Method for External Sterilization of a Drug Delivery Device

Abstract

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.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Patent Application No. 62 / 901,179, filed on September 16, 2019; U.S. Patent Application No. 62 / 905,341, filed on September 24, 2019; and U.S. Patent Application No. 62 / 942,382, filed on December 2, 2019. These priority applications are hereby incorporated by reference in their entirety.

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

[0004] Syringes often include a barrel portion adapted to hold a medicament. The distal end of the barrel often includes and / or is configured to 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 by engagement of the plunger rod with an elastomeric or rubber-like stopper element substantially fluid-tight within the interior of the barrel, a user can apply manual force to the plunger to deliver the medicament through the piercing element. A flange is also often provided around the open distal end of the syringe barrel in the form of a finger rest to facilitate operation of the device by the user. In some examples, the syringe may also include a backstop, or a component (also known as a “backstop”) coupled or connected to the flange to improve the syringe's grip, usability, and / or ergonomic design. As a more specific example, the backstop may have a radial length longer than the length of the flange, thereby effectively extending the length of the grip surface. Alternatively or additionally, the backstop and / or the plunger rod may reduce or prevent inadvertent movement of the plunger rod and / or the stopper component. As a more specific example, the backstop and / or the plunger rod may have components that engage with each other to define a maximum point in the retraction direction at which the plunger rod can move.

[0005] For both the integrity of the drug and the safety of the patient, it may be desirable to fully sterilize the components of the syringe. Sterilization can be performed at several stages of the assembly process, including the pre-filling stage (e.g., sterilization of the empty barrel and / or plunger) and the post-filling stage (e.g., external sterilization of the assembled pre-filled syringe). External sterilization is typically performed after the pre-filled syringe has been filled, fully assembled, and placed in at least some parts of its final package. In the United States Federal Regulations, external sterilization may be required for some use applications, such as certain ophthalmic applications, under certain conditions, parameters, and / or results.

[0006] External sterilization can be a design challenge. For example, the agent may be sensitive to sterilization and / or its conditions such as temperature, gas, radiation, etc. Further, it can be difficult to achieve the desired or necessary level of sterilization of the syringe and / or its components, especially from the perspective of the sensitivity of the agent. As a more specific example, surface interactions between various components of the syringe and the backstop device and / or between the syringe and the package can create or facilitate occluded spaces that may not be effectively and / or completely sterilized during the external sterilization process performed on the syringe. As a more specific example, surface interactions between the syringe and the backstop and / or between the syringe and the package can create or facilitate occluded spaces. If the occluded space prevents or hinders the effective level of sterilizing gas from reaching an area, that area may not be effectively sterilized. If the occluded space prevents or hinders the purging of an area with sterilizing gas, patients such as those visually apparent as being susceptible prior to treatment can be at risk of developing more serious conditions such as superficial eye infections or endophthalmitis. Thus, it is desirable to maintain the integrity of the agent while achieving an appropriate level of sterilization of all relevant parts and components of the syringe. Further, some sterilizing gases can be absorbed by many types of plastics and rubbers, which can have an adverse and / or undesirable effect on the internal drug product and, subsequently, can have an adverse effect on the efficacy, quality, and / or safety of the drug product. Other sterilizing gases can cause discoloration on the surface of the syringe, which can be undesirable for various reasons.

[0007] The present disclosure describes a technique that can embody an advantageous alternative to existing external sterilization techniques, address one or more of the problems or needs described herein, and 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), the method comprising: placing the drug delivery device in a sterilization chamber; applying a vacuum level of about 10 to 600 Torr and maintaining the vacuum level for a residence time of about 2 to 20 minutes to introduce into the chamber a NO2 dosage having a concentration of about 2 to 20 milligrams per liter; repeating the step of introducing the NO2 dosage 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 can be a prefilled syringe including a barrel, a stopper, a plunger rod, and a backstop. The barrel of the prefilled 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 to 500 Torr, about 150 to 400 Torr, about 150 to 300 Torr, or another suitable vacuum level.

[0011] The concentration of the NO2 dosage can be about 2 to 10 milligrams per liter, about 2 to 7 milligrams per liter, or another suitable dosage concentration.

[0012] The chamber can 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] The step of venting the sterilization chamber may include venting the sterilization chamber for a number of cycles of about 12 to 70 or another suitable number of cycles to at least substantially prevent discoloration of the drug delivery device.

[0016] Methods of externally sterilizing a drug delivery device can achieve at least a 2-log reduction of microorganisms, at least a 3-log reduction of microorganisms, at least a 4-log reduction of microorganisms, at least a 5-log reduction of microorganisms, at least a 6-log reduction of microorganisms, or another suitable reduction of microorganisms.

[0017] The present disclosure is considered to be more fully understood by interpreting the following description in conjunction with the accompanying drawings. Some of the drawings may be simplified by omitting selected elements to more clearly show other elements. The omission of such elements in some of the drawings does not necessarily indicate the presence or absence of a particular element in any of the exemplary embodiments, except as specifically described in the corresponding written specification. Further, none of the drawings are necessarily shown to scale.

Brief Description of the Drawings

[0018]

Figure 1

Figure 2A

Figure 2B

Figure 2C

Figure 2D

Figure 2E

Figure 2F

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Figure 2H

Figure 3A

Figure 3B

Figure 3C

Figure 4

Figure 5A

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Figure 8

DETAILED DESCRIPTION OF THE INVENTION

[0019] The present disclosure generally relates to an infusion device that can be safely and reliably activated for a user to administer a drug or, if the patient is the user, for self - administration of a drug. More specifically, the present disclosure generally relates to methods of externally sterilizing a drug delivery device, which in some examples includes a syringe, a check valve configured to receive and / or support the syringe, and / or a package. The infusion device may be a syringe such as a pre - filled syringe that contains a medicament. Using the techniques and / or “recipes” described herein and variations thereof, a user may be enabled to utilize a desired level of dead contaminating microorganisms while minimizing or avoiding undesirable effects on the medicament. As used herein, the term “about” is considered to mean + / −10% of the least significant digit.

[0020] FIG. 1 is a perspective view of an infusion device 10, such as a syringe 10, 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 check valve 20.

[0021] In some instances, due to the engagement between the stop and the syringe, the sterilizing gas may not reach the enclosed space or partially enclosed space between each stop and the syringe, thereby potentially failing to fully or properly sterilize these surfaces. Additionally or alternatively, the sterilizing gas may not be effectively purged from these enclosed or partially enclosed spaces, thereby potentially exposing the drug to the sterilizing gas for longer than the specified sterilization process 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 the syringe barrel and flange, and in particular, the surfaces that may be particularly susceptible to the effects of occlusion are indicated by reference numeral 11c (proximal section of barrel 11) and reference numeral 12c (proximal section of flange 12). For example, the flange top surface 12c and the barrel outer surface 11c may be particularly susceptible to the effects of occlusion by engaging with a stop well known in the art, respectively.

[0022] The distal end 11b of the syringe barrel includes and / or supports other suitable components for completing a fluid path to the needle or patient. For example, the distal end of the syringe barrel may include a luer lock component 17 (Figs. 2A and 2B) and / or a protective cap 19 (Fig. 5A) that covers the luer lock component 17. The protective cap 19 can be removed so that the luer lock component 17 can receive a needle prior to use. The proximal end 11a of the syringe barrel (see Fig. 2A) may receive a plunger rod 16 for pushing a stopper component 18 in the distal direction 15 to expel a drug from the syringe 10. For example, the stopper component 18 can form a fluid-tight relationship with the cavity 13 while being able to move in the distal direction 15 along the cavity 13 to push the drug out of the distal end of the syringe 10. The plunger rod 16 may include a plunger rod end 14 having a diameter larger than the body portion of the plunger rod 16 to limit the travel distance of the plunger rod 16 in the distal direction 15 and / or to make it easier for a user to push the plunger rod 16. The plunger rod 16 may be a one-way component, and since the plunger rod is not fixedly connected to the stopper, the stopper 18 does not move with the plunger rod 16 when the plunger rod 16 moves in the proximal direction (opposite to the distal direction 15).

[0023] Figs. 5A and 5B show a syringe 10 (collectively, the packaged syringe 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 the base portion 9a and / or is sealed to the base portion 9a. The Tyvek cover 9b may extend outside the frame of the base portion 9a at at least one portion such as one side to make it easier to remove 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] The syringe barrel 11 may be made of plastic, glass, or any suitable material. As a more specific example, the syringe barrel 11 may be made of a plastic material including at least one or more of the following materials, namely, a specific grade of polypropylene (homopolymer and / or copolymer polypropylene), cycloolefin copolymer (COC), cycloolefin polymer (COP), or other suitable materials. As a more specific example, the syringe barrel may be made of cycloolefin polymer (COP).

[0025] The backstop 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 that enables the user to operate the syringe 10 during use. For example, the user can place two or more of their fingers on the flange 12 while pressing the plunger rod end 14 using their thumb. As a more specific example, the backstop 20 may be coupled to the flange portion 12 to effectively extend the flange portion and thereby extend the length of the grip surface. As an even more specific example, particularly in specific applications of the syringe such as ophthalmic applications, it may be desirable for the 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 distribution and the advantages of scale in using a standard syringe / flange configuration, it may not be desirable to increase the size of the flange portion 12. Furthermore, the syringe is generally used in autoinjectors having an outer shape that cannot accommodate syringes with an enlarged flange size. Therefore, it may be desirable to have additional components such as a backstop component that can be attached to and / or coupled to the syringe at the time of the manufacturing process.

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

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

[0028] For the above reasons and perhaps other reasons, the user generally does not remove the detent 20 before using the syringe 10.

[0029] It may be desirable and / or required by regulations to externally sterilize the injection device during the manufacturing and / or assembly process. Further, external sterilization is required for some uses of prefilled syringes (such as certain ophthalmic uses). For example, 21 CFR 200.50 states that "ophthalmic preparations and dispensers should be sterile". Further, ANSI / AAMI ST67:2011 / (R)2017 includes "Sterilization of health care products - Requirements and guidance for selecting a sterility assurance level (SAL) for products labeled'sterile'", and section 4.1.1 states that "in general, a SAL value of 10-6 is used for the terminal sterilization of health care products". Further, 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 being present on / in the device should be 1 x 10-6 or less." Therefore, it is desirable and / or may be required that the number of contaminating microorganisms be less than 1 x 10-6 (e.g., 1 x 10 -6 ) and / or required.

[0030] Accordingly, the embodiments disclosed herein are particularly advantageous in these types of applications. As used herein, the terms "external sterilization" and / or "externally sterilize" refer to the sterilization process of the infusion device after the infusion device has been assembled. For example, the infusion device shown in the figures can be externally sterilized after the syringe 10 (having a drug in the cavity 13), the plunger rod 16, the backstop 20, and a protective cap (not shown) are all assembled. During the external sterilization process, the infusion device is typically placed in a sterilization chamber and exposed to a sterilizing gas such as ethylene oxide (EtO), nitrogen dioxide (NO2), vaporized hydrogen peroxide (VHP), carbon dioxide (CO2), chlorine dioxide, or any other suitable gas for a predetermined length of time and other specified conditions (such as temperature and pressure). Thereafter, after the sterilization cycle, the sterilizing gas is purged from the chamber, and for another predetermined length of time and other specified conditions (such as temperature and pressure), the infusion device remains in the chamber (substantially or completely free of the sterilizing gas).

[0031] Figures 2A - 2H show another exemplary backstop 120 that can be used with the syringe 10 as shown in Figures 2A - 2C. The backstop 120 generally includes a collar portion 130 that extends around at least a portion of the syringe 10, an external grip portion 140 for a user to handle and / or grip, at least one protrusion such as a ridge 150 that serves to allow or facilitate air flow through the space between the backstop 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 backstop 120.

[0032] As best shown in FIGS. 2D-2H, the color portion 130 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. This portion will be described in 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 along the inner surface of the collar 130 in a generally circular / annular state except at the location where the collar 130 and the inner surface 132 are interrupted across the opening 134 of the collar 130, which allows the detent 120 to engage the syringe 10. As a more specific example, the opening 134 allows the detent 120 to receive the syringe 10 by sliding the syringe 10 toward (or vice versa) the detent 120 until the syringe 10 contacts the detent 120 in a snap-fit configuration. As another example, the inner surface 132 extends around the circumference of the barrel 11 for approximately 270 degrees. 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 can become more secure. Alternatively or additionally, as the axial length of the collar 130 increases, the center of gravity can move further away from the midpoint of the axial length. Thereby, it becomes 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 simplify the manufacturing process by automatically assembling the syringe and similarly orienting multiple detent components within a shaking tray. The feeder bowl may, for example, have a central receptacle with a helical track along the sidewall of the receptacle, and the helical track carries the components upward toward the upper edge of the receptacle (where the components can be supplied to the assembly station) through the sidewall.Often, the feeder bowl is such that the center of gravity of the component is at least somewhat distant from the midpoint of the axial length of the component, whereby reliability and / or effectiveness is increased when all or substantially all of the components flip towards the "heavier side" of the component. The center of gravity of the detent 120 is indicated by reference numeral 136 in FIG. 2F. Further, the feeder is often more reliable when the parts have some asymmetric feature (along at least one or two axes), and the feeder has a track edge or pattern that can push misoriented parts back into the bowl. In this case, the track edge or pattern feature serves as a gate. That is, when the part is in the correct orientation, the part does not interact with this feature, but when the part is in the wrong orientation, the part interacts with this feature and drops back into the bowl.

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

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

[0035] As described above, the backstop 120 may also include at least one protrusion, such as at least one ridge 150 that engages the syringe 10 such that the colored inner surface 132 moves away from the syringe 10. As a more specific example, the backstop inner surface 132 may include at least one protrusion 150, which extends away from the inner surface 132 and engages the flange 12 and / or the barrel 11 and is configured to allow or facilitate air flow through the space 152 between the inner surface 132 and the syringe 10. In FIGS. 2A-2H, the backstop includes five ridges 150a, 150b, 150c, 150d, and 150e, and the five ridges 150a, 150b, 150c, 150d, and 150e are generally spaced apart from each other around the colored inner surface 132, and more preferably, are generally equally spaced apart from each other so as to form a five-point engagement between the backstop 120 and the syringe 10. However, any suitable number of ridges, such as one, or two, or three, or four, or five, or six, or seven, or eight, or nine, or ten or more, may be used. The ridges 150 may be integrally formed with the colored inner surface 132 of the backstop 120, or the ridges 150 may be separate components attached to the colored inner surface 132. In either case, the ridges 150 may cooperate to provide a relatively snug fit between the backstop 120 and the syringe 10 while providing a space 152 between the inner surface 132 and the syringe 10. For example, the ridges 150 may engage the barrel 11 in a snap-fit relationship. The ridges 150a, 150b, 150c, 150d, and 150e shown in the figures are generally parallel to the syringe axis 11d, but they may have another configuration. 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 enabling air flow to pass through the space 152 (FIG. 2D) between the inner surface 132 and the syringe 10, the check valve 120 and the syringe 10 cooperate to minimize or eliminate any closed regions between the inner surface 132 of the collar and the barrel or flange. For example, in one embodiment, the ridge 150 is only at the portion where the inner surface 132 of the collar engages the barrel 11.

[0037] Alternatively, the protrusions of the check valve 120 shown in FIGS. 2A-2H may have any suitable configuration that enables air flow to pass through the space 152 between the inner surface 132 and the syringe 10. For example, in one embodiment, the protrusions may be replaced with substantially circular masses, bumps, or other non-linear protrusions. As a more specific example, the protrusions of the check valve 120 may be disposed on the collar 130 instead of within the cavity.

[0038] As described above, the check valve 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 the opposing surface 162 and the opposing surface 164 may be greater than the axial height of the flange 12 such that there is a gap 166 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 may exist on both sides (upper and lower) of the flange 12. The gap 166 and other similar gaps described herein may be advantageous for allowing or facilitating air flow and / or for preventing or reducing closed spaces.

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

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

[0041] Referring to FIG. 7, an exemplary method of assembling and externally sterilizing a drug delivery device according to an embodiment of the present disclosure is described. During the first step (Box 2), at least some of the individual components of the drug delivery device are often sterilized before being accepted by the manufacturing facility. For example, the syringe barrel, the plunger stopper, and any other components that may come into direct contact with the drug product can be sterilized during this step. In 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, namely, the plunger rod, the flange extender, the tip cap with a luer lock, the needle, the rigid needle shield, and / or a backstop such as those shown in FIGS. 1-6C. 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. Also, the syringe typically has either a tip cap luer lock tip or an attached (e.g., fixed) needle, rather than both components. Then, the external sterilization process (indicated by the dashed box 1) is proceeded to.

[0042] In Box 4, the syringe is prepped. In a process using nitrogen dioxide (NO2), the prep may include at least some or all of the following steps: removing the sample from the storage vault, conditioning the syringe to an equilibrium state at room temperature 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 the sterilization chamber. The prep can be done either inside or outside the chamber.

[0043] When using ethylene oxide (EtO), the pre - preparation process may differ slightly from the process described for NO2. For example, the syringe can be pre - prepared for 360 minutes (or another desired length of time) (without gas injection) inside the sterilization chamber. However, similar to the process using NO2, the pre - preparation process using EtO may be performed inside or outside the chamber.

[0044] Next, in Box 5, the sterilization chamber is closed and all or substantially all of the air is exhausted from the chamber. Then, in Box 6, the sterilization chamber is humidified to a desired setting, such as 75 or 80 (or any desired percentage amount of relative humidity).

[0045] Next, in Box 7, the desired sterilizing gas is injected and held inside the chamber for the desired residence time. In the recipe using NO2, the gas injection step 7 may include some or all of the following steps: delivering a dose of NO2 by pulling a vacuum inside the chamber over a desired amount of time (i.e., residence time) while injecting a desired amount of gas (dose concentration), purging the gas, releasing the vacuum, and then repeating these steps over a desired number of pulses. When the desired number of pulses is complete, finally, the gas is purged (in Box 8) and the gas is removed from the sterilization chamber. Finally, in Box 9, the chamber is vented (also known as "vent exchange") over a desired number of cycles so that all or substantially all of the sterilizing gas is flushed from the syringe and the package. In some examples, the vacuum level can vary during these steps. For example, the vacuum during the residence time can be a minimum of about 590 Torr.

[0046] This method can include any suitable parameters for steps 7 - 9, such as the following. - The vacuum level can be about 100 - 500 Torr, about 150 - 400 Torr, about 150 - 300 Torr, or another suitable vacuum level. - The concentration of the dosage of NO2 can be about 2 to 20 milligrams per liter, about 2 to 10 milligrams per liter, about 2 to 7 milligrams per liter, or another suitable dosage concentration. - The chamber can have a relative humidity of about 70 to 90 percent or another suitable humidity. - The residence time can 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 ventilating the sterilization chamber can include ventilating the sterilization chamber for about 12 to 35 cycle numbers or another suitable number of cycles.

[0047] As a more specific example, Table 1 shows different variables of 10 different exemplary recipes for sterilizing a drug delivery device using nitrogen dioxide (NO2).

[0048]

Table 1

[0049] As another example, Table 2 shows different variables of 6 different exemplary recipes for sterilizing a drug delivery device using NO2.

[0050]

Table 2

[0051] 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 of Figure 1. As shown, the vacuum force varies from 20 Torr to 500 Torr, although different vacuum forces may be appropriate. The stated vacuum force numbers are the inverse of their strength, with a 20 Torr force being stronger than a 100 Torr force, and a 100 Torr force being stronger than a 500 Torr force (atmospheric pressure is typically about 760 Torr). The stronger the vacuum force, the higher the likelihood of indicating the death of the target number of contaminating microorganisms. However, if the vacuum force becomes too high, the process may have undesirable effects on the drug, such as moving the plunger undesirably (i.e., moving 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 dose of NO2 at this step, the more rapidly and completely the drug delivery device is sterilized. However, if the dose of the sterilizing gas becomes too high, the process may have undesirable effects on the drug, such as contaminating the interior of the drug barrel with the sterilizing gas (i.e., intrusion of the sterilizing 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 of Figure 7. As shown, the relative humidity in each column of 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 indicating the death of the target number of contaminating microorganisms. The "Residence Time (min:sec)" column refers to the amount of time the drug delivery device is in the sterilization chamber while the sterilizing gas is present. For Tables 1 and 2, the "Total Residence Time" is equal to the "Residence Time" column multiplied by the "Number of Pulses" column. For example, for the first row of Table 1, the sample has a total residence time of 80 minutes. As shown, the residence times described in Tables 1 and 2 vary from 5 to 20 minutes, although different residence times may be appropriate. The residence time also increases the likelihood of indicating the death of the target number of contaminating microorganisms.However, if the residence time becomes too high, the process may have an undesirable effect on the drug, such as contaminating the interior of the drug barrel with the sterilizing gas. The "number of pulses" column refers to the number of times the gas is injected by drawing a vacuum during the NO2 process. As shown, the pulses for each row in Tables 1 and 2 vary from 1 to 24, but different values may be appropriate. The higher the number of pulses, the higher the likelihood of indicating the death of the target number of contaminating microorganisms. However, if the number of pulses becomes too high, the process may have an undesirable effect on the drug, such as contaminating the interior of the drug barrel with the sterilizing gas. The column referring to the "number of ventings" refers to the number of times the chamber is vented (box 9 in FIG. 7) after the gas is purged from the chamber (box 8 in FIG. 7). An exemplary process may use 12, 24, 28, 70 vent exchanges, or any desired number. Up to a certain point, by increasing the number of ventings, the manufacturer 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, each step placed within box 1 of FIG. 1 can be performed at room temperature (25 degrees Celsius), although other appropriate temperatures may be used. However, other temperatures 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, may be used.

[0053] Table 3 shows different variables for ten different exemplary recipes for sterilizing a drug delivery device using NO2.

[0054]

Table 3

[0055] When using ethylene oxide (EtO), the gas injection step (Box 7) is slightly different. For example, the gas injection step 7 may include some or all of the following steps, namely, delivering a dose of EtO by pulling a vacuum in the chamber over a desired amount of time (i.e., residence time) while injecting a desired amount (dose concentration) of the gas, and then purging the gas. In other words, when using EtO, it may be desirable to perform only one pulse rather than the preferred multiple pulses described above for NO2. For steps 8 (gas purge) and 9 (ventilation), the exemplary process using EtO proceeds as described above for NO2.

[0056] Lethality tests were performed on at least some of the backstops shown in the figures. For example, before the sterilization cycle, 1x10^6 to 6x10^6 CFU (e.g., 1,000,000 to 6,000,000 CFU) of Geobacillus stearothermophilus was "added" to the prefilled syringe. As a more specific example, 1 to 6x10^6 CFU of Geobacillus stearothermophilus was added to the backstop portion and barrel portion of the prefilled syringe. As used herein, the term "CFU" refers to "colony forming unit". A "colony forming unit" is a unit used to estimate the number of viable bacterial or fungal cells in a sample ("viable" means the ability to grow by binary fission under controlled conditions). Geobacillus stearothermophilus (formerly Bacillus stearothermophilus) is a rod-shaped gram-positive bacterium and is a member of the phylum Firmicutes. This bacterium is thermophilic and is widely distributed in soil, hot springs, and marine sediments, and may cause food spoilage. Therefore, the prefilled syringes with the added bacteria were sterilized using various sterilization parameters, the lethality of the sterilization process was measured, and the sterility assurance level (SAL) was evaluated. As described in more detail below, biological indicators were added to or directly inoculated into the prefilled syringes.

[0057] In particular, lethality tests were performed on different backstop portions such as the backstop portion 20 disclosed herein. Table 4 shows the results of the lethality tests evaluating the effect of NO2-based sterilization on various prefilled syringes having the backstop portion 20.

[0058]

Table 4

[0059] For each recipe number, tests were performed on five samples (or at least five test locations for one or more samples). Table 4 shows, in the "Added Retainer" and "Added Barrel" columns, for each recipe, how many of the five samples reached the target lethality. 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 (before sterilization vs. after sterilization). As a more specific example, for recipe number 1, for the retainer region (the row corresponding to recipe number 1 in the "Added Retainer" column), one of the five samples tested reached this target lethality, while for the barrel region (the row corresponding to recipe number 1 in the "Added Barrel" column), all five of the samples tested reached this target lethality. It should be noted that the test results for the added retainers for recipe numbers 1 - 4 (using retainer 20 shown in FIGS. 2A - 2H) were tested by direct inoculation, while the test results for the added retainers for recipe numbers 5 - 14 (using another retainer 120) were tested by biological indicator. Also, note that the "-" symbol indicates that no data has been reported for these parameters / samples. Aside from the difference in test methods, samples tested using a retainer with a protrusion achieved the target lethality at a higher rate than samples using a retainer without a protrusion. As described above, the raised portion minimizes and / or blocks the occluded space and, instead, enables the sterilizing agent to reach various components of the prefilled syringe, particularly the retainer region and the flange region, completely or substantially.

[0060] For different sterilization parameters, tests on penetration studies were also conducted. As described 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 penetration of the sterilization gas into the drug product chamber. However, the two goals (achieving lethality and minimizing penetration) can be conflicting or offsetting concerns. For example, some sterilization parameters that can improve the possibility of achieving a higher lethality rate may increase the possibility of higher penetration of the sterilization gas. The following Table 5 and Figure 8 show the results of penetration studies evaluating the effects of different recipes of NO2-based sterilization on the drug product chamber.

[0061]

Table 5

[0062] The last four columns on the right (labeled together as "NO2 content in the product (PPM)") refer to the content of NO2 that penetrated into the drug product container, more specifically, the content of NO2 that penetrated into the drug container, and more specifically, the NO2 level measured as parts per million of nitrate in the liquid. The first three columns labeled "Day 1", "Day 14", and "Day 30" within this group refer to the penetration rates measured at different times after the sterilization process. The last column labeled "Control" within this group refers to the reference levels of NO2 and nitrate (NO3), the product of the sample (water for injection). Comparing the "exposed" samples such as on Day 1 with the "unexposed" control samples provides the basic difference between the exposed samples and the control. For example, for Test No. 5, the penetration rate on Day 1 is 0.342 and the control is 0.336, so the difference between the exposed sample and the unexposed sample can be 0.006 PPM. As another potentially relevant parameter, the test method can have an error rate of + / - 0.1 PPM.

[0063] Generally, it may be desirable to minimize or substantially or completely prevent ingress, but it may also be desirable to avoid exceeding an ingress amount of 3 PPM, 1 PPM, or another suitable limit. It may be desirable to use "raw" day 30 values such as those listed in the columns of Table 5 above, or "corrected" day 30 values adjusted based on control values. As shown in Table 5 and FIG. 8 above, almost all ingress values are below the 1 PPM threshold (the only exception being the day 30 measurement for Sample 11). Also, as shown in Table 5 and FIG. 8 above, changes in different vacuum forces, pulse numbers, and vent numbers have different effects on the ingress measurement values. These parameters and trends can be utilized to determine sterilization parameters that achieve the target lethality while maintaining an ingress level below the desired level.

[0064] Nitrogen dioxide (NO2) offers many advantages as a sterilizing gas, but in some instances, discoloration may occur on the surface of injection devices and / or their components as a result of the sterilization process. For example, one or more of the following components, namely, the syringe, syringe barrel, backcheck device, stopper, plunger rod, and / or protective cap, may discolor. As another example, the package of an 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 can be related to reducing, alleviating, and / or preventing discoloration during an external sterilization process. For example, some plastic materials can more effectively prevent and / or hide discoloration compared to other plastic materials. As a more specific example, polypropylene can provide a reduction in discoloration (e.g., a reduction in yellowing) compared to other materials such as polycarbonate. Even more specifically, certain polypropylene blends can be even more effective at preventing and / or hiding discoloration compared to others. As another example, polyethylene is another material that can more effectively prevent and / or hide discoloration compared to other materials. As yet another example, polyesters such as polyethylene terephthalate (PET) and polyethylene terephthalate glycol (PETG) can more effectively prevent and / or hide discoloration compared to other materials. As another example, polystyrene such as polystyrene (PS) or acrylonitrile styrene acrylate (ASA) can also more effectively prevent and / or hide discoloration compared to other materials. Polystyrene can be resistant to oxidation reactions, including those that occur during interaction with NO2. Acrylonitrile butadiene styrene (ABS) can be suitable for specific components of an injection device and / or package because ABS is a white styrenic resin rather than a transparent color, thereby potentially preventing and / or hiding discoloration. The blister pack may be made from any suitable material such as polyethylene terephthalate glycol (PETG).

[0066] The color of the material may also be related to reducing, alleviating, and / or preventing discoloration during the external sterilization process. For example, as described above for ABS, some materials may naturally have certain colors, pigments, or color tones that make them more suitable for reducing, alleviating, and / or preventing discoloration. Additionally or alternatively, by adding a tint to the materials used to form the injection device components and / or the package, discoloration and / or its effects can be blocked. As a more specific example, a blue or gray color tone may be particularly suitable for this purpose. The blue or gray color tone can be added, for example, from a mixture of titanium dioxide (generally for obtaining a white pigment) and / or carbon black (generally for obtaining a black pigment).

[0067] Additives and / or stabilizers may also be used to reduce, alleviate, and / or prevent discoloration during the external sterilization process. For example, increasing the levels of resin additives and stabilizers, such as, but not limited to, antioxidants, may be beneficial in reducing the occurrence of discoloration. As described above, at least some of the discoloration due to NO2 sterilization may be related to the oxidation process, so discoloration can be reduced by minimizing or reducing the effect of oxidation. Such additives are currently added to standard resins, but specially formulated resins with increased amounts of additives may be beneficial for reducing, alleviating, and / or preventing discoloration.

[0068] As yet another example, post-sterilization processes may also be used to reduce, alleviate, and / or prevent discoloration during the external sterilization process. For example, by venting NO2 gas, the effect of discoloration can be reduced. As a more specific example, immediate and / or venting processes or other processes involving exposure to fresh air can reduce and / or alleviate the effect of discoloration. The venting process will be described in more detail below.

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

[0070] Figures 3A - 3C show a package 200 for an infusion device according to another embodiment of the present disclosure. The package 200 includes a support wall 210 for receiving and supporting an infusion device such as the syringe 10 shown in Figures 2A - 2H. The package 200 may be used during various stages of the life cycle of the infusion device, including at least one or more of the following processes: external sterilization, transportation to the user, storage by the user before use, preparation of the infusion device and the infusion site for use, and storage after infusion. For example, at the manufacturing site, the manufacturer can place an assembled prefilled syringe (e.g., syringe barrel, backstop, stopper, plunger rod, drug, and protective cap) into the package such that the assembled prefilled 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 process on the assembled prefilled syringe while the assembled prefilled syringe is being supported by the package 200. Thereafter, the manufacturer may also add a protective coating (not shown) on the top wall 212 of the package to form an airtight seal and define a chamber 214 within the package 200 that protects the assembled prefilled syringe from external air and / or contaminants. The protective coating may be a transparent plastic layer bonded to the package 200 by any suitable means such as an adhesive and / or a heat - sealing process. During another stage of the infusion device's life - style, the user can peel off the protective coating to gain access to the prefilled syringe.

[0071] Package 200 may include projections or spacers to limit surface area contact between the tray and the injection device, thereby reducing or preventing an occluded space therebetween. For example, package 200 may include projection 220 that extends outwardly from support wall 210 of package 200, creating a gap between the injection device and package 200, thereby minimizing or preventing an occluded space between the injection device and package 200. Thereby, the projections or spacers enable an effective connection between the package and the injection device while allowing a sterilizing gas to flow between the components during an external sterilization process. The projections or spacers may also improve (reduce time and / or improve effectiveness) venting of the sterilizing gas after the external sterilization process. Package 200 shown in FIGS. 3A-3C includes two projections 220, although any suitable number may be used. Also, projection 220 shown in FIGS. 3A-3C has a generally pyramidal shape, although any suitable shape may be used. As another example, package 200 may not include a snap-fit configuration with the syringe, but instead may allow the syringe to rest within package 200 and may allow a 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 a space between support wall 210 and the syringe. Also, in such a design, it is preferred that the Tyvek cover prevent the syringe from exiting the package.

[0072] Package 200 includes a central section 240 of the cavity (between the two snap-fit regions 110) that is wider than other known central sections. For example, the distance 244 shown in FIG. 3C is preferably at least 1.5 centimeters in order to provide the user with space to grip the syringe 10 when removing the syringe 10 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 shows a package 300 of an injection device according to another embodiment of the present disclosure. For example, package 300 includes a raised wall section 360. The raised wall section 360 is disposed in the vicinity of the portion of the package 300 that receives the plunger rod and fixes the plunger rod of the injection device and / or prevents unintentional movement of the plunger of the injection device. For example, the package 300 shown 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, and the raised wall section 360 has a side wall 360a for receiving and supporting the plunger rod 16 and another wall 360c extending substantially perpendicular to the support wall 310 and the side wall 360a for receiving the plunger rod end 14 and preventing and / or restricting the distal movement of the plunger rod end 14 (and the entire plunger rod 16) until the syringe 10 is removed from the package 300.

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

[0075] Similarly, it may be desirable to use one or more of the above-described properties to reduce or mitigate discoloration of dyes, colors, additives / stabilizers, etc., or components having a coating added to prevent or ward off discoloration due to NO2 treatment of prefilled syringes, syringe components, and / or packages. In other cases, certain adhesives (e.g., Oliver 27 HT-6 adhesive) may produce desirable results under NO2 external sterilization and may minimize significant signs of discoloration compared to alternatives.

[0076] Of course, the devices and methods according to the present disclosure can have one or more advantages over the prior art, and any one or more of them can exist in a particular embodiment in accordance with the features of the present disclosure included in that embodiment. The same may be understood for other advantages not specifically mentioned herein.

[0077] Preferably, the prefilled syringe does not include an internal coating. The syringe may also include a coating on the outer surface of the syringe that contacts the environment, such as an oxygen barrier coating.

[0078] The syringe barrel may have a length of 45 to 85 mm, 60 to 65 mm, or another suitable length. The length of the syringe barrel is the length between the rear end and the outlet to which the needle is attached (however, if a needle is present, the needle is not included).

[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 can 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 can 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 the entry of sterilizing gas into the interior of the syringe, thereby minimizing or preventing contact with the liquid formulation contained within the prefilled syringe.

[0081] The foregoing description has been directed to 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 with drugs including, but not limited to, the drugs specified below, as well as their generic and biosimilar equivalents. As used herein, the term agent can be used interchangeably with other similar terms and is used to refer to any kind of agent or therapeutic material, including traditional and non-traditional pharmaceuticals, nutraceuticals, supplements, biological agents, biologically active agents and compositions, macromolecules, biosimilars, biological equivalents, therapeutic antibodies, polypeptides, proteins, small molecules, and generic pharmaceuticals. Non-therapeutic injectable materials are also included. The drug 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 the liquid composition filled in 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 more than the amount actually administered to the patient in order to take into account any dead space in the syringe and the needle and losses due to preparing the syringe for injection. Thus, the amount actually administered to the patient can 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 prefilled 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 activity, and / or vascular permeability activity. The VEGF inhibitor is 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, which is currently marketed under the name Eylea® and is also known as 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 IgG1 (Holash et al. (2002) Proc. Natl. Acad. Sci. USA 99(17):11393-11398, WO 00 / 75319(A1) pamphlet).

[0084] In some embodiments, the reservoir of the drug delivery device may be filled with a colony stimulating factor such as granulocyte colony stimulating factor (G-CSF), or the device can be used 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 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) formulation that can 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 in the present invention, "erythropoiesis stimulating protein" means, for example, any protein that binds to a receptor and directly or indirectly causes activation of the erythropoietin receptor by causing dimerization of the receptor. Erythropoiesis stimulating proteins include erythropoietin and its variants, analogs, or derivatives that bind to and activate the erythropoietin receptor, antibodies that bind to and activate the erythropoietin receptor, or peptides that bind to and activate the erythropoietin receptor.Examples of erythropoietin-stimulating proteins include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methoxypolyethylene glycol epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin iota, epoetin omega, epoetin delta, epoetin zeta, epoetin theta, and epoetin delta, PEGylated erythropoietin, carbamylated erythropoietin, and their molecules or variants or analogs, but are not limited thereto.

[0085] Among certain exemplary proteins are the specific proteins described below, including their fusions, fragments, analogs, variants, or derivatives. 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 human monoclonal antibodies; Myostatin-binding proteins, peptibodies, related proteins, etc., including myostatin-specific peptibodies; IL-4 receptor-specific antibodies, peptibodies, related proteins, etc., particularly those that inhibit activities mediated by binding to the receptors for IL-4 and / or IL-13; Interleukin 1-receptor 1 (「IL1-R1」)-specific antibodies, peptibodies, related proteins, etc.; Ang2-specific antibodies, peptibodies, related proteins, etc.; NGF-specific antibodies, peptibodies, related proteins, etc.; CD22-specific antibodies, peptibodies, related proteins, etc., particularly humanized and fully human monoclonal antibodies, including but not limited to human CD22-specific IgG antibodies such as the human CD22-specific fully humanized antibody of epratuzumab (CAS registration number 501423-23-0), which is a dimer of a human-mouse monoclonal hLL2γ chain disulfide bound to a human-mouse monoclonal hLL2κ chain; Humanized and fully human antibodies, including but not limited to humanized and fully human monoclonal antibodies, such as human CD22-specific 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, related proteins, etc. (also referred to as 「B7RP-1」, B7H2, ICOS-L, B7h, and CD275), including but not limited to fully human monoclonal IgG2 antibodies that bind to the epitope of the first immunoglobulin-like domain of B7RP-1, 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; IL-15-specific antibodies, peptibodies, related proteins, etc., including but not limited to HuMax IL-15 antibodies and related proteins, such as 146B7, particularly humanized monoclonal antibodies; Human IFNIFN-γ specific antibodies, peptibodies, related proteins, etc., including but not limited to 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 (「HGF」) specific antibodies, peptibodies, 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 / scatter factor (HGF / SF); TRAIL-R2 specific antibodies, peptibodies, related proteins, etc.; activin A specific antibodies, peptibodies, proteins, etc.; TGF-β specific antibodies, peptibodies, related proteins, etc.; amyloid-β protein specific antibodies, peptibodies, related proteins, etc.; c-Kit specific antibodies, peptibodies, related proteins, etc., including but not limited to proteins that bind to c-Kit and / or other stem cell factor receptors; OX40L specific antibodies, peptibodies, related proteins, etc., including but not limited to proteins that bind to OX40L and / or other ligands of the OX40 receptor; Activase® (alteplase, tPA), Aranesp® (darbepoetin 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-α4β7mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alpha), 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® (sargramostim, rhuGM-CSF), LymphoCide® (epratuzumab, anti-CD22 mAb), Benlysta™ (lynfostat 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 (registered trademark) (IDM-1), OvaRex (registered trademark) (B43.13), Nuvion (registered trademark) (Visilizumab), Cantuzumab mertansine (huC242-DM1), NeoRecormon (registered trademark) (Epoetin beta), Neumega (registered trademark) (Oprelvekin, human interleukin-11), Orthoclone OKT3 (registered trademark) (Muromonab-CD3, anti-CD3 monoclonal antibody), Procrit (registered trademark) (Epoetin alpha), Remicade (registered trademark) (Infliximab, anti-TNFα monoclonal antibody), Reopro (registered trademark) (Abciximab, anti-GP IIb / IIIa receptor monoclonal antibody), Actemra (registered trademark) (anti-IL6 receptor mAb), Avastin (registered trademark) (Bevacizumab), HuMax-CD4 (Zanolimumab), Rituxan (registered trademark) (Rituximab, anti-CD20 mAb), Tarceva (registered trademark) (Erlotinib), Roferon-A (registered trademark) (Interferon α-2a), Simulect (registered trademark) (Basiliximab), Prexige (registered trademark) (Lumiracoxib), Synagis (registered trademark) (Palivizumab), 146B7-CHO (anti-IL15 antibody, see US Patent No. 7,153,507), Tysabri (registered trademark) (Natalizumab, anti-α4 integrin mAb), Valortim (registered trademark) (MDX-1303, anti-anthrax protective antigen mAb), ABthrax (trademark), Xolair (registered trademark) (Omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (Fc portion of human IgG1 and extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)), VEGF trap (Ig domain of VEGFR1 fused to IgG1 Fc), Zenapax (registered trademark) (Daclizumab), Zenapax (registered trademark) (Daclizumab, anti-IL-2Rα mAb), Zevalin (registered trademark) (Ibritumomab tiuxetan), Zetia (registered trademark) (Ezetimibe), Orencia (registered trademark) (Abatacept, 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 (mapatumumab, human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, anti-CD20 human mAb), HuMax-EGFR (zalutumumab), M200 (volociximab, anti-α5β1 integrin mAb), MDX-010 (ipilimumab, anti-CTLA-4 mAb, and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. difficile toxin A and toxin B C 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 idiopathic pulmonary fibrosis phase 1 fibrinogen (FG-3019), anti-CTLA4 mAb, anti-eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2 mAb, anti-ganglioside GM2 mAb, anti-GDF-8 human mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12 mAb (ABT-874), anti-IL12 / IL23 mAb (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), anti-TRAIL receptor-2 human mAb (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, and anti-ZP3 mAb (HuMax-ZP3).

[0086] In some embodiments, the drug delivery device contains a sclerostin antibody such as, but not limited to, romosozumab, blosozumab, or BPS 804 (Novartis). In other embodiments, the drug delivery device may contain or be used with 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 with rilotumumab, vectibix, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the reservoir of the drug delivery device may be filled 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, or the device may be used with these. In some embodiments, the drug delivery device may contain or be used with an endogenous tissue inhibitor of metalloproteinase (TIMP) such as, but not limited to, TIMP-3. Antagonistic antibodies to the human calcitonin gene-related peptide (CGRP) receptor, such as, but not limited to, eptinezumab and bispecific antibody molecules that target the CGRP receptor and other headache targets, may also be delivered using the drug delivery devices of the present disclosure. Additionally, bispecific T cell engager (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 device may contain or be used with an APJ macromolecule agonist such as, but not limited to, apelin or an analog 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 devices of the present disclosure.

[0087] Drug delivery devices, assemblies, components, subsystems, and methods have been described from the perspective of exemplary embodiments, but they are not limited to the exemplary embodiments. This detailed description should be construed as illustrative only and does not describe all possible embodiments 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 are still within the scope of the claims that define the invention disclosed herein.

[0088] Those skilled in the art will understand that various modifications, changes, and combinations can be made to the above embodiments without departing from the spirit and scope of the invention disclosed herein, and such modifications, changes, and combinations should be construed as being within the scope of the concept of the invention.

Claims

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

2. The method according to claim 1, wherein the drug delivery device is a prefilled syringe comprising a barrel, a stopper, a plunger rod, and a backstop, and the barrel contains a drug.

3. The method according to claim 2, wherein the drug is a VEGF inhibitor.

4. The method according to any one of claims 2 to 3, wherein the barrel is a plastic barrel.

5. The vacuum level is a) about 100 to 500 Torr, or b) about 150 to 400 Torr, or c) about 150 to 300 Torr, according to any one of claims 1 to 4.

6. The concentration of the NO₂ dosage is a) about 2 to 10 milligrams per liter, or b) about 2 to 7 milligrams per liter, according to any one of claims 1 to 5.

7. The sterilization chamber has a relative humidity of about 70 to 90 percent, according to any one of claims 1 to 6.

8. The residence time is a) about 2 to 12 minutes, or b) about 2 to 7 minutes, according to any one of claims 1 to 7.

9. The number of pulses is a) about 1 to 12, or b) about 1 to 8, or c) about 1 to 4, or d) about 1 to 2, according to any one of claims 1 to 8.

10. The step of venting the sterilization chamber includes venting the sterilization chamber a number of cycles of about 12 to 70 to at least substantially prevent discoloration of the drug delivery device, according to any one of claims 1 to 9.

11. The method for externally sterilizing the drug delivery device is (a) achieve at least a 2-log reduction of the microorganism, (b) achieve at least a 3-log reduction of the microorganism, (c) achieve at least a 4-log reduction of the microorganism, (d) achieve at least a 5-log reduction of the microorganism, or (e) achieve at least a 6-log reduction of the microorganism, the method according to any one of claims 1 to 10.

12. A method for externally sterilizing a drug delivery device using nitrogen dioxide (NO₂), comprising the steps of placing the drug delivery device in a sterilization chamber; applying a vacuum level of about 150 to 500 Torr and introducing into the sterilization chamber a NO₂ dosage having a concentration of about 5 to 20 milligrams per liter by maintaining the vacuum level for a residence time of about 5 to 10 minutes; repeating the step of introducing the NO₂ dosage into the sterilization chamber over a pulse number of about 1 to 8; purging at least substantially all of the NO₂ from the sterilization chamber; venting the sterilization chamber for a cycle number of about 20 to 90, the method comprising.

13. A method for externally sterilizing a prefilled syringe having a drug container and a drug contained in the drug container, comprising the steps of placing the prefilled syringe in a sterilization chamber; applying a predetermined vacuum level and introducing into the sterilization chamber a nitrogen dioxide (NO₂) dosage having a predetermined concentration by maintaining the vacuum level for a predetermined residence time; repeating the step of introducing the NO₂ dosage into the sterilization chamber over a predetermined pulse number; purging at least substantially all of the NO₂ from the sterilization chamber; venting the sterilization chamber for a predetermined cycle number, having achieving at least a log 6 lethality target with respect to the prefilled syringe and realizing an ingress rate of NO₂ gas into the drug container of less than 3.0 parts per million in a measurement 30 days after externally sterilizing the prefilled syringe, the method.

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