferably at least 2.0 centimeters. Even more preferably, the distance 244 shown in FIG. 3C is preferably at least 2.5 centimeters. Even more preferably, the distance 244 shown in FIG. 3C is preferably at least 3.0 centimeters. Even more preferably, the distance 244 shown in FIG. 3C is preferably at least 4.0 centimeters. Even more preferably, the distance 244 shown in FIG. 3C is preferably at least 5.0 centimeters. Even more preferably, the distance 244 shown in FIG. 3C is preferably at least 6.0 centimeters.

[0073] FIG. 4 illustrates an injection device package 300 according to another embodiment of the present disclosure. For example, the package 300 includes a raised wall section 360. The raised wall section 360 is disposed near the portion of the package 300 that receives the plunger rod to secure the plunger rod of the injection device and / or prevent unintentional movement of the plunger of the injection device. For example, the package 300 illustrated in FIG. 4 includes a support wall 310 similar to that shown in FIGS. 3A-3C for receiving and supporting the barrel of the syringe 10. However, the package 300 shown in FIG. 4 also includes a raised wall section 360 having, for example, a side wall 360a for receiving and supporting the plunger rod 16 to receive the plunger rod end 14 and prevent and / or limit distal movement of the plunger rod end 14 (and the entire plunger rod 16) until the syringe 10 is removed from the package 300, and another wall 360c extending generally perpendicular to the support wall 310 and the side wall 360a.

[0074] In some instances, sterilization may cause discoloration. For example, a peel-off paper liner for a blister pack, such as Tyvek, that has been treated with NO2 may have a yellowish hue compared to an unsterilized sample. It may be desirable to use a peel-off paper liner for a blister pack that has one or more of the above-mentioned properties to reduce or mitigate discoloration, such as dyes, colors, additives / stabilizers, or a coating added to prevent or repel discoloration due to NO2 treatment. For example, it may be desirable to use an adhesive for Tyvek that is resistant to and / or hides discoloration due to NO2 sterilization. As a more specific example, ethylene vinyl acetate (EVA) may be used. However, in other instances, it may be desirable to use a hot melt. A hot melt is a material composed of wax and resin that is resistant to discoloration.

[0075] Similarly, it may be desirable to use components with one or more of the above-mentioned properties to reduce or mitigate discoloration, such as dyes, colors, additives / stabilizers, or coatings added to prevent or repel discoloration due to NO2 treatment of the prefilled syringe, syringe components, and / or packaging. In another example, certain adhesives (e.g., Oliver 27 HT-6 adhesive) may provide desirable results under NO2 external sterilization and may show minimal noticeable signs of discoloration compared to alternatives.

[0076] It will be understood that 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 in accordance with the features of the present disclosure included in that embodiment, and other advantages not specifically recited herein may be understood as well.

[0077] 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.

[0078] 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).

[0079] 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.

[0080] 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.

[0081] 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 refer to any type of pharmaceutical or therapeutic material, 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.

[0082] The drug is contained in a reservoir. In some cases, 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.

[0083] 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)).

[0084] 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 erythropoiesis. In some embodiments, the ESA is an erythropoiesis-stimulating protein. As used herein, "erythropoiesis-stimulating protein" refers to any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to the receptor and causing receptor dimerization. Erythropoietin-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), and 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.

[0085] 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, and related proteins, including fully humanized and human OPGL-specific antibodies, particularly fully humanized monoclonal antibodies; myostatin-binding proteins, peptibodies, and related proteins, including myostatin-specific peptibodies; IL-4 receptor-specific antibodies, peptibodies, and related proteins, particularly those that inhibit activities mediated by binding of IL-4 and / or IL-13 to their receptors. 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., especially dimers of human-mouse monoclonal hLL2 gamma chain disulfide bound to human-mouse monoclonal hLL2 kappa chain, e.g., the human form of epratuzumab (CAS Registry Number 501423-23-0). Human CD22-specific antibodies, including but not limited to, humanized and fully human 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 CD22-specific fully humanized antibodies; IGF-1 receptor-specific antibodies, peptibodies, and related proteins, including but not limited to, anti-IGF-1R antibodies; B-7-related protein 1-specific antibodies, peptibodies, and related proteins, including but not limited to, those that inhibit the interaction of B7RP-1 with ICOS, the natural receptor for B7RP-1 on activated T cells, including but not limited to, a B7RP-specific fully human monoclonal IgG2 antibody; HuMax, e.g., 146B7; IL-15 specific antibodies, peptibodies, related proteins, etc., including, but not limited to, IL-15 antibodies and related proteins, particularly humanized monoclonal antibodies; human IFNIFN-γ specific antibodies, peptibodies, related proteins, etc., including but not limited to, IFN-γ specific antibodies, and fully human anti-IFN-γ antibodies; TALL-1 specific antibodies, peptibodies, related proteins, etc., and other TALL specific binding proteins; parathyroid hormone ("PTH") specific antibodies, peptibodies, related proteins, etc.; thrombopoietin receptor ("TPO-R") specific antibodies, peptibodies, related proteins, etc.; hepatocyte growth factor / scatter factor (HGF / SF):cMet axis (HGF / SF): such as fully human monoclonal antibodies that neutralize HGF / SF. Hepatocyte growth factor ("HGF")-specific antibodies, peptibodies, related proteins, etc., including those targeting TRAIL-R2 (TGF / SF: c-Met); Activin A-specific antibodies, peptibodies, proteins, etc.; TGF-β-specific antibodies, peptibodies, related proteins, etc.; Amyloid β protein-specific antibodies, peptibodies, related proteins, etc.; antibodies that bind to c-Kit and / or other stem cell factor receptors; c-Kit-specific antibodies, peptibodies, related proteins, etc., including but not limited to proteins that bind to OX40L and / or other ligands of the OX40 receptor; 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® (darbepoetin alfa), Epogen® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon-beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-α4β7mAb), 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)

[0086] 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.

[0087] 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 will still fall within the scope of the claims that define the invention disclosed herein.

[0088] Those skilled in the art will appreciate that numerous modifications, variations, and combinations can be made to the above-described embodiments without departing from the spirit and scope of the invention disclosed herein, and that such modifications, variations, and combinations should be construed as falling within the scope of the inventive concept.

Claims

1. 1. A method for externally sterilizing a drug delivery device using nitrogen dioxide (NO), comprising: placing the drug delivery device in a sterilization chamber; introducing a NO dose having a concentration of about 2 to 20 milligrams per liter into the chamber by applying a vacuum level of about 10 to 600 Torr and maintaining said vacuum level for a residence time of about 2 to 20 minutes; repeating the step of introducing a dose of NO into the chamber for a number of pulses between about 1 and 24; purging the sterilization chamber of at least substantially all of the NO2; venting the sterilization chamber; A method comprising:

2. 10. The method of claim 1, wherein the drug delivery device is a pre-filled syringe including a barrel, a stopper, a plunger rod, and a detent, the barrel containing a medication.

3. The method of claim 1 or 2, wherein the drug is a VEGF inhibitor.

4. The method according to any one of claims 1 to 3, wherein the barrel is a plastic barrel.

5. The method of any one of claims 1 to 4, wherein the vacuum level is about 100 to 500 Torr.

6. The method of any one of claims 1 to 5, wherein the vacuum level is about 150 to 400 Torr.

7. The method of any one of claims 1 to 6, wherein the vacuum level is about 150 to 300 Torr.

8. 8. The method of any one of claims 1 to 7, wherein the concentration of the NO2 dose is about 2 to 10 milligrams per liter.

9. 9. The method of any one of claims 1 to 8, wherein the concentration of the NO2 dose is about 2 to 7 milligrams per liter.

10. The method of any one of claims 1 to 9, wherein the chamber has a relative humidity of about 70 to 90 percent.

11. The method according to any one of claims 1 to 10, wherein the residence time is about 2 to 12 minutes.

12. The method according to any one of claims 1 to 11, wherein the residence time is about 2 to 7 minutes.

13. The method of any one of claims 1 to 12, wherein the number of pulses is about 1 to 12.

14. The method of any one of claims 1 to 13, wherein the number of pulses is about 1 to 8.

15. The method of any one of claims 1 to 14, wherein the number of pulses is about 1 to 4.

16. The method of any one of claims 1 to 15, wherein the number of pulses is about 1 to 2.

17. 17. The method of any one of claims 1 to 16, wherein venting the sterilization chamber comprises venting the sterilization chamber for a number of cycles between about 12 and 70 cycles to at least substantially prevent discoloration of the drug delivery device.

18. The method of any one of claims 1 to 17, wherein the method of externally sterilizing the drug delivery device achieves at least a 2 log reduction in microorganisms.

19. The method of any one of claims 1 to 18, wherein the method of externally sterilizing the drug delivery device achieves at least a 3 log reduction in microorganisms.

20. The method of any one of claims 1 to 19, wherein the method of externally sterilizing the drug delivery device achieves at least a 4 log reduction in microorganisms.

21. The method of any one of claims 1 to 20, wherein the method of externally sterilizing the drug delivery device achieves at least a 5 log reduction in microorganisms.

22. The method of any one of claims 1 to 21, wherein the method of externally sterilizing the drug delivery device achieves at least a 6 log reduction in microorganisms.

23. 1. A method for externally sterilizing a drug delivery device using nitrogen dioxide (NO), comprising: placing the drug delivery device in a sterilization chamber; introducing a NO dose having a concentration of about 5 to 20 milligrams per liter into the chamber by applying a vacuum level of about 150 to 500 Torr and maintaining said vacuum level for a residence time of about 5 to 10 minutes; repeating the step of introducing a dose of NO into the chamber for about 1 to 8 pulses; purging the sterilization chamber of at least substantially all of the NO2; venting the sterilization chamber for about 20 to 90 cycles; A method comprising:

24. 1. A method for externally sterilizing a pre-filled syringe having a drug container and a drug contained in the drug container, comprising: placing the drug delivery device in a sterilization chamber; introducing a dose of nitrogen dioxide (NO2) having a predetermined concentration into the chamber by applying a predetermined vacuum level and maintaining said vacuum level for a predetermined dwell time; repeating the step of introducing a dose of NO into the chamber for a predetermined number of pulses; purging the sterilization chamber of at least substantially all of the NO2; venting the sterilization chamber for a predetermined number of cycles; Achieve at least a log 6 lethality target for the pre-filled syringe and achieve an ingress rate of NO gas into the medication container of less than 3.0 parts per million when measured 30 days after external sterilization of the pre-filled syringe. method.

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