Stopper arrangement in syringe

Abstract

A method of placing a plunger in a syringe barrel filled with a drug product. The method includes aligning a stopper with a longitudinal axis of the syringe barrel. The syringe barrel includes a proximal end, a distal end, and a reservoir. The drug product is disposed in the reservoir at the distal end. The method includes applying a vacuum pressure to the reservoir of the syringe barrel. The method includes forcing the stopper into the reservoir of the syringe barrel to a first depth with a plunger rod. The method includes removing the plunger rod from the reservoir of the syringe barrel after forcing the stopper to the first depth. The stopper moves to a second depth, different from the first depth, in response to a pressure differential in the reservoir of the syringe barrel.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 285,789, filed December 3, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to a method for placing a stopper in a syringe, and more particularly, to a method for placing a stopper in a syringe having a low drug product load. [Background technology]

[0003] A syringe is a medical delivery device used to administer a drug product to a patient. Syringes are often commercially available either in a pre-filled form, in which a set dose of drug product is already provided therein, or in an empty state, in which the syringe is adapted to be filled by an end user from a vial or other drug source when administration of the drug is desired. An exemplary syringe 10 is shown in FIG. 1 and includes a barrel 11 adapted to hold a drug product in a reservoir 13. The barrel 11 includes a proximal end 11A, a distal end 11B, a flange portion 12, and a cavity or reservoir 13 extending between the proximal end 11A and the distal end 11B. The distal end 11B of the barrel 11 is often configured to include and / or mate with a conventional piercing element, such as a sharpened needle cannula or a cannula with a blunt end, to deliver the drug contained within the barrel 11. For example, the syringe barrel distal end 11B may include a luer lock component. 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 11A of the syringe barrel 11, and engagement of the plunger rod with an elastomeric or rubbery stopper element mounted substantially fluid-tight within the inner wall 11C of the barrel 11 allows a user to apply manual force to the plunger to deliver the medicament through the piercing element. The syringe barrel proximal end 11A is open to receive the plunger rod and stopper components. A flange 12 is often provided around the open distal end 11A of the syringe barrel 11 as a form of finger rest to facilitate manipulation of the device by the user.

[0004] It may be desirable to thoroughly sterilize the components of the syringe 10 for both drug integrity and patient safety. External sterilization may occur, for example, after the prefilled syringe has been filled, fully assembled, and placed in at least some portion of its final package. However, during sterilization, the stopper may move from an initial position to a final position within the reservoir 13 of the barrel 11. In a typical prefilled syringe, the reservoir 13 is mostly filled with drug product, leaving little room for the stopper to move. However, in a syringe with a low drug product load (i.e., the reservoir 13 is mostly empty), the stopper is positioned further down within the barrel 11, leaving more room for the stopper to move during the sterilization process. Thus, the initial positioning of the stopper within the barrel 11 of the syringe 10 may take into account movement during the sterilization process to ensure that the plunger moves to an acceptable final position.

[0005] Known methods of stopper placement in prefilled syringes 10 include rod insertion or mechanical placement, vacuum-assisted ("VA") placement, and vacuum compression ("VC") placement. However, each of these methods faces its own unique challenges when placing a stopper deep inside a syringe barrel with a low drug product load. Mechanical stopper placement (e.g., plunger rod insertion) faces undesirable results because the mechanical requirement to insert and remove components from each syringe barrel slows the rate at which stoppering can occur, thereby reducing line throughput. Furthermore, in some cases, mechanical insertion of the stopper can cause forced deformation of the stopper itself. In the VA and VC methods, a vacuum applied to the syringe barrel 11 removes the headspace above the drug product and drives stopper placement into the reservoir 13. In particular, the stopper is partially placed on the flange 12 within the syringe barrel 11, and the vacuum pressure within the barrel 11 drives the movement of the stopper to its final depth. The VA method also involves compressing the stopper before inserting it into the barrel 11, which results in drug product between the stopper ribs and deformation of the plunger. While the VC method may not have drug product in the stopper ribs, the VC method is much slower and is not practical for processing large volumes of prefilled syringes. In both the VA and VC methods, relying on pressure differentials to place the stopper deep within the reservoir 13 results in variability in stopper placement, thus leading to poor process capability scores and long transfer times. Typically, the stopper reaches its final position after 12-24 hours, thus delaying the process of determining whether the prefilled syringe is suitable for use. As a result, these methods lead to unacceptable prefilled syringe reject rates due to plunger deformation, drug product between the stopper or plunger ribs, and a high rate of stopper migration outside the target placement range, thereby increasing the prefilled syringe reject rate. These rejects often occur at a sterilization location different from the filling location, thus leading to inefficiencies and waste. Summary of the Invention [Means for solving the problem]

[0006] The proposed approach to placing stoppers in syringes having low drug product loads involves more predictable and accurate results in placing stoppers within tolerances in pre-filled syringes by supplementing known vacuum-assisted and vacuum compression techniques with mechanical insertion components.

[0007] According to a first aspect of the present disclosure, a method of disposing a stopper in a syringe barrel partially filled with a drug product may include aligning the stopper with a longitudinal axis of the syringe barrel. The syringe barrel may include a proximal end, a distal end, and a reservoir. The drug product may be disposed within a distal end of the reservoir at the distal end of the syringe barrel. The method may include applying a vacuum pressure to the reservoir of the syringe barrel. The vacuum pressure may be in a range of about 70 mBar to about 85 mBar. The method may further include forcing the stopper into the reservoir of the syringe barrel to a first depth with a plunger rod, thereby creating a pressure differential on either side of the stopper. The first depth may be in a range of about 20 mm to about 40 mm from the distal end of the reservoir. Further, the method may include releasing the plunger rod from the stopper after pushing the stopper to the first depth, thereby creating a pressure differential on either side of the stopper to displace the stopper to a second depth different from the first depth.

[0008] According to a second aspect of the disclosure, a method of disposing a stopper in a syringe barrel partially filled with a drug product may include aligning the stopper with a longitudinal axis of the syringe barrel. The syringe barrel may include a proximal end, a distal end, and a reservoir. The drug product may be disposed within a distal end of the reservoir at the distal end of the syringe barrel. The method may include applying a vacuum pressure to the reservoir of the syringe barrel and forcing the stopper into the reservoir of the syringe barrel to a first depth with a plunger rod, thereby creating a pressure differential on either side of the stopper. The plunger rod may extend into the reservoir of the syringe barrel. Additionally, the method may include releasing the plunger rod from the stopper after forcing the stopper to the first depth, thereby creating a pressure differential on either side of the stopper to displace the stopper to a second depth different from the first depth.

[0009] Further, according to any one or more of the first and second aspects above, the method of disposing a stopper in a syringe barrel may include any one or more of the following aspects.

[0010] In one form, pressing the stopper can include inserting a plunger rod into a reservoir of the syringe barrel.

[0011] In another form, the application of vacuum pressure may at least partially correspond to forcing the stopper into the reservoir of the syringe barrel with a plunger rod.

[0012] In yet another form, pushing the stopper can include pushing the stopper into the syringe barrel a distance within a range of about 23 mm to 32 mm from the distal end.

[0013] In some forms, pushing the stopper can include pushing the stopper after applying vacuum pressure to the syringe barrel.

[0014] In another embodiment, pushing the stopper can include pushing the stopper into the syringe barrel a distance within a range of about 30 mm to about 35 mm from the distal end of the reservoir.

[0015] In another form, aligning the stopper can include positioning the stopper adjacent the proximal end of the syringe barrel prior to inserting the stopper into the reservoir of the syringe barrel.

[0016] In one form, aligning the stopper may include compressing the stopper with a grip near the proximal end of the syringe barrel and forcing the compressed stopper through the grip and into the reservoir of the barrel with a plunger rod.

[0017] In some forms, applying vacuum pressure can include evacuating a headspace above the drug product in the syringe barrel and applying a vacuum to the proximal end of the syringe barrel.

[0018] In another aspect, the method may include removing the plunger rod from the reservoir of the syringe barrel.

[0019] In yet another aspect, applying a vacuum pressure to the syringe barrel can include applying a pressure in the range of about 70 mBar to about 85 mBar.

[0020] In one form, pushing the stopper can include pushing the stopper into the syringe barrel a distance within a range of about 20 mm to about 40 mm from the distal end of the reservoir. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 is a perspective view of a known syringe. [Diagram 2] 2 is a flow chart depicting a method of placing a stopper on the syringe of FIG. 1 having a low drug product load in accordance with the teachings of the present disclosure. [Diagram 3]FIG. 1 is a schematic diagram of a stopper insertion assembly and a pre-filled syringe having a low drug product load in accordance with the teachings of the present disclosure showing the stopper in an initial position. [Figure 4] 4 is the stopper insertion assembly and syringe of FIG. 3 showing the stopper in a partially inserted position. [Diagram 5] 4 is the stopper insertion assembly and syringe of FIG. 3 showing the stopper at a first depth. [Figure 6] 4 is the stopper insertion assembly and syringe of FIG. 3 showing the stopper at a first depth with the plunger rod removed from the syringe. [Figure 7] 4 is the syringe of FIG. 3 showing the stopper in a final depth position. [Figure 8] 1 is a schematic diagram of a pre-filled syringe having a different stopper insertion assembly and a low drug product load according to the teachings of the present disclosure showing the stopper in an initial position. [Figure 9] 9 is the stopper insertion assembly and syringe of FIG. 8 showing the stopper in a partially inserted position. [Figure 10] 9 is the stopper insertion assembly and syringe of FIG. 8 showing the stopper at a first depth. [Figure 11] 9 is the stopper insertion assembly and syringe of FIG. 8 showing the stopper at a first depth with the plunger rod removed from the syringe. [Figure 12] 9 is the syringe of FIG. 8 showing the stopper in a final depth position. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] An exemplary method 100 of placing a stopper in a syringe barrel having a low drug product load of the present disclosure is shown in the flow chart of FIG. 2. The exemplary method 100 may result in higher process capability values ​​("PPK"), lower reject rates, and faster throughput compared to conventional stoppering methods. The method of FIG. 2 may be implemented by a one-step process including vacuum-assisted ("VA") and mechanical insertion techniques shown in FIGS. 3-7, and a two-step process including vacuum-compressed ("VC") and mechanical insertion techniques shown in FIGS. 8-12. Both the one-step and two-step processes utilize vacuum and mechanical methods to drive the stopper to a target depth in a prefilled syringe having a low drug product load.

[0023] Generally speaking, both the one-step and two-step processes may be performed according to the steps of method 100 of Figure 2. Method 100 integrates vacuum pressure and mechanical rod insertion techniques to place a stopper deep within reservoir 13 of a syringe 10, such as the syringe of Figure 1. A first step 110 of method 100 involves aligning a stopper with longitudinal axis A of syringe barrel 11, and a second step 120 of method involves applying vacuum pressure to reservoir 13 of syringe barrel 11. Following or simultaneously with applying vacuum pressure to syringe barrel 11, method 100 includes step 130 of pushing the stopper through an opening in proximal end 11A of syringe barrel 11 with a plunger rod. The plunger rod extends through opening 11A into reservoir 13 and positions the stopper at a first depth within a range of about 20 mm to about 40 mm from the proximal end of reservoir 13 (i.e., near flange 12). Finally, method 100 includes a step 140 of removing the plunger rod from syringe barrel 11, thereby moving the stopper to a second final depth, different from the first depth, in response to a pressure differential within reservoir 13 of syringe barrel 11. In some embodiments, the plunger rod is separate from the syringe and may be a component of an assembly device (e.g., an insertion assembly system) used to position the stopper in the syringe barrel, as described. In such embodiments, the plunger rod is not part of the final product including the syringe, but rather is completely removed from the syringe after positioning the stopper, such that the syringe and stopper may be separated from the plunger rod for further processing and / or use. In other embodiments, the plunger rod may form a component of a final product that also includes a syringe, such as a pre-filled syringe or other injector.

[0024] 3-8, a one-step process of placing a stopper at a target depth within a syringe barrel includes operating a stopper insertion assembly 14 on a prefilled syringe 10 having a low drug product fill 18. Referring first to FIG. 3, a first step 110 of a method 100 of aligning a stopper 30 with a syringe barrel 11 of a prefilled syringe 10 is shown. The prefilled syringe 10 is partially filled with a drug product 18 disposed with a meniscus at a depth P at the distal end 22 of the reservoir 13. The stopper insertion assembly 14 includes a grip 26 or vice that holds the stopper 30 above the open proximal end 11A of the syringe barrel 11 and aligns the stopper 30 with the longitudinal axis A of the syringe 10. The grip 26 may be part of a machine or automated system, such as a filling machine. Grip 26 includes an angled chute 34 that compresses stopper 30 in an initial position to facilitate insertion of stopper 30 into syringe barrel 11 .

[0025] 4 and 5, steps 120 of applying vacuum pressure and 130 of forcing stopper 30 into syringe barrel 11 are performed together or partially together. Grip 26 engages flange 12 of syringe 10, drawing a vacuum on the headspace above drug product 18 in reservoir 13 as plunger rod 38 of assembly 14 forces stopper 30 distally through chute 34, proximal end 11A, and into reservoir 13 of barrel 11. Reservoir 13 of syringe barrel 11 is subjected to a vacuum pressure in the range of about 70 mBar to about 85 mBar to assist in the distal insertion of plunger rod 38. In FIG. 5, the plunger rod 38 extends into the reservoir 13 of the syringe barrel 11 to position the stopper 30 at a first depth D1 above the meniscus P of the drug product 18 and within a range of about 23 mm to about 32 mm from the distal end 22 of the reservoir 13. In the illustrated example, the stopper insertion assembly 14 performs both the steps of applying a vacuum and forcing the stopper 30 into the syringe barrel 11. Specifically, the vacuum is pulled through an associated stoppering bar attached to the filling machine. A vacuum line is attached to the bar and suction is achieved by removing air within the bar and associated syringe barrel 11 while a vacuum bellows is in contact with the syringe barrel 11. If a vacuum is not actively pulled through the bar and attached syringe barrel 11 during stoppering (e.g., step 130), the compressed air within the syringe barrel 11 may push back against the placement of the stopper, causing the stopper to pop out of place. To avoid this, a vacuum is applied within the syringe barrel 11 to equilibrate the pressure within the syringe barrel 11 for a short period of time. However, in other examples, the steps of drawing a vacuum and pushing the stopper 30 may be performed sequentially or simultaneously by different assemblies or mechanisms. In FIG. 6, the plunger rod 38 and grip 26 of the stopper insertion assembly 14 move away from the syringe barrel 11, and the plunger rod 38 moves proximally and out of the syringe barrel 11, leaving the stopper 30 at a depth D1. The remaining vacuum pressure between the drug product 18 and the stopper 30 drives the stopper 30 to a final depth D2 as shown in FIG. 7. The final depth D2 is in the range of about 30 mm to 35 mm.Stopper 30 relaxes to its initial size once it reaches final depth D2 within syringe barrel 11. In particular, method 100 will position stopper 30 to a final depth D2 of 34.1±0.27 mm from distal end 22 of the reservoir of a 0.5 mL Thermo syringe when the plunger rod depth parameter is approximately 25.9 mm from distal end 22 of reservoir 13 and the vacuum pressure parameter is approximately 80 mBar.

[0026] The one-step method of placing a stopper in a prefilled syringe with a low drug product load, as shown in Figures 3-7, offers many advantages over current stoppering methods, particularly the VA method. For example, the one-step process reduces the variability of the final stopper position, thereby providing more uniform and predictable results, resulting in fewer prefilled syringe rejects after sterilization. The combination of mechanical insertion and vacuum-assisted technology provides a lower pressure differential in the reservoir, as compared to, for example, the VA method. As a result, the stopper 30 moves less than it does to reach its final depth, leading to minimal depth variability and more predictable placement within the target range. Furthermore, the plunger rod insertion assembly 24 allows the plunger rod 38 to drive the stopper 30 closer to the final depth D2, and the movement time of the stopper 30 from the initial depth D1 to the final depth D2 is significantly reduced compared to the VA method. Furthermore, the one-step method described herein reduces the potential risk of liquid in the stopper ribs, as shown in Table 1 below.

[0027] 9-12, a two-step process of placing a stopper at a target depth in a syringe barrel includes operating a stopper insertion assembly 54 on a pre-filled syringe 10 having a small drug product fill 18. FIG. 8 shows a first step 110 of a method 100 of aligning a stopper 30 with a syringe barrel 11. The pre-filled syringe 10 is partially filled with drug product 18 disposed in a reservoir 13 with a meniscus at a depth P. In one example using a 0.5 mL syringe, the depth P is in the range of about 0.15 mL to about 0.2 mL. The stopper insertion assembly 54 includes a grip 56 or vice that holds the stopper 30 over the open proximal end 11A of the syringe barrel 11 and aligns the stopper 30 with the longitudinal axis A of the syringe 10. The grip 56 may be part of a machine or automated system, such as a filling machine.

[0028] In a two-step process, the method 100 includes step 120 of applying vacuum pressure to the reservoir 11 prior to step 130 of forcing the stopper 30 into the syringe barrel 11. In FIG. 8, the grip 56 of the stopper insertion assembly 54 engages the flange 12 of the syringe 10 and draws a vacuum from the reservoir 13, thereby removing headspace from the syringe barrel 11. The application of a vacuum pressure in the range of about 70 mBar to about 85 mBar assists in the distal insertion of the plunger rod 68 through the syringe barrel 11, as shown in FIG. 9. In other words, the syringe barrel 11 is pressurized upon performing step 130 of forcing the stopper 30 distally by the plunger rod 68 of the insertion assembly 54. The plunger rod 68 sealingly engages the inner wall of the syringe barrel 11, driving the stopper 30 through the grip 56 and the open proximal end 11A of the syringe barrel 11. 10, plunger rod 58 extends into reservoir 13 of syringe barrel 11 and pushes stopper 30 to a first depth D1 above the meniscus of drug product 18 and within a range of about 30 mm to about 35 mm from distal end 22 of reservoir 13. In the illustrated example, stopper insertion assembly 54 performs the steps of drawing a vacuum and pushing stopper 30 with plunger rod 68. However, in other examples, the steps of drawing a vacuum and pushing stopper 30 may be performed by different assemblies or mechanisms.

[0029] In FIG. 11, the plunger rod 68 and grip 56 of the stopper insertion assembly 54 are disengaged from the syringe barrel 11, and the plunger rod 68 moves proximally and out of the syringe barrel 11. The remaining vacuum pressure between the drug product 18 and the stopper 30 drives the stopper 30 to a final depth D2 as shown in FIG. 12. The final depth D2 is in the range of about 30 mm to 35 mm. In particular, the method 100 will position the stopper 30 at a final depth D2 of 34.6±0.14 mm from the distal end 22 of the reservoir 13 when the plunger rod depth parameter is about 34.4 mm from the distal end 22 of the reservoir 13 and the vacuum pressure parameter is about 80 mBar.

[0030] The two-step method of placing the stopper in a prefilled syringe with a low drug product load, as shown in Figures 9-12, offers many advantages over current stoppering methods, particularly the VC method. For example, the two-step process reduces the variability of the final stopper position, thereby providing more uniform and predictable results, resulting in fewer prefilled syringe rejects after sterilization. The combination of mechanical insertion and vacuum compression technology provides a lower pressure differential in the reservoir, as compared to, for example, the VC method. As a result, the stopper 30 moves less than it would otherwise have to before reaching the final depth D2. Furthermore, the plunger rod insertion assembly 54 allows the plunger rod 68 to drive the stopper 30 closer to the final depth D2, and the movement time of the stopper to the final depth is significantly reduced. Furthermore, the two-step method described herein reduces the risk of plunger deformation, as shown in Table 1 below.

[0031] Table 1 below compares known methods (e.g., VA and VC) with the methods described herein (e.g., one-stage or VA+rod insertion method and two-stage or VC+rod insertion method), resulting in improved performance of the methods described herein. Specifically, the one-stage and two-stage methods shown in Figures 3-8 and 9-12, respectively, provide higher PPK values ​​and line speeds, as well as lower plunger travel speeds, deformations, and final depth variations.

[0032] [Table 1]

[0033] As shown in Table 1 above, the one-stage and two-stage methods disclosed herein provide improved standard deviations in final depth. For example, with the VA method, the final plunger depth is about 34.8±0.35 mm compared to about 34.6±0.14 mm for the one-stage method disclosed herein. This standard deviation is smaller for the VC+rod insertion method, but the failure rate is higher for the VC alone.

[0034] There are several factors that govern the performance of the plunger placement process, namely, the variability of the plunger position, the plunger deformation / defect rate, and the filling and stoppering line speed (i.e., the number of syringes filled and plunger plunged per unit time). As shown in Table 1 above, the PPK value of the one-step method disclosed herein is improved compared to the VA method. For example, the VA method had a PPK value of 3.17, while the one-step method disclosed herein had a PPK value of 3.7. Although the VC-only method shows a larger PPK, better performance can be achieved by VC+rod insertion. For each method shown in Table 1 (except VC-only), 800 syringes were filled and stoppered. For the VC-only method, the defect rate was very high and a large sample size was not obtained.

[0035] Additionally, the line speed of the VA+ rod insertion method was reduced as a result of the time required to physically insert the stoppering rod into the syringe. For example, manually placing bottle caps onto bottles can be significantly faster than manually pushing each bottle cap into the neck of the bottle. Speeding up the process to match the speed of the non-rod insertion technique can increase the probability of introducing defects or machine errors due to the rapid pace of operation and rapid movements. Under ideal conditions, faster operating line speeds can be beneficial to reach increased throughput. While the plunger depth travel is faster, the line speed can be slower to avoid defects and machine errors.

[0036] Importantly, the disclosed one-stage and two-stage methods disclosed herein result in significantly faster stopper migration times. Typically, stoppers reach their final depth after 12-24 hours using the VA or VC methods. In comparison, stoppers reach their final depth in 5-20 minutes using the one-stage and two-stage methods disclosed herein. Plunger depth measurements were taken 20 minutes after stoppering, and results indicate that the plunger had reached 99% of the target depth.

[0037] Rejections due to stopper deformation and drug product between the stopper ribs were also significantly reduced. For example, with the VA-only method, 1.2% of the prefilled syringes had liquid in the stopper ribs, and with the VC-only method, 4.2% of the prefilled syringes had plunger deformation. Rejections due to liquid in the stopper ribs and plunger deformation were comparatively reduced when mechanical insertion components were integrated with each vacuum process. For example, when mechanical insertion was combined with VA, instances of liquid in the stopper ribs were reduced to 0.6% of the prefilled syringes. Furthermore, when mechanical insertion was combined with VC, plunger deformation was reduced to less than 0.1% of the prefilled syringes. The incidence of deformation was reduced and the severity of the "bending" of the main ribs of the stopper was also less pronounced.

[0038] Table 2 below compares the one-stage and two-stage methods described herein. As shown in the table, other factors may be considered when determining the appropriate "recipe" for plunger placement when using these methods. For example, the insertion rod speed, aeration time, and vacuum start stopper time and pressure may be altered to obtain more accurate results. The insertion rod speed refers to the speed at which the rod physically moves. The insertion position versus final plunger depth may vary depending on the balance of vacuum forces within the syringe barrel. As an example, if the stopper is physically placed just inside the top of the syringe barrel but a strong vacuum force is applied inside the syringe, the stopper will tend to move deeper into the syringe beyond the initial placement stage as pressures equilibrate.

[0039] [Table 2]

[0040] The stopper placement method 100 of Figure 2, which can be either a one-step or two-step process, uses vacuum and mechanical placement methods to place a stopper deep inside a syringe barrel 11 containing a drug product. For example, the syringe 10 can be a 0.5 mL Thermo syringe. However, the method 100 described herein can be useful with a variety of syringe sizes (e.g., 1 mL syringes, 2.25 mL syringes, 5 mL cartridges, etc.) filled with a drug product that occupies less than half the volume of the syringe barrel reservoir.

[0041] The above description describes various devices, assemblies, components, subsystems, and methods of use related to drug delivery devices. The devices, assemblies, components, subsystems, methods, or drug delivery devices may further include or be used with drugs, including, but not limited to, the drugs identified below and their generic and biosimilar equivalents. The term drug, as used herein, may be used interchangeably with other similar terms and may be used to refer to any type of drug or therapeutic material, including traditional and non-traditional drugs, nutraceuticals, supplements, biologics, biologically active agents and compositions, large molecules, biosimilars, biological equivalents, therapeutic antibodies, polypeptides, proteins, small molecules, and generic drugs. Non-therapeutic injectable materials are also included. The drugs may be in liquid form, lyophilized form, or reconstituted from a lyophilized form. The following exemplary list of drugs should not be considered exhaustive or limiting.

[0042] The drug is contained within a reservoir. In some cases, the reservoir is a primary container into which the drug is filled or pre-filled for treatment. The primary container can be a vial, cartridge, or pre-filled syringe.

[0043] In some embodiments, the reservoir of the drug delivery device may be loaded with or the device may be used with colony stimulating factors such as granulocyte colony stimulating factor (G-CSF). Such G-CSF formulations 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), UDENYCA® (pegfilgrastim-cbqv), Ziextenzo® (LA-EP2006; pegfilgrastim-bmez), or FULPHILA (pegfilgrastim-bmez).

[0044] In other embodiments, the drug delivery device may contain or be used with an erythropoietin stimulating agent (ESA), which may be in liquid or lyophilized form. An ESA is any molecule that stimulates erythropoietin. In some embodiments, an ESA is an erythropoietin stimulating protein. As used herein, "erythropoietin stimulating protein" refers to any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to the receptor and causing receptor dimerization. Erythropoietin stimulating proteins include erythropoietin and 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 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 molecules or variants or analogs thereof.

[0045] Among certain exemplary proteins are the specific proteins described below, including fusions, fragments, analogs, variants, or derivatives thereof: OPGL-specific antibodies (also referred to as RANKL-specific antibodies, peptibodies, etc.), peptibodies, and related proteins, including fully humanized and human OPGL-specific antibodies, particularly fully humanized monoclonal antibodies; myostatin-binding proteins, peptibodies, related proteins, including myostatin-specific peptibodies; IL-4 receptor-specific antibodies, peptibodies, related proteins, and the like, which in particular inhibit activities mediated by binding of IL-4 and / or IL-13 to its receptors; Interleukin 1-receptor 1 ("IL1-R1") specific antibodies, peptibodies, related proteins, etc.; Ang2 specific antibodies, peptibodies, related proteins, etc.; NGF specific antibodies, peptibodies, related proteins, etc.; CD22 specific antibodies, peptibodies, related proteins, etc., especially dimers of human-mouse monoclonal hLL2 gamma chain disulfide bound to human-mouse monoclonal hLL2 kappa chain, e.g., the human form of epratuzumab (CAS Registry No. 501423-23-0). Human CD22-specific antibodies, including but not limited to humanized and fully human antibodies, including but not limited to humanized and fully human monoclonal antibodies, including but not limited to human CD22-specific IgG antibodies, such as a CD22-specific fully humanized antibody; IGF-1 receptor-specific antibodies, peptibodies, and related proteins, including but not limited to anti-IGF-1R antibodies; B-7-related protein 1-specific antibodies, peptibodies, and related proteins, including but not limited to those that inhibit the interaction of B7RP-1 with ICOS, the natural receptor for B7RP-1 on activated T cells, including but not limited to a B7RP-specific fully human monoclonal IgG2 antibody, including but not limited to a fully human IgG2 monoclonal antibody that binds to an epitope in the first immunoglobulin-like domain of B7RP-1; HuMax IL-15 specific antibodies, peptibodies, related proteins, etc., including, but not limited to, IL-15 antibodies and related proteins, particularly humanized monoclonal antibodies; human IFNIFN gamma specific antibodies, peptibodies, related proteins, etc., including but not limited to, anti-IFN gamma specific antibodies, and including but not limited to, fully human anti-IFN gamma 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 that target HGF / SF; hepatocyte growth factor ("HGF") specific antibodies, peptibodies, related proteins, etc., including those that bind to hepatocyte growth factor ("HGF") specific antibodies, peptibodies, related proteins, etc.; 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, including but not limited to proteins that bind to c-Kit and / or other stem cell factor receptors. etc.; OX40L-specific antibodies, peptibodies, related proteins, etc., including but not limited to proteins that bind OX40L and / or other ligands of the OX40 receptor; Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), erythropoietin [30-asparagine, 32-threonine, 87-valine, 88-asparagine, 90-threonine], darbepoetin alfa, novel erythropoiesis-stimulating protein (NESP), Epog en® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon-beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-alpha4beta7mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Kanjinti™ (trastuzumab-anns) anti-HER2 monoclonal antibody, a biosimilar of Herceptin® or another product containing trastuzumab for the treatment of breast or gastric cancer, Humatrope® (somatropin, human growth hormone), Humira® (adalimumab), (panitumumab), Vectibix® (panitumumab), Xgeva® (denosumab), Prolia® (denosumab), immunoglobulin G2 human monoclonal antibody against RANK ligand, Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Nplate® (romiplostim), rilotumumab, ganitumab, conatumumab, brodalumab, insulin in solution, Infergen® (interferon alfacon-1), Natrecor® (nesiritide, recombinant human B-type natriuretic peptide (hBNP), Kineret® (anakinra), Leukine® (sargamostim, rhuGM-CSF), LymphoCide® (epratuzumab, anti-CD22 mAb), Benlysta™ (Lymphostat B, Belimumab, Anti-BlySmAb), Metalyse® (tenecteplase, t-PA analog), Mircera® (methoxypolyethylene glycol-epoetin beta), Mylotarg® (gemtuzumab ozogamicin), Raptiva® (efalizumab), Cimzia® (certolizumab pegol, CDP870), Soliris™ (eculizumab), pexelizumab (anti-complement C5), Numax® (MEDI-524), Lucentis® (ranibizumab), Panorex® (17-1A, edrecolomab), Trabio® (lerdelimumab), TheraCim hR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem® (IDM-1), OvaRex® (B43.13), Nuvion® (vigilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GP IIb / IIia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolimumab), Mvasi™ (bevacizumab-awwb), Rituxan® (rituximab, anti-CD20mAb), Tarceva® (erlotinib), Roferon-A® (interferon alpha-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 145c7-CHO (anti-IL15 antibody, see U.S. Pat. No. 7,153,507), Tysabri® (natalizumab, anti-alpha4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax™, Xolair® (omalizumab), ETI211 (anti-MRSA mAb), IL-1 trap (the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)), VEGF trap (VEGFR1 Ig domain fused to IgG1 Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimibe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23 mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist), CNTO148 (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-Clostridium difficile toxin A and toxin BC mAbs MDX-066 (CDA-1) and MDX-1388), anti-CD22 dsFv-PE38 conjugate (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax-TAC), anti-CD3 mAb (NI-0401), adecatumumab, anti-CD30 mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMaxCD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF Idiopathic Pulmonary Fibrosis Phase 1 Fibrogen (FG-3019), anti-CTLA4 mAb, anti-Eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-Ganglioside GD2 mAb, anti-Ganglioside GM2 mAb, anti-GDF-8 Human mAb (MYO-029), anti-GM-CSF Receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-198), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12 mAb (ABT-874), anti-IL12 / IL23 mAb (CNTO1275), anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 Receptor mAb, anti-Integrin Receptor mAb (MDX-018, CNTO95), 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).

[0046] In some embodiments, the drug delivery device may contain or be used in conjunction with a sclerostin antibody, such as, but not limited to, romosozumab, brosozumab, BPS 804 (Novartis), Evenity™ (romosozumab-aqqg), another product containing romosozumab for the treatment of postmenopausal osteoporosis and / or fracture healing, and in other embodiments, a monoclonal antibody (IgG) that binds to human proprotein convertase subtilisin / kexin type 9 (PCSK9). Such PCSK9-specific antibodies include, but are not limited to, Repatha® (evolocumab) and Praluent® (alirocumab). In other embodiments, the drug delivery device may contain or be used in conjunction with rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the reservoir of the drug delivery device may be loaded with, or the device may be used with, IMLYGIC® (talimogene laherparepvec) or another oncolytic HSV for the treatment of melanoma or other cancers, including but not limited to, OncoVEXGALV / CD; OrienX010; G207, 1716; NV1020; NV12023; NV1034; and NV1042. In some embodiments, the drug delivery device may contain, or be used with, an endogenous tissue inhibitor of metalloproteinases (TIMP), such as but not limited to, TIMP-3. In some embodiments, the drug delivery device may contain, or be used with, Aimovig® (erenumab-aooe), anti-human CGRP-R (calcitonin gene-related peptide type 1 receptor), or another product containing erenumab for the treatment of migraines. Antagonistic antibodies to the human calcitonin gene-related peptide (CGRP) receptor, including but not limited to erenumab and bispecific antibody molecules targeting the human CGRP receptor and other headache targets, may also be delivered using the drug delivery devices of the present disclosure.In addition, bispecific T cell engager (BiTE®) molecules, such as, but not limited to, BLINCYTO® (blinatumomab), may be used in or with the drug delivery device of the present disclosure. In some embodiments, the drug delivery device may contain or be used with an APJ large molecule 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 device of the present disclosure. In some embodiments, the drug delivery device may contain or be used with Avsola™ (infliximab-axxq), an anti-TNFα monoclonal antibody, a biosimilar of Remicade® (infliximab) (Janssen Biotech, Inc.), or another product containing infliximab for the treatment of autoimmune diseases. In some embodiments, the drug delivery device may contain or be used in conjunction with Kyprolis® (carfilzomib), (2S)-N-((S)-1-((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4-methylpentanamide, or another product containing carfilzomib for the treatment of multiple myeloma. In some embodiments, the drug delivery device may contain or be used in conjunction with Otezla® (apremilast), N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide, or another product containing apremilast for the treatment of various inflammatory diseases.In some embodiments, the drug delivery device may contain or be used in conjunction with Parsabiv™ (etelcalcetide HCl, KAI-4169) or another product containing etelcalcetide HCl for the treatment of secondary hyperparathyroidism (sHPT), such as in patients with chronic kidney disease (KD) undergoing hemodialysis. In some embodiments, the drug delivery device may contain or be used in conjunction with ABP 798 (rituximab), a biosimilar candidate of Rituxan® / MabThera™, or another product containing an anti-CD20 monoclonal antibody. In some embodiments, the drug delivery device may contain or be used in conjunction with a VEGF antagonist, such as a non-antibody VEGF antagonist, and / or a VEGF trap, such as aflibercept (Ig domain 2 from VEGFR1 and Ig domain 3 from VEGFR2 fused to the Fc domain of IgG1). In some embodiments, the drug delivery device may contain or be used with ABP 959 (eculizumab), a biosimilar candidate of Soliris®, or another product containing a monoclonal antibody that specifically binds to complement protein C5. In some embodiments, the drug delivery device may contain or be used with rogivafusp alfa (formerly AMG 570), a new bispecific antibody-peptide conjugate that simultaneously blocks ICOSL and BAFF activity. In some embodiments, the drug delivery device may contain or be used with omecamtiv mecarbil, a small molecule selective cardiac myosin activator or myotrope that directly targets the contractile machinery of the heart, or another product containing a small molecule selective cardiac myosin activator. In some embodiments, the drug delivery device may contain or be used with sotorasibe (formerly known as AMG 510), a KRASG12C small molecule inhibitor, or another product containing a KRASG12C small molecule inhibitor. In some embodiments, the drug delivery device may contain or be used in conjunction with tezepelumab, a human monoclonal antibody that inhibits the action of thymic stromal lymphopoietin (TSLP), or another product containing a human monoclonal antibody that inhibits the action of TSLP.In some embodiments, the drug delivery device may contain or be used with AMG 714, a human monoclonal antibody that binds interleukin-15 (IL-15), or another product that contains a human monoclonal antibody that binds interleukin-15 (IL-15). In some embodiments, the drug delivery device may contain or be used with AMG 890, a lipoprotein(a)-reducing antibody also known as Lp(a), a small interfering RNA (siRNA) or another product that contains a small interfering RNA (siRNA) that reduces lipoprotein(a). In some embodiments, the drug delivery device may contain or be used with ABP 654, a human IgG1 kappa antibody, a biosimilar candidate of Stelara®, or another product that contains a human IgG1 kappa 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 contain or be used with another product that includes Amjevita™ or Amgevita™ (formerly ABP501) (monoclonal antibody anti-TNF human IgG1), a biosimilar candidate for Humira®, or a human monoclonal antibody anti-TNF human IgG1. In some embodiments, the drug delivery device may contain or be used with another product that contains AMG 160, or a half-life extended (HLE) anti-prostate specific membrane antigen (PSMA) x anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with another product that contains AMG 119, or a 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 another product that contains AMG 119, or a 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 polypeptide receptor (GIPR) antagonist and a GLP-1R agonist. In some embodiments, the drug delivery device may contain or be used with AMG 171, or another product containing a growth differentiation factor 15 (GDF15) analog. In some embodiments, the drug delivery device may contain or be used with AMG 176, or another product containing a small molecule inhibitor of myeloid cell leukemia 1 (MCL-1). In some embodiments, the drug delivery device may contain or be used with AMG 199, or another product containing a half-life extended (HLE) bispecific T cell engager construct (BiTE®). In some embodiments, the drug delivery device may contain or be used with AMG 256, or another product containing an anti-PD-1 x IL21 mutein 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 contain or be used with AMG 330, or another product containing an anti-CD33 x anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with AMG 404, or another product containing a human anti-programmed cell death-1 (PD-1) monoclonal antibody being investigated as a treatment for patients with solid tumors. In some embodiments, the drug delivery device may contain or be used in conjunction with AMG 427 or another product containing a half-life extended (HLE) anti-fms-like tyrosine kinase 3 (FLT3) x anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used in conjunction with AMG 430 or another product containing an anti-Jagged-1 monoclonal antibody.In some embodiments, the drug delivery device may contain or be used with AMG 506 or another product containing a multispecific FAPx4-1BB targeted DARPin® biologic being investigated as a treatment for solid tumors. In some embodiments, the drug delivery device may contain or be used with AMG 509 or another product containing a bivalent T cell engager and designed using XmAb® 2+1 technology. In some embodiments, the drug delivery device may contain or be used with AMG 562 or another product containing a half-life extended (HLE) CD19xCD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with efavalukin alfa (formerly AMG 592) or another product containing an IL-2 mutein Fc fusion protein. In some embodiments, the drug delivery device may contain or be used with. AMG 596, or another product containing CD3 x epidermal growth factor receptor vIII (EGFRvIII) BiTE® (bispecific T cell engager) molecules. In some embodiments, the drug delivery device may contain or be used with AMG 673, or another product containing a half-life extended (HLE) anti-CD33 x anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with AMG 701, or another product containing a half-life extended (HLE) anti-B cell maturation antigen (BCMA) x anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with AMG 757, or another product containing a half-life extended (HLE) anti-delta-like ligand 3 (DLL3) x anti-CD3 BiTE® (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used in conjunction with AMG 910 or another product containing the half-life extended (HLE) epithelial cell tight junction component protein claudin 18.2 x CD3 BiTE® (bispecific T cell engager) construct.

[0047] Although the drug delivery devices, assemblies, components, subsystems and methods have been described in terms of exemplary embodiments, they are not limited to the exemplary embodiments. The detailed description should be construed as merely exemplary and does not describe all possible embodiments of the present disclosure. Various alternative embodiments can be implemented using either current technology or technology developed after the filing date of this patent, but such embodiments still fall within the scope of the claims that define the invention disclosed herein.

[0048] Those skilled in the art will understand that various modifications, alterations and combinations may be made to the above-described embodiments without departing from the spirit and scope of the present invention disclosed herein, and that such modifications, alterations and combinations are to be construed as falling within the scope of the concept of the present invention.

Claims

1. 1. A method of placing a stopper on a syringe barrel partially filled with a drug product, comprising: aligning the stopper with a longitudinal axis of the syringe barrel, the syringe barrel including a proximal end, a distal end, and a reservoir, the drug product being disposed within the distal end of the reservoir at the distal end of the syringe barrel; applying a vacuum pressure to the reservoir of the syringe barrel, the vacuum pressure being in the range of about 70 mBar to about 85 mBar; using a plunger rod to push the stopper into the reservoir of the syringe barrel to a first depth, thereby creating a pressure differential across the stopper, the first depth being within a range of about 20 mm to about 40 mm from the distal end of the reservoir; releasing the plunger rod from the stopper after pushing the stopper to the first depth, thereby creating the pressure differential across the stopper and displacing the stopper to a second depth different from the first depth; A method comprising:

2. The method of claim 1 , wherein pressing the stopper comprises inserting the plunger rod into the reservoir of the syringe barrel.

3. 3. The method of claim 1 or 2, wherein applying the vacuum pressure at least partially corresponds to forcing the stopper into the reservoir of the syringe barrel with the plunger rod.

4. 4. The method of claim 3, wherein pushing the stopper comprises pushing the stopper into the syringe barrel a distance in the range of about 23 mm to 32 mm from the distal end.

5. 3. The method of claim 1, wherein pushing the stopper comprises pushing the stopper after applying the vacuum pressure to the syringe barrel.

6. 6. The method of claim 5, wherein pushing the stopper comprises pushing the stopper into the syringe barrel a distance in a range of about 30 mm to about 35 mm from the distal end of the reservoir.

7. 3. The method of claim 1, wherein aligning the stopper comprises positioning the stopper near the proximal end of the syringe barrel before inserting the stopper into the reservoir of the syringe barrel.

8. 3. The method of claim 1 or 2, wherein aligning the stopper comprises compressing the stopper using a grip near the proximal end of the syringe barrel and pushing the compressed stopper through the grip and into the reservoir of the barrel using the plunger rod.

9. 3. The method of claim 1 or 2, wherein applying the vacuum pressure comprises evacuating a headspace above the drug product in the syringe barrel and applying a vacuum to the proximal end of the syringe barrel.

10. The method of claim 1 or 2, further comprising removing the plunger rod from the reservoir of the syringe barrel.

11. 1. A method of placing a stopper on a syringe barrel partially filled with a drug product, comprising: aligning the stopper with a longitudinal axis of the syringe barrel, the syringe barrel including a proximal end, a distal end, and a reservoir, the drug product being disposed within the distal end of the reservoir at the distal end of the syringe barrel; applying a vacuum pressure to the reservoir of the syringe barrel; forcing the stopper into the reservoir of the syringe barrel to a first depth using a plunger rod, thereby creating a pressure differential across the stopper, the plunger rod extending into the reservoir of the syringe barrel; releasing the plunger rod from the stopper after pushing the stopper to the first depth, thereby creating the pressure differential across the stopper and displacing the stopper to a second depth different from the first depth; A method comprising:

12. 12. The method of claim 11, wherein applying the vacuum pressure to the syringe barrel comprises applying a pressure in a range of about 70 mBar to about 85 mBar.

13. 13. The method of claim 11 or 12, wherein pushing the stopper comprises pushing the stopper into the syringe barrel a distance in a range of about 20 mm to about 40 mm from the distal end of the reservoir.

14. 13. The method of claim 11 or 12, wherein applying the vacuum pressure at least partially coincides with forcing the stopper into the reservoir of the syringe barrel with the plunger rod.

15. 13. The method of claim 11 or 12, wherein pushing the stopper comprises pushing the stopper after applying the vacuum pressure to the syringe barrel.

16. 15. The method of claim 14, wherein pushing the stopper comprises pushing the stopper into the syringe barrel a distance within a range of about 23 mm to 32 mm from the distal end of the reservoir.

17. 16. The method of claim 15, wherein pushing the stopper comprises pushing the stopper into the syringe barrel a distance in a range of about 30 mm to about 35 mm from the distal end of the reservoir.

18. 13. The method of claim 11 or 12, wherein aligning the stopper comprises: (a) positioning the stopper near the proximal end of the syringe barrel before inserting the stopper into the reservoir of the syringe barrel; and / or (b) compressing the stopper using a grip near the proximal end of the syringe barrel and using the plunger rod to push the compressed stopper through the grip and into the reservoir of the barrel.

19. 13. The method of claim 11 or 12, wherein applying the vacuum pressure comprises evacuating a headspace above the drug product in the syringe barrel and applying a vacuum to the proximal end of the syringe barrel.

20. 13. The method of claim 11 or 12, further comprising removing the plunger rod from the reservoir of the syringe barrel.

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