Method of assessing stopper movement in a drug delivery device

Abstract

A method of assessing stopper movement in a syringe is provided, the syringe including a syringe barrel and a stopper movably disposed within the syringe barrel. The method includes seeding biological particles through an open proximal end of the syringe barrel such that the biological particles cover at least a portion of an interface between a proximal face of the stopper and an inner wall of the syringe barrel. A lumen of the syringe contains a fill volume of liquid. Thereafter, the method includes subjecting the syringe to one or more conditions, extracting the fill volume of liquid from the lumen of the syringe, performing a sterility test on the extracted fill volume of liquid, and determining stopper movement in the syringe based on the sterility test.

Description

Technical Field

[0001] This disclosure generally relates to injection devices used for drug delivery. More specifically, this disclosure generally relates to a method for assessing stopper movement in a drug delivery device (such as a syringe) and determining any risk of contamination of the drug product due to breach of container seal integrity (CCI). Background Technology

[0002] As is known in the art, a syringe is a medical delivery device for administering medication to a patient. Syringes are typically sold in pre-filled form (i.e., pre-filled syringes), in which a pre-dose dose of medication is already provided, or they are empty and intended to be filled by the end user from a vial or other source of medication when medication is required.

[0003] Syringes typically include a barrel portion adapted to contain a medication. The distal end of the barrel is usually configured to include, or engage with, a conventional piercing element (such as a needle cannula or a flat-end cannula) to deliver the medication contained within the barrel. The piercing element can be made of steel, plastic, or any other suitable material. A plunger rod can be inserted through the open proximal end of the syringe barrel, and through its engagement with an elastomeric or rubber-like stopper element fitted within the syringe barrel in a substantially leak-proof manner, the user can apply manual force to the plunger to deliver the medication through the piercing element.

[0004] Sterilization of the outer surface of syringes may be desired or required while maintaining container seal integrity (CCI) to prevent contamination of the medication or pharmaceutical product contained within the syringe barrel. External sterilization typically occurs after prefilled syringes have been filled, fully assembled, and are located in at least some part(s) of their final packaging. For certain usage instructions (e.g., certain ophthalmological instructions), federal regulations may require external sterilization under certain conditions, parameters, and / or results.

[0005] However, pre-filled syringes or their components may move due to pressure changes and other conditions that can occur during manufacturing, assembly, and external sterilization, and one or more components (such as the stopper) may move within the pre-filled syringe due to various shipping, handling, and transport conditions. Furthermore, external sterilization of pre-filled syringes can present additional challenges. For example, the stopper may move within the syringe barrel due to various conditions during the external sterilization process (such as pressure differences that may occur during external sterilization). If the stopper moves beyond the sterile barrier height of the stopper (i.e., the distance from rib to rib) before external sterilization, a breach of the container seal integrity may occur, and the medication or drug product within the pre-filled syringe cavity may be potentially contaminated due to contact between the medication or drug product and the non-sterile surface of the syringe barrel.

[0006] Conventional methods exist for indirect analysis of the risk of pharmaceutical product contamination due to stopper movement and related breaches of container seal integrity. However, these conventional methods for assessing stopper movement and analyzing pharmaceutical product contamination risk only provide indirect analysis because they rely on measuring stopper movement under simulated conditions. The various assumptions and theoretical parameters incorporated in existing simulation methods not only create ambiguity but also fail to provide an accurate and commercially representative assessment of stopper movement and pharmaceutical product contamination risk in pre-filled syringes. Therefore, an improved and accurate method is needed to directly assess stopper movement in pre-filled syringes and determine any risk of pharmaceutical product contamination due to breaches of container seal integrity.

[0007] This disclosure describes methods for implementing advantageous alternatives to existing approaches that can address one or more of the challenges or needs mentioned herein, as well as provide additional benefits and advantages. Summary of the Invention

[0008] According to embodiments of this disclosure, a method for evaluating stopper movement in a syringe is provided, the syringe including a syringe barrel and a stopper movably disposed within the syringe barrel. The method includes inoculating the syringe barrel with biological particles through an open proximal end such that the biological particles cover at least a portion of the interface between the proximal side of the stopper and the inner wall of the syringe barrel. A cavity of the syringe contains a fill volume of liquid. The method further includes subjecting the syringe to one or more conditions, extracting a fill volume of liquid from the syringe cavity, performing a sterility test on the extracted fill volume of liquid, and determining stopper movement in the syringe based on the sterility test.

[0009] In some embodiments, subjecting the syringe to one or more conditions may include at least one of the following: externally sterilizing the syringe, subjecting the syringe to shipping and handling conditions, or performing a manufacturing process using the syringe. In some embodiments, subjecting the syringe to one or more conditions may include externally sterilizing the syringe, and externally sterilizing the syringe may include placing the syringe in a sterilization chamber, introducing a dose of sterilizing agent gas into the sterilization chamber and applying a predetermined vacuum level, maintaining the vacuum level for a predetermined residence time, and purging at least substantially all of the sterilizing agent gas from the sterilization chamber.

[0010] In some embodiments, the stopper may include a body portion having generally cylindrical sidewalls and one or more ribs projecting radially outward from the sidewalls of the body portion near the proximal side of the stopper. The one or more ribs of the stopper may be configured to form a leak-proof relationship with the cavity of the syringe. In some embodiments, the method may further include inoculating bioparticles through the open proximal end of the syringe barrel such that the bioparticles cover at least a portion of the interface between the one or more ribs near the proximal side of the stopper and the inner wall of the syringe barrel.

[0011] In some embodiments, biological particles may be inoculated at multiple locations around the diameter of the proximal side of the stopper along the interface between the proximal side of the stopper and the inner wall of the syringe barrel. In some embodiments, the biological particles may comprise at least one of the following: microorganisms, fungi, bacteria, spores, viruses, biological cells, biological antigens, proteins, or protein antigens.

[0012] In other embodiments, performing a sterility test on the extracted liquid may include suspending the extracted liquid in a test medium containing tryptone soy broth (TSB) or thioglycolate fluid medium (FTM) and determining whether the extracted liquid contains biological particles. The presence of biological particles in the extracted liquid can indicate stopper movement in the syringe. In other embodiments, the filling volume of the liquid may include a test medium containing tryptone soy broth (TSB) or thioglycolate fluid medium (FTM), and performing a sterility test on the extracted liquid may include determining whether the extracted liquid contains biological particles.

[0013] In some embodiments, the syringe barrel may include a distal end configured to support a needle. An open proximal end of the syringe barrel may be configured to receive a plunger rod configured to push a stopper toward the distal end of the syringe barrel in a distal direction. In some embodiments, the syringe may be a pre-filled syringe, and the syringe barrel of the pre-filled syringe may be configured to contain a drug substance. In other embodiments, the proximal side of the stopper may include a convex surface. In yet another embodiment, the proximal side of the stopper may include a plurality of protrusions projecting axially from the proximal side. In some embodiments, the method may further include identifying a risk of drug product contamination based at least on determined stopper movement. A risk of drug product contamination may exist when the distance the stopper moves is greater than or equal to the axial length of the stopper.

[0014] According to another embodiment of this disclosure, a method is provided for determining the risk of contamination of a pharmaceutical product in a syringe, the syringe including a syringe barrel and a stopper movably disposed within the syringe barrel. The method includes inoculating the syringe barrel with biological particles through an open proximal end such that the biological particles cover at least a portion of the interface between the proximal side of the stopper and the inner wall of the syringe barrel. The syringe cavity contains a fill volume of liquid, and the biological particles include at least one of the following: microorganisms, fungi, bacteria, spores, viruses, biological cells, biological antigens, proteins, or protein antigens. The method further includes subjecting the syringe to one or more conditions, extracting the fill volume of liquid from the syringe cavity, performing a sterility test on the extracted fill volume of liquid, determining stopper movement in the syringe based on the sterility test, and identifying the risk of pharmaceutical product contamination based at least on the determined stopper movement. A risk of pharmaceutical product contamination exists when the stopper moves a distance greater than or equal to the axial length of the stopper.

[0015] In some embodiments, subjecting the syringe to one or more conditions may include at least one of the following: externally sterilizing the syringe, subjecting the syringe to shipping and handling conditions, or performing a manufacturing process using the syringe. In other embodiments, subjecting the syringe to one or more conditions may include externally sterilizing the syringe, and externally sterilizing the syringe may include placing the syringe in a sterilization chamber, introducing a dose of sterilizing agent gas into the sterilization chamber and applying a predetermined vacuum level, maintaining the vacuum level for a predetermined residence time, and purging at least substantially all of the sterilizing agent gas from the sterilization chamber.

[0016] In some embodiments, the stopper may include a body portion having generally cylindrical sidewalls and one or more ribs projecting radially outward from the sidewalls of the body portion near the proximal side of the stopper. The one or more ribs of the stopper may be configured to form a leak-proof relationship with the cavity of the syringe. In some embodiments, the method may further include inoculating bioparticles through the open proximal end of the syringe barrel such that the bioparticles cover at least a portion of the interface between the one or more ribs near the proximal side of the stopper and the inner wall of the syringe barrel.

[0017] In some embodiments, bioparticles may be inoculated at multiple locations around the diameter of the proximal side of the stopper at the interface between the proximal side of the stopper and the inner wall of the syringe barrel. In other embodiments, performing a sterility test on the extracted liquid may include suspending the extracted liquid in a test medium containing tryptone soy broth (TSB) or thioglycolate fluid medium (FTM) and determining whether the extracted liquid contains bioparticles. The presence of bioparticles in the extracted liquid may indicate stopper movement in the syringe. In other embodiments, the filling volume of the liquid may include a test medium containing tryptone soy broth (TSB) or thioglycolate fluid medium (FTM), and performing a sterility test on the extracted liquid may include determining whether the extracted liquid contains bioparticles.

[0018] In some embodiments, the syringe barrel may include a distal end configured to support a needle. An open proximal end of the syringe barrel may be configured to receive a plunger rod configured to push a stopper toward the distal end of the syringe barrel in a distal direction. In some embodiments, the syringe may be a pre-filled syringe, and the syringe barrel of the pre-filled syringe may be configured to contain a drug. In other embodiments, the proximal side of the stopper may include a convex surface. In yet another embodiment, the proximal side of the stopper may include a plurality of protrusions projecting axially from the proximal side. Attached Figure Description

[0019] We believe that this disclosure will be more fully understood from the following description taken in conjunction with the accompanying drawings. To illustrate other elements more clearly, some drawings may be simplified by omitting selected elements. In some drawings, such omission of elements does not necessarily indicate the presence or absence of a particular element in any exemplary embodiment, unless it can be clearly indicated in the corresponding written description. Furthermore, not all drawings need to be drawn to scale.

[0020] Figure 1 This is a front view of an exemplary drug delivery device according to different embodiments of this disclosure.

[0021] Figure 2 Different embodiments based on this disclosure Figure 1An exploded cross-sectional view of an exemplary syringe barrel of an exemplary drug delivery device.

[0022] Figure 3 These are examples of inoculating biological particles using exemplary methods according to different embodiments of this disclosure. Figure 2 A cross-sectional view of an exemplary syringe barrel.

[0023] Figure 4 This refers to a different embodiment of the present disclosure, using another exemplary method to inoculate biological particles. Figure 2 A cross-sectional view of an exemplary syringe barrel.

[0024] Figure 5 This refers to a different embodiment of the present disclosure, using another exemplary method to inoculate biological particles. Figure 2 A cross-sectional view of an exemplary syringe barrel.

[0025] Figure 6A This is a perspective view of another exemplary plug according to different embodiments of the present disclosure.

[0026] Figure 6B It is configured to be consistent with different embodiments of this disclosure. Figure 6A A perspective view of another exemplary plunger rod in the form of an exemplary plug engagement.

[0027] Figure 7A This is a perspective view of another exemplary plug according to different embodiments of the present disclosure.

[0028] Figure 7B It is configured to be consistent with different embodiments of this disclosure. Figure 7A A perspective view of another exemplary plunger rod in the form of an exemplary plug engagement.

[0029] Figure 8 This is a flowchart illustrating an exemplary method for evaluating stopper movement in a prefilled syringe according to different embodiments of this disclosure.

[0030] Figure 9 This is a flowchart illustrating an exemplary method for determining the risk of contamination of a pharmaceutical product in a pre-filled syringe according to different embodiments of this disclosure. Detailed Implementation

[0031] This disclosure generally relates to injection devices that can be safely and reliably activated by a user to administer a drug or, in the case of a patient self-administering the drug. More specifically, this disclosure generally relates to methods for assessing the movement of components of a drug delivery device, in some examples, which includes a syringe stopper (also referred to as a "plunger stopper"). The drug delivery device and injection device can be a syringe, such as a pre-filled syringe containing a drug substance. Additionally, this disclosure generally relates to methods for identifying and / or determining the risk of drug product contamination from a drug delivery device, in some examples, which includes a syringe, such as a pre-filled syringe. Using the methods described herein and variations thereof, the movement of the stopper within the syringe can be assessed directly and accurately, and any risk of drug product contamination due to breaches of container seal integrity can also be assessed.

[0032] Figure 1 This is a front view of an exemplary drug delivery device (such as syringe 10) according to different embodiments of this disclosure. Syringe 10 generally includes: a syringe barrel 11 having an open proximal end 11a, a distal end 11b, and a cavity 19; a flange portion 12; a plunger rod 16; and a stopper 18 (also referred to as a "plunger stopper") movably disposed within the cavity 19 of the syringe barrel 11. The syringe barrel 11 also includes an annular inner wall 13 defining the cavity 19 of the syringe barrel 11. The stopper 18 may be movably disposed within the cavity 19, and the stopper 18 may abut against the annular inner wall 13 to form a leak-proof relationship with the cavity 19 of the syringe 10. Syringe 10 may be a pre-filled syringe, and syringe barrel 11 may be pre-filled with a drug or pharmaceutical agent.

[0033] The distal end 11b of the syringe barrel 11 may be configured to receive and / or support a needle or other component suitable for completing a fluid pathway into a patient's body. For example, the distal end 11b of the syringe barrel 11 may include a Luer lock component 17. In some embodiments, the Luer lock component 17 may be configured to receive a needle or other component suitable for completing a fluid pathway into a patient's body, such as a cannula. The open proximal end 11a of the syringe barrel 11 may be configured to receive a plunger rod 16 for pushing a stopper 18 distally toward the distal end 11b of the syringe barrel 11 and dispensing a fill volume 20 of medication or agent from the cavity 19 of the syringe 10. For example, the stopper 18 may form a leak-proof relationship with the cavity 19 of the syringe 10 while also being able to travel distally along the cavity 19 and advance a fill volume 20 of medication from the distal end 11b of the syringe barrel 11. The fill volume 20 may refer to the volume of any liquid (such as a medication or agent) contained within the syringe barrel 11.

[0034] The plunger rod 16 may include a plunger rod end 14 with a diameter larger than that of the body portion of the plunger rod 16 to limit the travel distance of the plunger rod 16 in the distal direction and / or to make it easier for the user to press the plunger rod 16. The stopper 18 may be a one-way component, and the plunger rod 16 may not be fixedly connected to the stopper 18, such that if the plunger rod 16 moves in the proximal direction (opposite to the distal direction), the stopper 18 will not move with the plunger rod 16.

[0035] In some embodiments, 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: certain grades of polypropylene (homopolymer and / or copolymer polypropylene), cyclic olefin copolymers, cyclic olefin polymers, cyclic olefin copolymers (COC), cyclic olefin polymers (COP), or other suitable materials. As a more specific example, the syringe barrel 11 may be made of a cyclic olefin polymer (COP).

[0036] The diameter of flange 12 can be larger than the diameter of syringe barrel 11 and can serve as a finger rest to allow the user to manipulate syringe 10 during use. For example, the user can place two or more of their fingers on flange 12 when pressing the plunger rod end 14 with their thumb. Flange 12 can have a generally elliptical or oblong configuration, with a width 12a of approximately 13 mm, and the diameter of syringe barrel 11 can be approximately 9.5 mm. Therefore, flange 12 can have an effective gripping surface of approximately 2 mm on each side of flange 12.

[0037] The syringe barrel 11 may have a length of approximately 45 mm to 85 mm, approximately 60 mm to 65 mm, or another suitable length. The length of the syringe barrel 11 is the length between the proximal end 11a and the distal end 11b (excluding the needle, if present). The syringe barrel 11 may have an inner diameter of approximately 4 mm to 6.5 mm. If the syringe 10 has a nominal maximum filling volume 20 of approximately 1 ml, the inner diameter of the syringe barrel 11 may be approximately 5.5 mm to 6.5 mm. If the syringe 10 has a nominal maximum filling volume 20 of approximately 0.5 ml, the inner diameter of the syringe barrel 11 may be approximately 4 mm to 5 mm. Additionally, the wall of the syringe barrel 11 may have a thickness of at least 1 mm; approximately 1 mm to 3 mm; approximately 1.5 mm to 3 mm; or approximately 2.4 mm to 2.8 mm.

[0038] In some embodiments, it may be desirable and / or regulations may require external sterilization of the injection device (e.g., syringe 10) during manufacturing and / or assembly. Additionally, certain applications of pre-filled syringes (e.g., certain ophthalmic applications) require external sterilization. For example, 21 CFR 200.50 states that “ophthalmic preparations and dispensers shall be sterile.” Furthermore, ANSI / AAMI ST67:2011 / (R)2017 states: “Sterilization of health care products – Requirements and guidance for selecting a sterility assurance level (SAL) for products labeled as ‘sterile’” – Section 4.1.1 states: “Generally, a SAL value of 10⁻⁶ is used for the terminal sterilization of health care products.” Additionally, Annex A of ST67 and EN556-1:2006 provides: “Sterilization of medical devices – Requirements for medical devices to be labeled as ‘sterile’ – Part 1: Requirements for terminally sterilized medical devices”… Section 4.1 states: “For a terminally sterilized medical device to be labeled as ‘sterile,’ the theoretical probability of the presence of viable microorganisms on / within the device should be equal to or less than 1 × 10⁻⁶.” Therefore, a bioburden of less than 1 × 10⁻⁶ (e.g., 1 × 10⁻⁶) may be expected and / or required. -6 ).

[0039] As used herein, the terms “external sterilization” and / or “performing external sterilization” refer to the process of sterilizing an injection device (such as syringe 10) after it has been assembled. For example, the injection device may be externally sterilized after syringe 10 (containing medication in cavity 19), plunger 16, stopper 18, and protective cap (not shown) have been fully assembled and sealed in a blister tray with a vented cap that acts as a sterile barrier while allowing gas and airflow (such as sterilizing agent gas). During external sterilization, the syringe 10 can be placed in a sterilization chamber and exposed to sterilizing gases (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 under other specified conditions (e.g., temperature and pressure). Then, after a sterilization cycle, the sterilizing gases are removed from the chamber, and the syringe device is left in the chamber (substantially or completely free of sterilizing gases) for another predetermined length of time, and under other specified conditions (e.g., temperature and pressure). The external sterilization process also... The external sterilization process may include a drying phase prior to sterilizer injection and a gas-filling phase following sterilizer removal. For each type of phase, several vacuum pressures are applied and released as pressure evacuation and pressure injection, respectively, to remove humidity from the chamber or to remove sterilizer gas from the load and the chamber. The external sterilization process may also include a humidification phase just prior to sterilizer gas injection, in which humidified air is injected into the sterilization chamber in one or more pulses. The external sterilization process may also include multiple sets of phases, including sterilizer gas injection and residence phases, where each set of phases may constitute a sterilizer pulse.

[0040] For example, in order to assemble and externally sterilize syringe 10, according to different embodiments of this disclosure, at least some individual components of syringe 10 may be sterilized first, typically before being received by the manufacturing facility. For instance, syringe barrel 11 and stopper 18, as well as any other components that may come into direct contact with the drug product or agent, may be sterilized during an initial step. This step can utilize a wide variety of known techniques to sterilize the individual unassembled components of the drug delivery device. Afterward, syringe barrel 11 may be filled with the drug product or agent, and stopper 18 may be assembled or movably disposed within syringe barrel 11. This assembly step may also include adding at least some of the following: plunger rod 16, end cap with Luer lock 17, needle, rigid needle guard, and / or protective cap. At least some of these components may be pre-assembled with each other, but they may also be assembled on a filling line, for example, if the filling process is performed aseptically. Afterward, the assembled syringe 10 may be placed in packaging (e.g., secondary packaging) at the manufacturing or assembly site. The packaged syringe 10 may then be externally sterilized. While the assembled syringe 10 is supported by and contained within the packaging, an external sterilization step can be performed on the syringe 10.

[0041] In order to perform external sterilization of the syringe 10, in some embodiments, it may be necessary to pre-treat the syringe 10. For processes utilizing nitrogen dioxide (NO2), pre-treatment may include at least some or all of the following steps: removing the syringe 10 from the storage device, allowing the syringe 10 to equilibrate to room temperature for a desired amount of time (e.g., 30 minutes, 90 minutes, 2 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, or any desired amount of time), and then placing the syringe 10 into a sterilization chamber. Pre-treatment can be performed inside or outside the sterilization chamber.

[0042] When using ethylene oxide (EtO), the pretreatment steps can vary slightly from those described for NO2. For example, the syringe 10 can be pretreated (without gas injection) inside the sterilization chamber for 360 minutes (or another desired duration). However, as with the process using NO2, the pretreatment steps using EtO can be performed inside or outside the sterilization chamber. Furthermore, although the gas-filling step is typically performed inside the sterilization chamber, it can also be performed outside the sterilization chamber when using EtO.

[0043] Next, the sterilization chamber can be closed, and all or substantially all of the air can be extracted from it. Next, the sterilization chamber can be humidified to a desired setpoint, such as 75 or 80 (or any desired percentage of relative humidity). Next, the desired sterilizing gas (also referred to as "sterilizing agent gas") can be injected into the sterilization chamber and held in the sterilization chamber for the desired residence time. For schemes utilizing NO2, the sterilizing agent gas injection step may include some or all of the following steps: delivering a dose of NO2 by injecting a desired amount of sterilizing agent gas (dose concentration) while maintaining a vacuum in the sterilization chamber for a desired amount of time (i.e., residence time), purging the sterilizing agent gas and releasing the vacuum, and then repeating these steps for a desired number of pulses. Once the desired number of pulses has been completed, the sterilizing agent gas can be finally purged, thus removing it from the sterilization chamber. Finally, the sterilization chamber can be inflated for the desired number of cycles to ensure that all or substantially all of the sterilizing gas has been flushed out of the syringe 10. In some examples, the vacuum level may vary during these steps; for example, the vacuum may be at its minimum during the residence time, such as approximately 590 Torr.

[0044] The aforementioned external sterilization methods can include any suitable parameters, such as:

[0045] - The vacuum level can be between approximately 100 and 500 Torr, between approximately 150 and 400 Torr, between approximately 150 and 300 Torr, or another suitable vacuum level.

[0046] The concentration of NO2 can be between about 2 to 20 mg per liter, between about 2 to 10 mg per liter, between about 2 to 7 mg per liter, or another suitable concentration.

[0047] The relative humidity of the room can be between approximately 70% and 90%, or another suitable humidity.

[0048] - The stay can be between approximately 2 to 20 minutes, between approximately 2 to 12 minutes, between approximately 2 to 7 minutes, or another suitable stay.

[0049] - The number of pulses can be between approximately 1 and 24, between approximately 1 and 12, between approximately 1 and 8, between approximately 1 and 4, between approximately 1 and 2, or another suitable number of pulses.

[0050] - The step of inflating the sterilization chamber may include inflating the sterilization chamber to a number of cycles between approximately 100 and 400, approximately 150 and 350, or another suitable number of cycles.

[0051] However, during the aforementioned external sterilization process, for example due to pressure changes in the sterilization chamber, one or more individual components of the injection device (such as the stopper 18 of the syringe 10) may be easily moved within the syringe barrel 11. Additionally, when the syringe 10 is shipped to the manufacturing facility or when it is assembled at the filling line, one or more individual components of the syringe 10 (such as the stopper 18 movably disposed within the syringe barrel 11) may be easily moved in response to various shipping and handling conditions. Finally, when individual components (such as the plunger rod 16) are being manufactured and assembled into the syringe 10 separately, the stopper 18 may move during manufacturing and assembly.

[0052] Any movement of the stopper 18 in the syringe 10 could pose a potential risk of drug product contamination due to the contact between the filled volume of drug or agent contained in the cavity 19 and the non-sterile surface of the syringe barrel 11. Figure 2 An exploded front view of the syringe barrel 11 of the syringe 10 according to different embodiments of this disclosure is shown. Figure 2 As shown, the stopper 18 includes a body portion 203 having generally cylindrical sidewalls and a plurality of ribs 202a, 202b projecting radially outward from the sidewalls of the body portion 203. A first rib 202a may project radially outward from the sidewall of the body portion 203 near the proximal side 201 of the stopper 18, while a second rib 202b may project radially outward from the sidewall of the body portion 203 near the distal side 204 of the stopper 18. As used herein, the “proximal side” of the stopper refers to the side of the stopper opposite to and not in contact with the filling volume, while the “distal side” of the stopper refers to the side of the stopper in contact with the filling volume. The sidewalls of the ribs 202a, 202b may abut against the annular inner wall 13 of the syringe barrel 11 around its entire diameter. Accordingly, the ribs 202a and 202b can be configured to form a leak-proof relationship between the stopper 18 and the cavity 19 of the syringe barrel 11, so that the drug or agent in the filling volume 20 below the distal side 204 of the stopper 18 cannot travel in the proximal direction across the distal side 204 of the stopper 18. Although Figure 2 A plug 18 with two ribs 202a and 202b is shown, but the plug 18 can have any number of ribs that project radially outward from the sidewall of the body portion 203 and form a leak-proof relationship with the cavity 19. For example, the plug 18 can have one rib, three ribs, four ribs, five ribs, or six ribs. In other embodiments, the plug 18 may not have ribs.

[0053] In some embodiments, such as Figures 2 to 5As shown, the proximal side 201 of the stopper 18 may further include a convex surface 220. The convex surface 220 may be configured to allow gravity to pull any inoculated bioparticles or liquid inoculum towards the outer periphery of the rib 202a, and to ensure that the inoculated bioparticles cover the interface between the rib 202a of the stopper 18 and the annular inner wall 13 of the syringe barrel 11. Therefore, the convex surface 220 allows gravity to help ensure that the inoculated bioparticles are present at the interface between the edge of the rib 202a and the annular inner wall 13 of the syringe barrel 11.

[0054] refer to Figure 2 For example, if the amount of movement of the stopper 18 in the proximal direction (towards the proximal end 11a of the syringe barrel 11) is equal to or exceeds the axial length between the proximal side 201 and the distal side 204 of the stopper 18 (i.e., Figure 2 If the “sterile barrier height” is not properly defined, a breach of container seal integrity (CCI) may occur. That is, because the sterile area of ​​the cavity 19 of the syringe barrel 11, containing a fill volume 20 of drug or pharmaceutical agent, comes into contact with the non-sterile area of ​​the syringe barrel 11, there is a potential risk of contamination of the pharmaceutical product. Therefore, it may be crucial to assess whether any stopper movement will occur during shipping, handling, manufacturing, or assembly, and during any external sterilization process, before assembling and externally sterilizing the syringe to ensure that any pharmaceutical product contained within the syringe is not contaminated. As used herein, the “sterile barrier height” of the stopper may refer to (a) the distance between the nearest side surface of the stopper in contact with the inner wall of the syringe barrel 11 and (b) the farthest side surface of the stopper in contact with the inner wall of the syringe barrel 11. For example, in… Figure 2 In this context, the sterile barrier height refers to the distance between the proximal end of the proximal side 201 of the stopper 18 that contacts the inner wall of the syringe barrel 11 and the distal end of the distal side 204 that contacts the inner wall of the syringe barrel 11.

[0055] As stated above, conventional methods exist for indirect analysis of the risk of pharmaceutical product contamination due to stopper movement and related breaches of container seal integrity. For example, conventional methods (such as charcoal displacement testing, microbial intrusion testing, dye intrusion testing, and mass extraction testing) primarily assess stopper movement indirectly based on measuring the final distance traveled by the stopper under simulated conditions. Because conventional assessments are performed under simulated conditions, the various assumptions made about the syringe configuration and the theoretical worst-case conditions used not only create ambiguity in the assessment but also fail to provide an accurate assessment of the risk of stopper movement and pharmaceutical product contamination within the syringe. This disclosure describes advantageous alternatives to these conventional methods that can address one or more of the challenges or needs mentioned herein, as well as provide additional benefits and advantages.

[0056] For example, Figure 8 Method 800 for evaluating stopper movement in a syringe by directly inoculating biological particles into the syringe barrel and onto the proximal side of the stopper, according to different embodiments of this disclosure, is illustrated. Method 800 will refer to Figures 3 to 5 The figures described herein illustrate an exploded front view of the syringe barrel 11 of a syringe 10 according to a different embodiment of the present disclosure, wherein a stopper 18 is movably disposed within a cavity 19 of the syringe barrel 11. The cavity 19 may contain a liquid (such as a drug or agent) in a fill volume 20. In other embodiments, the cavity 19 may contain a test solution instead of a drug or agent in a fill volume 20.

[0057] refer to Figures 3 to 5 and Figure 8 The method 800 for evaluating the movement of the stopper 18 in the syringe 10 begins at step 802. At step 802, the bioparticle 300 is passed through the open proximal end 11a of the syringe barrel 11 (… Figure 1 (As shown) Directly inoculate and inoculate onto the proximal side 201 of the stopper 18. Inoculate the bioparticles 300 such that the bioparticles 300 cover at least a portion of the interface between the proximal side 201 of the first rib 202a of the stopper 18 and the annular inner wall 13 of the syringe barrel 11. Accordingly, this method of assessing stopper movement will ensure that the bioparticles 300 are inoculated in a non-sterile area (as shown). Figure 2 At the precise location shown, if the stopper 18 moves beyond the sterile barrier height during the process of interest, that location will first come into contact with the drug or agent in the filling volume 20.

[0058] like Figure 3 As shown, the bioparticles 300 can be directly inoculated onto the proximal side 201 of the stopper 18, such that the bioparticles 300 cover (1) the entire proximal side 201, and (2) the interface between the proximal side 201 of the first rib 202a and the annular inner wall 13 of the syringe barrel 11. In other embodiments, such as Figure 4 As shown, the bioparticles 300 can be directly inoculated onto the interface between the proximal side 201 and the annular inner wall 13 of the syringe barrel 11 by scribing. This scribing method can minimize the increased resistance to stopper movement that may be caused by the inoculation of the bioparticles 300. Although Figure 4 The illustration shows the inoculation of bioparticles 300 with a single streak, but any number of individual streaks can be used to inoculate bioparticles 300. In yet another embodiment, as... Figure 5As shown, a rod with a foam or sponge-like tip can be used to directly inoculate the bioparticles 300 at the interface between the proximal side 201 and the annular inner wall 13 of the syringe barrel 11 using a single indentation. The profile of the rod is configured to conform to the shape of this interface. The bioparticles 300 can be inoculated at one or more locations around the diameter of the proximal side 201 of the stopper 18. For example, as... Figure 4 As shown, the bioparticle 300 can be seeded at a location around the diameter of the proximal side 201 along the interface between the proximal side 201 and the annular inner wall 13. Alternatively, as Figure 5 As shown, the bioparticles 300 can be inoculated at multiple locations around the diameter of the proximal side 201 along the interface between the proximal side 201 and the annular inner wall 13.

[0059] In some embodiments, the bioparticles 300 are liquid inoculums comprising at least one of the following: microorganisms, fungi, bacteria, spores, viruses, biological cells, biological antigens, proteins, or protein antigens. For example, the bioparticles 300 may comprise a bacterial spore suspension of approximately 10^5 or 10^5 CFU / mL.

[0060] Return to reference Figure 8 Once the syringe barrel 11 is inoculated with the biological particles 300, at step 804, the inoculated syringe 10 can be subjected to one or more conditions. That is, at step 804, one or more actual processes of interest can be performed with the inoculated syringe 10. For example, the inoculated syringe 10 can be subjected to the aforementioned actual external sterilization process, actual manufacturing process, actual syringe assembly process, actual shipping and handling conditions during manufacturing, assembly, and / or transportation, and / or any combination thereof. Additionally or alternatively, the inoculated syringe 10 can be subjected to nominal or adjusted parameters of one or more actual processes of interest, as well as test conditions. The parameters and test conditions can be selected to ensure that the stopper movement of the syringe 10 is assessed under conditions at or above the upper or lower limits of the parameters of the process of interest (i.e., increasing stopper movement beyond what is normally expected under the nominal parameters).

[0061] After subjecting syringe 10 to one or more conditions, method 800 may proceed to step 806, whereby liquid of fill volume 20 is extracted from the cavity 19 of syringe 10. In some embodiments, the liquid of fill volume 20 may have been pre-validated as sterile prior to step 804. At step 808, a sterility test may be performed on the extracted liquid of fill volume 20. Specifically, the extracted liquid of fill volume 20 may be suspended in a test medium. In some embodiments, the test medium may contain tryptone soy broth (TSB) or thioglycolate fluid medium (FTM). If any viable biological particles 300 are present in the extracted liquid of fill volume 20, the test medium may become turbid. Accordingly, if the test medium becomes turbid after the extracted liquid of fill volume 20 is suspended in the test medium, this may indicate a positive growth result (i.e., the presence of biological particles 300 in the extracted liquid of fill volume 20), and thus indicate that the movement of the stopper 18 in syringe 10 exceeds the sterility barrier height of the stopper, and the potential risk of drug product contamination in practice. On the other hand, if the sterility test yields a negative growth result, and the test medium does not become turbid after the extracted fill volume 20 is suspended in the test medium, this indicates that any movement of the stopper 18 has not exceeded the sterility barrier height of the stopper, and no risk of drug product contamination has been identified in practice. Therefore, at step 810, it can be determined whether any movement of the stopper 18 in the syringe 10 exceeds its sterility barrier height and causes drug product contamination based on the sterility test performed. In some embodiments, instead of suspending the extracted fill volume 20 in the test medium, the fill volume 20 may already contain the test medium, such as TSB or FTM. Accordingly, after extracting the liquid from the fill volume 20 at step 806, a sterility test can be performed directly on the extracted fill volume 20 at step 808 without first suspending the extracted fill volume 20 in the test medium.

[0062] Figure 9 A method 900 for determining the risk of contamination of a pharmaceutical product in a syringe according to different embodiments of this disclosure is illustrated. Similar to method 800, method 900 begins at step 902, where bioparticles 300 are passed through the open proximal end 11a of syringe barrel 11 ( Figure 1(As shown) The bioparticles 300 are directly inoculated onto the proximal side 201 of the stopper 18. Once the syringe barrel 11 is inoculated with the bioparticles 300, at step 904, the inoculated syringe 10 may be subjected to one or more conditions. Similar to step 804, at step 904, one or more actual processes of interest may be performed with the inoculated syringe 10. For example, the inoculated syringe 10 may be subjected to the aforementioned actual external sterilization process, actual manufacturing process, actual syringe assembly process, actual shipping and handling conditions during manufacturing, assembly and / or transportation, and / or any combination thereof. Additionally or alternatively, the inoculated syringe 10 may be subjected to nominal or adjusted parameters of one or more actual processes of interest, as well as test conditions. The parameters and test conditions may be selected to ensure that the stopper movement of the syringe 10 is assessed under conditions that are at or above the upper or lower limits of the parameters of the process of interest (i.e., increasing the stopper movement beyond what would normally occur under the nominal parameters).

[0063] After subjecting syringe 10 to one or more conditions, method 900 may proceed to step 906, whereby liquid of fill volume 20 is extracted from the cavity 19 of syringe 10. In some embodiments, the liquid of fill volume 20 may have been pre-validated as sterile prior to step 904. At step 908, a sterility test may be performed on the extracted liquid of fill volume 20. Specifically, the extracted liquid of fill volume 20 may be suspended in a test medium. In some embodiments, the test medium may contain tryptone soy broth (TSB) or thioglycolate fluid medium (FTM). If any viable biological particles 300 are present in the extracted liquid of fill volume 20, the test medium may become turbid. Accordingly, if the test medium becomes turbid after the extracted liquid of fill volume 20 is suspended in the test medium, this may indicate a positive growth result (i.e., the presence of biological particles 300 in the extracted liquid of fill volume 20), and thus indicate that the movement of the stopper 18 in syringe 10 exceeds the sterility barrier height of the stopper, and the potential risk of drug product contamination in practice. On the other hand, if the sterility test yields a negative growth result, and the test medium does not become turbid after the extracted filler volume 20 of liquid is suspended in the test medium, this indicates that any movement of the stopper 18 did not exceed the sterility barrier height of the stopper, and no risk of drug product contamination was identified in practice. Therefore, at step 910, it can be determined whether any movement of the stopper 18 in the syringe 10 exceeded its sterility barrier height and caused drug product contamination based on the sterility test performed.

[0064] Method 900 can then proceed to step 912, where any risk of drug product contamination is identified or determined based on the movement of at least one stopper determined in step 910. For example, if the stopper 18 moves a distance in the proximal direction within the syringe barrel 11 equal to or greater than the sterile barrier height of the stopper 18 (i.e., the axial length between the proximal side 201 and the distal side 204 of the stopper 18), there may be a risk of drug product contamination due to the contact of the filling volume of drug or pharmaceutical agent contained in the cavity 19 with the non-sterile surface or non-sterile area of ​​the syringe barrel 11. On the other hand, if the stopper 18 moves a distance in the proximal direction within the syringe barrel 11 less than the sterile barrier height of the stopper 18, there is no risk of drug product contamination.

[0065] The method for assessing stopper movement in a syringe and identifying the risk of drug product contamination due to stopper movement exceeding the sterile barrier height of the stopper, as described in this disclosure, may have one or more advantages over conventional methods, wherein any one or more advantages may be present in specific embodiments according to the features of this disclosure included in the embodiments. For example, the method according to this disclosure provides a direct assessment of stopper movement and drug product contamination using actual processes of interest (such as the actual external sterilization process described above, the actual manufacturing process, the actual syringe assembly process, actual shipping and handling conditions during manufacturing, assembly, and / or transportation, and / or any combination thereof). Accordingly, because the assessment and sterility testing performed are not conducted under simulated conditions, there is no need to make assumptions that could introduce ambiguity and subjectivity into the final analysis and results. Furthermore, the method according to this disclosure uses microbiological methods to perform sterility testing on the extracted fill volume of liquid, thereby providing an accurate measurement of stopper movement and potential drug product contamination. Furthermore, regarding the assessment of stopper movement caused by the external sterilization process, in some cases, the syringe can be subjected to pressure changes occurring at or near the end of the external sterilization cycle, causing the stopper to move beyond the sterile barrier height, even after the outer surface of the syringe has been sterilized or achieved kill effect only during the initial portion of the sterilization cycle. Accordingly, even if the stopper moves beyond the sterile barrier height, there may be no risk of drug product contamination because the drug product will only come into contact with sterile surfaces. The method according to this disclosure can provide validation that although the stopper moves beyond the sterile barrier height at the end of the external sterilization process, no drug product contamination occurs using the external sterilization process because the annular inner wall and any outer surface beyond the sterile zone of the syringe have been sterilized before the stopper moves. Other advantages not specifically listed herein can also be appreciated.

[0066] Now for reference Figure 6A , Figure 6B , Figure 7A and Figure 7BExemplary embodiments of the plunger rod and plug according to different embodiments of this disclosure are shown. Figure 6A and Figure 6B As shown, in some embodiments, the stopper 618 may include a body portion 603 having generally cylindrical sidewalls and a plurality of ribs 602a, 602b projecting radially outward from the sidewalls of the body portion 603. A first rib 602a may project radially outward from the sidewall of the body portion 603 near the proximal end of the stopper 618, while a second rib 602b may project radially outward from the sidewall of the body portion 603 near the distal end of the stopper 618. Although Figure 6A and Figure 6B A stopper 618 with two ribs 602a, 602b is shown, but the stopper 618 may have any number of ribs projecting radially outward from the sidewall of the body portion 603. For example, the stopper 618 may have one rib, three ribs, four ribs, five ribs, or six ribs. In an alternative embodiment, the stopper 618 may not have ribs. Accordingly, the sterile barrier height of a stopper without ribs may be defined as (a) the distance between the nearest side surface of the stopper in contact with the inner wall of the syringe barrel 11 and (b) the farthest side surface of the stopper in contact with the inner wall of the syringe barrel 11.

[0067] In some embodiments, such as Figure 6A and Figure 6B As shown, the stopper 618 may have a proximal side 601, and the proximal side 601 may include a convex surface. The convex proximal side 601 may be configured to allow gravity to pull any inoculated bioparticles or liquid inoculum toward the outer periphery of the first rib 602a, and to ensure that the inoculated bioparticles cover the first rib 602a of the stopper 618 and the annular inner wall 13 of the syringe barrel 11 (e.g., Figures 1 to 5 The interface between (shown). Because the proximal side 601 of the plug 618 includes a convex surface, the plunger rod 616 may include a concave distal end 615 to complement the convex proximal side 601 of the plug 618.

[0068] In other embodiments, such as Figure 7A and Figure 7B As shown, the stopper 718 may include a body portion 703 having generally cylindrical sidewalls and a plurality of ribs 702a, 702b projecting radially outward from the sidewalls of the body portion 703. A first rib 702a may project radially outward from the sidewall of the body portion 703 near the proximal end of the stopper 718, while a second rib 702b may project radially outward from the sidewall of the body portion 703 near the distal end of the stopper 718. Although Figure 7A and Figure 7BA plug 718 with two ribs 702a and 702b is shown, but the plug 718 may have any number of ribs projecting radially outward from the sidewall of the body portion 703. For example, the plug 718 may have one rib, three ribs, four ribs, five ribs, or six ribs.

[0069] Similar to Figure 6A and Figure 6B The stopper 618 and stopper 718 may have a convex proximal side 701. The convex proximal side 701 may be configured to allow gravity to pull any inoculated biological particles or liquid inoculum toward the outer periphery of the first rib 702a, and to ensure that the inoculated biological particles cover the first rib 702a of the stopper 718 and the annular inner wall 13 of the syringe barrel 11 (e.g., Figures 1 to 5 The interface between (shown). Because the proximal side 701 of the plug 718 includes a convex surface, the plunger rod 716 may include a generally concave distal end 715 to complement the convex proximal side 701 of the plug 718.

[0070] Additionally or alternatively, the stopper 718 may include a plurality of protrusions 705 projecting axially upward from a proximal side 701 of the stopper 718. Although Figure 7A and Figure 7B A plug 718 with four protrusions 705 on its proximal side 701 is shown, but the proximal side 701 may include any number of protrusions. For example, the proximal side 701 may have one, two, three, five, or six protrusions. The protrusions 705 may be configured to reduce the contact surface between the proximal side 701 of the plug 718 and the concave distal end 715 of the plunger rod 716. In some embodiments, the distal end 715 of the plunger rod 716 may also include one or more protrusions 717 configured to reduce the contact surface between the proximal side 701 of the plug 718 and the concave distal end 715 of the plunger rod 716. Reducing the contact surface between the plug 718 and the plunger rod 716 can optimize the flow of sterilizing agent gases and minimize blockages during the aforementioned external sterilization process.

[0071] The above description describes various devices, components, parts, subsystems, and methods of use related to drug delivery devices. Devices, components, parts, subsystems, methods, or drug delivery devices may further include or be used with drugs, including but not limited to those drugs identified below and their class and biosimilar counterparts. As used herein, the term "drug" is used interchangeably with other similar terms and can refer to any type of pharmaceutical agent or therapeutic material, including traditional and non-traditional drugs, nutritional supplements, tonics, biologics, bioactive agents and compositions, macromolecules, biosimilars, bioequivalents, therapeutic antibodies, peptides, proteins, small molecules, and class of substances. Non-therapeutic injectable materials are also included. Drugs may be in liquid form, lyophilized form, or in a form that can be reconstructed from lyophilized form. The following exemplary list of drugs should not be considered as all-encompassing or restrictive.

[0072] The medication will be contained in a reservoir. In some cases, the reservoir is a pre-filled syringe. A pre-filled syringe may have a maximum filling volume of 0.3 ml to 1.5 ml, preferably 0.5 ml to 1.0 ml, i.e., the maximum volume the syringe can occupy. The volume of the 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. Taking into account any dead space within the syringe and needle, and losses due to preparing the syringe for injection, the syringe is typically filled with a larger volume than the volume actually administered to the patient. Therefore, the volume actually administered to the patient may be between 0.01 ml and 1 ml; between 0.02 ml and 0.5 ml; between 0.025 ml and 0.5 ml; between 0.03 ml and 0.05 ml; or 0.05 ml.

[0073] In some embodiments, the reservoir of the prefilled syringe includes a VEGF antagonist. The term “VEGF antagonist” refers to a molecule that specifically interacts with VEGF and inhibits one or more of its biological activities, such as its mitogenic, angiogenic, and / or vascular permeability activities. It is intended to include antibodies against VEGF and their antigen-binding fragments as well as non-antibody VEGF antagonists. Non-antibody VEGF antagonists include aflibercept, pilgatanib, and antibody analogs. Preferably, the non-antibody VEGF antagonist is aflibercept. Aflibercept, currently marketed under the name Eylea® and 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).

[0074] In some embodiments, the reservoir of the drug delivery device may be filled with colony-stimulating factors (e.g., granulocyte colony-stimulating factor (G-CSF)), or the device may be used in conjunction with these colony-stimulating factors. Such G-CSF agents include, but are not limited to, Neulasta® (pefilgrastim, PEGylated filgrastim, PEGylated G-CSF, PEGylated hu-Met-G-CSF) and Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), UDENYCA® (pefilgrastim-cbqv), Ziextenzo® (LA-EP2006; pefilgrastim-bmez), or FULPHILA (pefilgrastim-bmez).

[0075] In other embodiments, the drug delivery device may include or be used with an erythropoiesis stimulant (ESA), which may be in liquid or lyophilized form. An ESA is any molecule that stimulates erythropoiesis. In some embodiments, the ESA is an erythropoiesis-stimulating protein. As used herein, "erythropoiesis-stimulating protein" means any protein that directly or indirectly causes activation of the erythropoietin receptor (e.g., by binding to and 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. Erythropoietin-stimulating proteins include, but are not limited to, Epogen® (epogen α), Aranesp® (dabepoetin α), Dynepo® (epogen δ), Mircera® (methoxy-polyethylene glycol-epogen β), Hematide®, MRK-2578, INS-22, Retacrit® (epogen ζ), Neorecormon® (epogen β), Silapo® (epogen ζ), Binocrit® (epogen α), epogen α Hexal, Abseamed® (epogen α), Ratioepo® (epogen θ), Eporatio® (epogen θ), Biopoin® (epogen θ), epogen α, epogen β, epogen ι, epogen ω, epogen δ, epogen ζ, epogen θ and epogen δ, pegylated erythropoietin, carbamylated erythropoietin, and their molecules or variants or analogues.

[0076] The specific illustrative proteins are those described below, including their fusions, fragments, analogs, variants, or derivatives: OPGL-specific antibodies, peptides, related proteins, etc. (also known as RANKL-specific antibodies, peptides, etc.), including fully humanized OPGL-specific antibodies and human OPGL-specific antibodies, especially fully humanized monoclonal antibodies; myostatin-binding proteins, peptides, related proteins, etc., including myostatin-specific peptides; IL-4 receptor-specific antibodies, peptides, related proteins, etc., particularly those inhibiting the activity of IL-4 and / or IL-4 receptors. -13-mediated activities involving receptor binding; interleukin-1 receptor 1 ("IL1-R1") specific antibodies, peptides, and related proteins; Ang2 specific antibodies, peptides, and related proteins; NGF specific antibodies, peptides, and related proteins; CD22 specific antibodies, peptides, and related proteins, especially human CD22 specific antibodies, such as, 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 human-mouse monoclonal hLL2. Dimers of the γ-chain linked to the human-mouse monoclonal hLL2 κ chain by disulfide, such as the fully humanized human CD22-specific antibody in epazuzumab (CAS Registry No. 501423-23-0); IGF-1 receptor-specific antibodies, peptides, and related proteins, including but not limited to anti-IGF-1R antibodies; B-7-related protein 1-specific antibodies, peptides, and related proteins (“B7RP-1”, also known as B7H2, ICOSL, B7h, and CD275), including but not limited to B7RP-specific fully human monoclonal IgG2 antibodies, including but not limited to fully human IgG2 monoclonal antibodies binding to epitopes in the first immunoglobulin-like domain of B7RP-1, including but not limited to those inhibiting the interaction of B7RP-1 with its native receptor ICOS on activated T cells; IL-15-specific antibodies, peptides, and related proteins, such as, in particular, humanized monoclonal antibodies, including but not limited to HuMaxIL-15 antibodies and related proteins, such as 145c7; IFN. γ-specific antibodies, peptides, and related proteins, including but not limited to human IFN γ-specific antibodies, and including but not limited to fully human anti-IFN γ antibodies; TALL-1 specific antibodies, peptides, and related proteins, as well as other TALL-specific binding proteins; parathyroid hormone (“PTH”) specific antibodies, peptides, and related proteins; thrombopoietin receptor (“TPO-R”) specific antibodies, peptides, and related proteins;Hepatocyte growth factor (“HGF”) specific antibodies, peptides, and related proteins, including those targeting the HGF / SF:cMet axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / dispersant (HGF / SF); TRAIL-R2 specific antibodies, peptides, and related proteins; activin A specific antibodies, peptides, and proteins; TGF-β specific antibodies, peptides, and related proteins; amyloid-β protein specific antibodies, peptides, and related proteins; c-Kit specific antibodies, peptides, and related proteins, including but not limited to proteins that bind to c-Kit and / or other stem cell factor receptors; OX40L specific antibodies, peptides, and related proteins, including but not limited to those that bind to OX40L and / or OX40 receptors. Other ligand proteins; Activase® (alteplase, tPA); Aranesp® (dabepoetin α) erythropoietin [30-asparagine, 32-threonine, 87-valine, 88-asparagine, 90-threonine], dabepoetin α, novel erythropoiesis-stimulating protein (NESP); Epogen® (epogenetin α, or erythropoietin); GLP-1, Avonex® (interferon β-1a); Bexxar® (tosimomab, anti-CD22 monoclonal antibody); Betaseron® (interferon-β); Camppath® (alemumab, anti-CD52 monoclonal antibody); Dynepo® (epogenetin δ); Velcade® (bortezomib); MLN0002 (anti-α4β7) mAb); MLN1202 (anti-CCR2 chemokine receptor mAb); Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker); Eprex® (ebertin α); Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1); Genotropin® (growth hormone, human growth hormone); Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb); Kanjinti™ (trastuzumab-anns), an anti-HER2 monoclonal antibody, a biosimilar of Herceptin®, or another product containing trastuzumab for the treatment of breast or gastric cancer; Humatrope® (growth hormone, human growth hormone); Humira® (adalimumab).Vectibix® (panitumumab), Xgeva® (dinosumab), Prolia® (dinosumab), RANK ligand immunoglobulin G2 human monoclonal antibody, Enbrel® (etanercept, TNF-receptor / Fc fusion protein, TNF blocker), Nplate® (romistamine), rilotumumab, ganitumab, conatumumab, brodalumab, insulin in solution; Infergen® (alfacon-1 interferon); Natrecor® (nesiritide; recombinant human B-type natriuretic peptide (hBNP)); Kineret® (anaspirin); Leukine® (saxaglastine, rhuGM-CSF); LymphoCide® (epazolizumab, anti-CD22 mAb); Benlysta™ (lymphostat B, belimumab, anti-BlyS) mAb); Metalyse® (tenectiplase, t-PA analog); Mircera® (methoxy-polyethylene glycol-ebertheline beta); Mylotarg® (gem-tuzumab-ozomicin); Raptiva® (efalizumab); Cimzia® (sertozumab, CDP 870); Soliris™ (eculizumab); Pexazumab (anti-C5 complement); Numax® (MEDI-524); Lucentis® (ranibumab); Panorex® (17-1A, ezolomide); Trabio® (lerdelimumab); TheraCim hR3 (Nimotuzumab); Omnitarg (Pertuzumab, 2C4); Osidem® (IDM-1); OvaRex® (B43.13); Nuvion® (Vencizumab); Cantuzumab Mertansine (huC242-DM1); NeoRecormon® (Ibertin β); Neumega® (Interleukin-11); Orthoclone OKT3® (Moromab-CD3, anti-CD3 monoclonal antibody); Procrit® (Ibertin α); Remicade® (Infliximab, anti-TNFα monoclonal antibody); Reopro® (Abciximab, anti-GP IIb / Ilia receptor monoclonal antibody); Actemra® (Anti-IL6 receptor mAb); Avastin® (Bevacizumab); HuMax-CD4 (Zanolimuab); Mvasi; TM(Bevacizumab - awwb); Rituxan® (rituximab, anti-CD20 mAb); Tarceva® (erlotinib); Roferon-A® (interferon alpha-2a); Simulect® (baliximab); Prexige® (romexicob); Synagis® (palizumab); 145c7-CHO (anti-IL15 antibody, see US Patent No. 7,153,507); Tysabri® (natelizumab, anti-alpha4 integrin mAb); Valortim® (MDX-1303, anti-anthrax protective antigen mAb); ABthrax™; Xolair® (omalizumab); ETI211 (anti-MRSA mAb); IL-1 trap (extracellular domain of the Fc portion of human IgG1 and IL-1 receptor components (type I receptor and receptor accessory proteins)); VEGF trap (with IgG1) Fc fusion of VEGFR1 Ig domain); Zenapax® (dalizumab); Zenapax® (dalizumab, anti-IL-2Rα mAb); Zevalin® (teimomab); Zetia® (ezetimibe); Orencia® (asceticipeptide, TACI-Ig); anti-CD80 monoclonal antibody (galiximab); anti-CD23 mAb (ruximab); 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 (ipramab, anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1); anti-BR3 mAb; anti-clostridium difficile toxin A and toxin BC mAb MDX-066 (CDA-1 and MDX-1388); anti-CD22 dsFv-PE38 conjugates (CAT-3888 and CAT-8015); anti-CD25 mAb (HuMax-TAC); anti-CD3 mAb (NI-0401); adecatumumab; anti-CD30 mAb (MDX-060); MDX-1333 (anti-IFNAR); anti-CD38 mAb (HuMax CD38); anti-CD40L mAb; anti-Cripto mAb;Anti-CTGF fibrinogen for stage I idiopathic pulmonary fibrosis (FG-3019); Anti-CTLA4 mAb; Anti-eosinophil chemokine 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-198); 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-TGFβ mAb (GC-1008); anti-TRAIL receptor-2 human mAb (HGS-ETR2); anti-TWEAK mAb; anti-VEGFR / Flt-1 mAb; and anti-ZP3 mAb (HuMax-ZP3).

[0077] In some embodiments, the drug delivery device may comprise or be used with sclerosing protein antibodies for the treatment of postmenopausal osteoporosis and / or fracture healing, such as, but not limited to, lomoxozimab, butozimab, or BPS 804 (Novartis), Evenity™ (lomoxozimab-aqqg), another product containing lomoxozimab, and in other embodiments, a monoclonal antibody (IgG) binding to the 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 include or be used with any of the following: rituximab, bisalometabolum, trebananib, ganitamumab, kanamumab, motesanib diphosphate, brodatumab, vidupiprant, or panitumumab. In some embodiments, the reservoir of the drug delivery device may be filled with IMLYGIC® (talimogenelaherparepvec) or another oncolytic HSV for the treatment of melanoma or other cancers, or the device may be used with such other oncolytic HSV, including but not limited to OncoVEX GALV / CD; OrienX010; G207; 1716; NV1020; NV12023; NV1034; and NV1042. In some embodiments, the drug delivery device may include or be used with an endogenous tissue metalloproteinase inhibitor (TIMP), such as, but not limited to, TIMP-3. In some embodiments, the drug delivery device may include or be used with Aimovig® (erenumab-aooe) for the treatment of migraines, anti-human CGRP-R (calcitonin gene-related peptide type 1 receptor), or another product containing erenumab. Antagonistic antibodies against 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 device disclosed herein. Additionally, bispecific T-cell binding agent (BiTE®) antibodies (such as, but not limited to, BLINCYTO®) may be used in or with the drug delivery device disclosed herein. In some embodiments, the drug delivery device may include or be used with an APJ macromolecular agonist, such as, but not limited to, apelin or an analogue thereof.In some embodiments, therapeutically effective amounts of anti-thymocyte stromal lymphopoietin (TSLP) or TSLP receptor antibodies are used in or in conjunction with the drug delivery device of this disclosure. In some embodiments, the drug delivery device may include Avsola for the treatment of autoimmune diseases. TM (infliximab-axxq), an anti-TNF α monoclonal antibody, a biosimilar of Remicade® (infliximab) (Janssen Biotech, Inc.) or another product containing infliximab, or used therewith. In some embodiments, the drug delivery device may contain Kyprolis® (carfilzomib) for the treatment of multiple myeloma, (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methylethyleneoxy-2-yl)-1-oxopentane-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamyl)-4-phenylbutamido)-4-methylpentanamide, or another product containing carfilzomib, or used therewith. In some embodiments, the drug delivery device may comprise or be used with Otezla® (apremilast), N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methanesulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, or another product containing apremilast for the treatment of various inflammatory conditions. In some embodiments, the drug delivery device may comprise Parsabiv for the treatment of, for example, secondary hyperparathyroidism (sHPT) in dialysis patients with chronic kidney disease (KD). TM(Vicocineptide HCl, KAI-4169) or another product containing vecocineptide HCl or used therewith. In some embodiments, the drug delivery device may contain ABP 798 (rituximab), a biosimilar candidate of Rituxan® / MabThera™, or another product containing an anti-CD20 monoclonal antibody or used therewith. In some embodiments, the drug delivery device may contain a VEGF antagonist (e.g., a non-antibody VEGF antagonist) and / or a VEGF-Trap (e.g., aflibercept (a fusion of the Fc domain of IgG1 with the Ig domain 2 of VEGFR1 and the Ig domain 3 of VEGFR2)) or used therewith. In some embodiments, the drug delivery device may contain ABP959 (eculizumab), a biosimilar candidate of Soliris®, or another product containing a monoclonal antibody that specifically binds to complement protein C5 or used therewith. In some embodiments, the drug delivery device may comprise or be used with Lobivup α (formerly AMG 570), a novel bispecific antibody-peptide conjugate that simultaneously blocks the activities of ICOSL and BAFF. In some embodiments, the drug delivery device may comprise or be used with omeprazole (a small molecule selective cardiac myosin activator), or myotrope which directly targets the cardiac contractile mechanism, or another product comprising or being used with a small molecule selective cardiac myosin activator. In some embodiments, the drug delivery device may comprise sotoraraciab (formerly AMG 510), KRAS G12C Small molecule inhibitors, or those containing KRAS G12CAnother product containing or used with a small molecule inhibitor. In some embodiments, the drug delivery device may comprise or be used with tezepelumab, a human monoclonal antibody that inhibits the action of thymic stromal lymphopoietin (TSLP), or another product containing or used with a human monoclonal antibody that inhibits the action of TSLP. In some embodiments, the drug delivery device may comprise or be used with rocatinlimab (AMG 451), a human anti-OX40 monoclonal antibody that expresses on activated T cells and blocks OX40 to inhibit and / or reduce the number of OX40-pathogenic T cells responsible for driving systemic and local atopic dermatitis inflammatory responses. In some embodiments, the drug delivery device may comprise or be used with AMG 714, a human monoclonal antibody that binds to interleukin-15 (IL-15), or another product containing or used with a human monoclonal antibody that binds to interleukin-15 (IL-15). In some embodiments, the drug delivery device may comprise or be used with AMG 890, a small interfering RNA (siRNA) that lowers lipoprotein(a) (also known as Lp(a)), or another product that comprises or is used with a small interfering RNA (siRNA) that lowers lipoprotein(a). In some embodiments, the drug delivery device may comprise or be used with ABP 654 (human IgG1κ antibody), a biosimilar candidate of Stelara®, or another product that comprises or is used with a human IgG1κ antibody and / or binds to the p40 subunit of the human cytokines interleukin (IL)-12 and IL-23. In some embodiments, the drug delivery device may comprise Amjevita. TM Or Amgevita TM(Previously ABP501) (mab anti-TNF human IgG1), a biosimilar candidate of Humira®, or another product containing or used with a human mab anti-TNF human IgG1. In some embodiments, the drug delivery device may contain or be used with AMG 160, or another product containing a half-life extended (HLE) anti-prostate-specific membrane antigen (PSMA) x anti-CD3 BiTE® (bispecific T-cell conjugate) construct. In some embodiments, the drug delivery device may contain or be used with AMG 119, or another product containing delta-like ligand 3 (DLL3) CAR T (chimeric antigen receptor T-cell) cell therapy. In some embodiments, the drug delivery device may contain or be used with AMG 119, or another product containing delta-like ligand 3 (DLL3) CAR T (chimeric antigen receptor T-cell) cell therapy. In some embodiments, the drug delivery device may contain or be used with AMG 133, or another product containing a gastric inhibitory peptide receptor (GIPR) antagonist and a GLP-1R agonist. In some embodiments, the drug delivery device may comprise or be used with AMG 171, or another product comprising a growth differentiation factor 15 (GDF15) analogue. In some embodiments, the drug delivery device may comprise or be used with AMG 176, or another product comprising a small molecule inhibitor of myeloid leukemia 1 (MCL-1). In some embodiments, the drug delivery device may comprise or be used with AMG 199, or another product comprising a bispecific T-cell conjugate with extended half-life (HLE) (BiTE®). In some embodiments, the drug delivery device may comprise or be used with AMG 256, or another product (comprising an anti-PD-1 x IL21 mutant protein and / or an IL-21 receptor agonist) designed to selectively activate the interleukin-21 (IL-21) pathway in programmed cell death-1 (PD-1) positive cells. In some embodiments, the drug delivery device may comprise or be used with AMG 330, or another product comprising an anti-CD33 x anti-CD3 BiTE® (bispecific T-cell conjugate) construct. In some embodiments, the drug delivery device may contain or be used with AMG 404, which is being investigated for the treatment of patients with solid tumors, or another product containing a human anti-programmed cell death-1 (PD-1) monoclonal antibody. In some embodiments, the drug delivery device may contain or be used with AMG 427, or another product containing or being used with an extended-life (HLE) anti-fms-like tyrosine kinase 3 (FLT3) x anti-CD3 BiTE® (bispecific T-cell binder) construct.In some embodiments, the drug delivery device may comprise or be used with AMG 430 or another product comprising an anti-Jagged-1 monoclonal antibody. In some embodiments, the drug delivery device may comprise or be used with AMG 506, which is being investigated for the treatment of solid tumors, or another product comprising a multispecific FAP x 4-1BB-targeting DARPin® biologic. In some embodiments, the drug delivery device may comprise or be used with AMG 509 or another product comprising a bivalent T-cell conjugate and designed using XmAb®2+1 technology. In some embodiments, the drug delivery device may comprise or be used with AMG 562 or another product comprising an extended half-life (HLE) CD19 x CD3 BiTE® (bispecific T-cell conjugate) construct. In some embodiments, the drug delivery device may comprise or be used with Efavaleukin α (formerly AMG 592) or another product comprising an IL-2 mutant Fc fusion protein. In some embodiments, the drug delivery device may comprise or be used with AMG 596 or another product comprising or using with a CD3 x epidermal growth factor receptor vIII (EGFRvIII) BiTE® (bispecific T-cell conjugate) molecule. In some embodiments, the drug delivery device may comprise or be used with AMG 673 or another product comprising or using with a half-life extended (HLE) anti-CD33 x anti-CD3 BiTE® (bispecific T-cell conjugate) construct. In some embodiments, the drug delivery device may comprise or be used with AMG 701 or another product comprising or using with a half-life extended (HLE) anti-B-cell maturation antigen (BCMA) x anti-CD3 BiTE® (bispecific T-cell conjugate) construct. In some embodiments, the drug delivery device may comprise or be used with AMG 757 or another product comprising or using with a half-life extended (HLE) anti-δ-like ligand 3 (DLL3) x anti-CD3 BiTE® (bispecific T-cell conjugate) construct. In some embodiments, the drug delivery device may be used with AMG 910 or another product containing an extended half-life (HLE) claudin 18.2 x CD3 BiTE® (bispecific T-cell binding agent) construct.

[0078] Although drug delivery devices, components, parts, subsystems, and methods have been described with reference to exemplary embodiments, they are not limited thereto. This detailed description is to be construed as exemplary only and does not describe every possible embodiment of this disclosure. Many alternative embodiments can be implemented using current technology or technology developed after the date of this patent application, and these embodiments still fall within the scope of the claims defining the invention disclosed herein.

[0079] Those skilled in the art will recognize that various modifications, alterations, and combinations can be made with respect to the embodiments described above without departing from the spirit and scope of the invention(s) disclosed herein, and such modifications, alterations, and combinations will be considered to be within the scope of the inventive concept.

Claims

1. A method for evaluating stopper movement in a syringe, the syringe comprising a syringe barrel and a stopper movably disposed within the syringe barrel, the method comprising: Biological particles are inoculated through the open proximal end of the syringe barrel such that the biological particles cover at least a portion of the interface between the proximal side of the plug and the inner wall of the syringe barrel, wherein the cavity of the syringe contains a fill volume of liquid. Subject the syringe to one or more conditions; Extract the filling volume of liquid from the cavity of the syringe; Perform a sterility test on the extracted fill volume of liquid; and This sterility test is used to determine the movement of the stopper in the syringe.

2. The method of claim 1, wherein subjecting the syringe to one or more conditions includes at least one of: externally sterilizing the syringe, subjecting the syringe to shipping and handling conditions, or performing a manufacturing process using the syringe.

3. The method of claim 1, wherein subjecting the syringe to one or more conditions includes external sterilization of the syringe, wherein, External sterilization of the syringe includes: Place the syringe in the sterilization chamber; A certain amount of sterilizing agent gas is introduced into the sterilization chamber and a predetermined vacuum level is applied; Maintain the vacuum level for a predetermined dwell time; and Remove at least substantially all of the sterilizing agent gas from the sterilization chamber.

4. The method of claim 1, wherein the stopper includes a body portion having generally cylindrical sidewalls and one or more ribs projecting radially outward from the sidewalls of the body portion near the proximal side of the stopper, wherein, The one or more ribs of the plug are configured to form a leak-proof relationship with the cavity of the syringe.

5. The method of claim 4, further comprising inoculating the bioparticles through the open proximal end of the syringe barrel such that the bioparticles cover at least a portion of the interface between the one or more ribs near the proximal side of the plug and the inner wall of the syringe barrel.

6. The method of claim 1, wherein the bioparticles are inoculated at a plurality of locations around the diameter of the proximal side of the stopper along the interface between the proximal side of the stopper and the inner wall of the syringe barrel.

7. The method of claim 1, wherein the biological particle comprises at least one of the following: microorganisms, fungi, bacteria, spores, viruses, biological cells, biological antigens, proteins, or protein antigens.

8. The method of claim 1, wherein performing a sterility test on the extracted liquid comprises: The extracted liquid was suspended in a test medium containing tryptic soybean broth (TSB) or thioglycolate fluid medium (FTM); as well as To determine whether the extracted liquid contains the biological particles. The presence of biological particles in the extracted liquid indicates that the stopper in the syringe is moving.

9. The method of claim 1, wherein the liquid filling volume comprises a test medium containing tryptone soybean broth (TSB) or thioglycolate fluid medium (FTM), and wherein, Performing a sterility test on the extracted liquid includes determining whether the extracted liquid contains the biological particles.

10. The method of claim 1, wherein the syringe barrel includes a distal end configured to support the needle.

11. The method of claim 10, wherein, The open proximal end of the syringe barrel is configured to receive a plunger rod, which is configured to push the plug toward the distal end of the syringe barrel in a distal direction.

12. The method of claim 1, wherein the syringe is a pre-filled syringe, and wherein, The syringe barrel of this pre-filled syringe is configured to contain the medication.

13. The method of claim 1, wherein the proximal side of the plug includes a convex surface.

14. The method of claim 1, wherein the proximal side of the plug includes a plurality of protrusions projecting axially from the proximal side.

15. The method of claim 1, further comprising identifying a risk of contamination of the pharmaceutical product based at least on the determined stopper movement, wherein, There is a risk of contamination of the drug product when the distance moved by the stopper is greater than or equal to the axial length of the stopper.

16. A method for determining the risk of contamination of a pharmaceutical product in a syringe, the syringe comprising a syringe barrel and a stopper movably disposed within the syringe barrel, the method comprising: Biological particles are inoculated through the open proximal end of the syringe barrel such that the biological particles cover at least a portion of the interface between the proximal side of the plug and the inner wall of the syringe barrel, wherein the cavity of the syringe contains a filling volume of liquid, and wherein the biological particles include at least one of the following: microorganisms, fungi, bacteria, spores, viruses, biological cells, biological antigens, proteins, or protein antigens. Subject the syringe to one or more conditions; Extract the filling volume of liquid from the cavity of the syringe; Perform a sterility test on the extracted fill volume of liquid; The aseptic test is used to determine stopper movement in the syringe; and The risk of contamination of a pharmaceutical product is identified at least based on the determined movement of the stopper, wherein the risk of contamination exists when the distance moved by the stopper is greater than or equal to the axial length of the stopper.

17. The method of claim 16, wherein, Subjecting the syringe to one or more conditions includes at least one of the following: external sterilization of the syringe, subjecting the syringe to shipping and handling conditions, or performing a manufacturing process using the syringe.

18. The method of claim 16, wherein, Exposing the syringe to one or more conditions includes external sterilization of the syringe, wherein external sterilization of the syringe includes: Place the syringe in the sterilization chamber; A certain amount of sterilizing agent gas is introduced into the sterilization chamber and a predetermined vacuum level is applied; Maintain the vacuum level for a predetermined dwell time; and Remove at least substantially all of the sterilizing agent gas from the sterilization chamber.

19. The method of claim 16, wherein, The stopper includes a body portion having a generally cylindrical sidewall and one or more ribs that project radially outward from the sidewall of the body portion near the proximal side of the stopper, wherein the one or more ribs of the stopper are configured to form a leak-proof relationship with the cavity of the syringe.

20. The method of claim 19, further comprising inoculating the bioparticle through the open proximal end of the syringe barrel such that the bioparticle covers at least a portion of the interface between the one or more ribs near the proximal side of the plug and the inner wall of the syringe barrel.

21. The method of claim 16, wherein, The bioparticles are inoculated at multiple locations along a diameter surrounding the proximal side of the stopper, at the interface between the proximal side of the stopper and the inner wall of the syringe barrel.

22. The method of claim 16, wherein, Performing sterility tests on the extracted liquid includes: The extracted liquid was suspended in a test medium containing tryptone soybean broth (TSB) or thioglycolate fluid medium (FTM); and To determine whether the extracted liquid contains the biological particles. The presence of biological particles in the extracted liquid indicates that the stopper in the syringe is moving.

23. The method of claim 16, wherein, The liquid filling volume includes a test medium containing tryptic soy broth (TSB) or thioglycolate fluid medium (FTM), and wherein performing a sterility test on the extracted liquid includes determining whether the extracted liquid contains the biological particles.

24. The method of claim 16, wherein, The syringe barrel includes a distal end configured to support the needle.

25. The method of claim 24, wherein, The open proximal end of the syringe barrel is configured to receive a plunger rod, which is configured to push the plug toward the distal end of the syringe barrel in a distal direction.

26. The method of claim 16, wherein, The syringe is a pre-filled syringe, wherein the syringe barrel of the pre-filled syringe is configured to contain a drug.

27. The method of claim 16, wherein, The near side of the plug includes a convex surface.

28. The method of claim 16, wherein, The proximal side of the plug includes a plurality of protrusions that project axially from the proximal side.

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