System and method for limiting sub-visible particles in syringe

Abstract

A method of confining sub-visible particles in a syringe partially filled with a pharmaceutical product. The method includes applying an amount of silicone oil to a syringe barrel of the syringe, and the amount of silicone oil is in a range of about 0.4 mg to about 0.6 mg. The syringe barrel includes a proximal end, a distal end, and a reservoir, and the drug product is disposed in the distal end of the reservoir at the distal end of the syringe barrel. The method further includes placing the plunger portion into the syringe barrel to a depth within the syringe barrel and creating an air gap between the plunger portion and the drug product. The plunger portion is spaced apart from the drug product, and the air gap has an air gap length in the range of about 1.2 mm to about 3.5 mm.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 402,355, filed on August 30, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to a syringe partially filled with a drug product, and more particularly to a system and method for limiting sub-visible particles in a large volume syringe partially filled with a drug product. Background Art

[0004] A syringe is a medical delivery device used to administer a drug product to a patient. Syringes are often sold in prefilled form with a set dose of drug product already placed in it. Additionally, some prefilled syringes are developed specifically for integration with autoinjectors or other injection devices. In order to be integrated with an autoinjector or other injection device, the prefilled syringe must meet certain requirements. One requirement is that the drug product in the prefilled syringe must comply with the United States Pharmacopeial Convention (USP) USP No. <787> Chapter (USP <787> ) "Subvisible Particles in Therapeutic Protein Injectables" includes 6,000 particles / container for particles ≥10 μm and 600 particles / container for particles ≥25 μm. As the biopharmaceutical industry moves toward higher viscosity and potentially larger volume injectables, there is a need for larger doses that can be delivered subcutaneously while still meeting USP <787> syringes per container. Because USP <787> Limits are defined per container rather than per volume, so larger syringe systems inherently present greater challenges in complying with specified limits. <787> Intrinsically generated subvisible particles, such as those generated by silicone oil, are not distinguished in determining the total subvisible particle count.

[0005] Silicone oil, commonly used in the pharmaceutical industry, is often applied to the inner surface of syringe barrels to facilitate movement of the plunger stopper during injection and / or actuation of the device. However, silicone oil is known to be a major source of subvisible particle counts, including subvisible particles (SbVP) in the 10 μm range. In addition, products shipped via a typical shipping channel produced higher average subvisible particle counts compared to unshipped controls. Summary of the invention

[0006] According to a first aspect of the present disclosure, a method of limiting subvisible particles in a syringe partially filled with a drug product includes: applying a certain amount of silicone oil to a syringe barrel of a syringe, the syringe barrel including a proximal end, a distal end, and a reservoir, wherein the drug product is placed in the distal end of the reservoir at the distal end of the syringe barrel, and the amount of silicone oil is in the range of about 0.4 mg to about 0.6 mg. The method further includes placing a plunger portion into the syringe barrel to a certain depth within the syringe barrel, the plunger portion being spaced apart from the drug product; and creating an air gap between the plunger portion and the drug product. The air gap length of the air gap is in the range of about 1.2 mm to about 3.5 mm.

[0007] According to a second aspect of the present disclosure, a method of limiting subvisible particles in a syringe partially filled with a drug product includes: applying a certain amount of silicone oil to a syringe barrel of a syringe, the syringe barrel including a proximal end, a distal end, and a reservoir, wherein the drug product is placed in the distal end of the reservoir at the distal end of the syringe barrel, and the amount of silicone oil is in the range of about 0.4 mg to about 0.6 mg. The method also includes placing the syringe in a carton and placing the carton in a suspension packaging system, the suspension packaging system being configured to reduce the generation of subvisible particles in the syringe during transportation of the carton. The suspension packaging system includes a packaging material that surrounds the carton including the syringe, thereby limiting contact between the carton and the packaging material.

[0008] According to another aspect of the present disclosure, a syringe partially filled with a drug product includes a syringe barrel, the syringe barrel including a proximal end, a distal end, and a reservoir, wherein the drug product is placed in the distal end of the reservoir at the distal end of the syringe barrel. The syringe barrel includes a certain amount of silicone oil in the range of about 0.4 mg to about 0.6 mg, and the amount of silicone oil is configured to limit the amount of subvisible particles generated in the syringe barrel. The syringe further includes: a plunger portion, which is placed at a certain depth in the syringe barrel and is spaced apart from the drug product; and an air gap, which is placed between the plunger portion and the drug product. The air gap length of the air gap is in the range of about 1.2 mm to about 3.5 mm.

[0009] In further accordance with any one or more of the foregoing aspects, a syringe partially filled with a drug product and a method of limiting subvisible particles in a syringe partially filled with a drug product may include any one or more of the following forms.

[0010] In one form, applying the amount of silicone oil to the syringe barrel may include applying the amount of silicone oil to the syringe barrel wherein the fill volume of the reservoir is in a range of about 1.0 mL to about 3.0 mL.

[0011] In another form, applying an amount of silicone oil to a syringe barrel may include applying the amount of silicone oil to an inner surface of the syringe barrel along the length of the syringe barrel, thereby facilitating movement of a plunger during injection of a drug product in the syringe and reducing the amount of subvisible particles generated in the syringe.

[0012] In another form, placing the plunger portion into the syringe barrel may include placing a stopper into the syringe barrel to a depth within the syringe barrel, the stopper being spaced apart from the drug product.

[0013] In one form, creating an air gap between the plunger portion and the drug product may include creating an air gap between a distal-most point of the plunger portion and a meniscus of the drug product disposed in the distal end of the reservoir.

[0014] In another form, the method may further include placing the syringe in a carton and placing the carton in a suspension packaging system configured to reduce generation of sub-visible particles in the syringe during transportation of the carton. In one form, placing the carton in the suspension packaging system may include placing the carton in a housing of the suspension packaging system and positioning packaging material at least partially around the carton including the syringe within the housing to limit contact of the carton with the packaging material during movement. The packaging material may include one or more of padding, foam, bubble wrap, or a cushioning plastic material.

[0015] In another form, the method may further include placing a plunger portion into the syringe barrel to a depth within the syringe barrel, the plunger portion being spaced apart from the drug product. Additionally, placing the plunger portion into the syringe barrel may include placing a stopper into the syringe barrel to a depth within the syringe barrel, the stopper being spaced apart from the drug product.

[0016] In yet another form, the method may include creating an air gap between a plunger portion disposed within the syringe barrel and the drug product, the air gap having an air gap length in a range of about 1.2 mm to about 3.50 mm.

[0017] In yet another form, the syringe barrel may further include an inner surface and a length, and the amount of silicone oil may be disposed on the inner surface along at least a portion of the length of the syringe barrel.

[0018] In another form, the fill volume of the reservoir of the syringe barrel may be in the range of about 1.0 mL to about 3.0 mL.

[0019] In another form, the plunger portion may be a stopper.

[0020] In yet another form, the air gap length may comprise the distance between the distal-most point of the plunger portion and the meniscus of the drug product disposed in the distal end of the reservoir.

[0021] In yet another form, a suspension packaging system may include: a housing having an inner wall forming an interior region; a packaging material disposed within the housing, adjacent to the inner wall and / or at least partially surrounding the inner wall; and a carton including a syringe. The carton may be disposed within the packaging material and may be constrained to contact the packaging material, thereby reducing the amount of subvisible particles generated in the syringe during transport. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] It is believed that the present disclosure will be more fully understood from the following description in conjunction with the accompanying drawings. Some of the drawings may have been simplified by omitting selected elements in order to more clearly illustrate other elements. In some drawings, such element omissions do not necessarily indicate the presence or absence of a particular element in any example embodiment, unless it may be clearly indicated in the corresponding written description. Moreover, all drawings are not necessarily drawn to scale.

[0023] Figure 1 is a partial cross-sectional view of a syringe partially filled with a drug product according to the present disclosure;

[0024] Figure 2 It is a depiction Figure 1 Figure 2 shows the effect of air gaps in syringes on subvisible particle generation;

[0025] Figure 3 is a graph depicting sub-visible particles as a function of air gap length in a syringe of the present disclosure;

[0026] Figure 4 is a graphical representation of the silicone oil thickness along the length of the syringe barrel as a function of distance from the syringe flange;

[0027] Figure 5 is a graph depicting the effect of silicone oil amount on subvisible particle generation;

[0028] Figure 6 is a graph depicting the effect of silicone oil nozzle on subvisible particle generation in a syringe;

[0029] Figure 7 is a graph depicting the effect of fill volume on subvisible particle generation in a syringe; and

[0030] Figure 8 is a suspension packaging system in which a syringe according to the present disclosure is disposed. DETAILED DESCRIPTION

[0031] Overall, the authors disclose methods for optimizing the production of large volume prefilled syringes to meet USP <787> Systems and methods for defining subvisible particle limits. The manufacturing attributes found to have the greatest impact and limit on average subvisible particle counts include: (1) the amount of silicone placed in the syringe barrel of a large volume syringe; (2) the packaging configuration system used to limit subvisible particles during shipping of the syringe; (3) the length of the air gap provided between the plunger portion placed in the syringe barrel and the drug product; and (4) the fill volume of the reservoir of the syringe barrel. More specifically, a method for limiting subvisible particles in a syringe partially filled with a drug product may include one or more of the following steps: (1) applying a certain amount of silicone oil to the inner surface of a syringe barrel of the syringe, wherein the amount of silicone oil is in the range of about 0.4 mg to 0.6 mg; (2) using a syringe barrel with a fill volume in the range of about 1.0 mL to about 3.0 mL; (3) placing a plunger portion into the syringe barrel and creating an air gap between the plunger portion and the drug product, the air gap having an air gap length in the range of about 1.2 mm to about 3.5 mm; and (4) placing the syringe in a carton and placing the carton within packaging material in a housing of a suspension packaging system, thereby reducing the generation of subvisible particles in the syringe during movement and / or transportation of the carton.

[0032] More specifically, now refer to Figure 1 , depicts a syringe 10 partially filled with a drug product that meets the subvisible particle limit. The syringe 10 includes a syringe barrel 12, which includes a proximal end 12a, a distal end 12b, an inner surface 12c, a flange 13 disposed near the proximal end 12a, and a reservoir 14. The reservoir 14 can have a larger fill volume, such as a fill volume in the range of about 1.0mL to 3.0mL, while still meeting the required subvisible particle limit, as explained in more detail below. The drug product 16 is placed in the distal end 14b of the reservoir 14 at the distal end 12b of the syringe barrel 12. In addition, the inner surface 12c of the syringe barrel 12 has a certain amount of silicone oil 18 applied thereto, and the amount of silicone oil 18 disposed on the inner surface 12c is in the range of about 0.4mg to about 0.6mg. In one example, the optimal amount of silicone oil 18 disposed on the inner surface 12c is 0.5mg, also as explained in more detail below. This amount of silicone oil is configured to limit the amount of sub-visible particles generated in the syringe barrel 12 .

[0033] Still refer to Figure 1, the plunger portion 20 is placed at a depth D within the syringe barrel 12, and the plunger portion 20 is spaced apart from the drug product 16. In one example, the plunger portion 20 is a stopper. Typically, and as will be appreciated, two stoppering techniques for placing a plunger into a prefilled syringe can be used to place the plunger portion 20 within the syringe barrel 12: (1) ventilated placement; and (2) vacuum assisted. For ventilated placement, the stopper 20 is placed on top of a thin tube (not shown) commonly referred to as a vent tube, which is then inserted into the syringe 10. A plunger placement pin (not shown) pushes the stopper 20 down the tube to a depth determined by the length of the pin. The vent tube is then retracted, allowing the stopper 20 to expand and fill the syringe diameter. For vacuum assisted, a vacuum chamber (not shown) is used to reduce the pressure in the filled syringe 10. Once the target vacuum pressure is reached, the plunger portion 20 is placed inside the syringe barrel 12 to seal the syringe 10, and the chamber is then depressurized. The plunger portion 20 is then advanced into the syringe barrel 12 to a depth D at which the "seal pressure" is equal to the ambient pressure, thus determining the plunger portion depth. There is no significant difference in the average sub-visible particle count generated in the syringe 10 when the plunger portion 20 is placed in the syringe barrel 12 using either the vacuum assist or vent tube (vent placement) technique.

[0034] The syringe 10 further includes an air gap 22 disposed between the plunger portion 20 and the drug product 18, and the length 23 of the air gap 22 is in the range of about 1.2 mm to about 3.5 mm. More specifically, in one example, the length of the air gap is 1.4 mm. Figure 1 In another example, the length 23 of the air gap 22 is 2.3 mm, and in another example, the air gap length is 3.5 mm. More generally, the length 23 of the air gap 22 includes the distance between the farthest point 24 of the plunger portion 22 and the meniscus 25 of the drug product 18 disposed in the distal end 12b of the reservoir 12. Figure 1 A specific length of the air gap 22 is depicted, but it will be understood that the length 23 of the air gap 22 can be any value within or within the range of about 1.2 mm to about 3.5 mm and still fall within the scope of the present disclosure. In conventional vacuum-assisted plunger placement systems, the air gap length 23 is determined by the amount of vacuum drawn prior to inserting the plunger portion 20 into the syringe barrel 12. Stronger vacuums drawn on the syringe 10 produce smaller air gaps 22.

[0035] Reference now Figure 2, depicts a graph demonstrating the effect of the length 23 of the air gap 22, and in particular depicts the proportional relationship between the length 23 of the air gap 22 and the generation of subvisible particles. Specifically, a smaller length 23 of the air gap 22 is associated with a lower level of subvisible particles in the syringe 10. Additionally, data from testing of syringes having each of air gap lengths of 1.4 mm, 2.3 mm, and 3.5 mm are provided. For example, the subvisible particle count per container of the syringe 10 having an air gap length of 1.4 mm was below the USP limit of 6,000 subvisible particles for the vast majority of each sample tested. Additionally, the subvisible particle count per container of the syringe 10 having an air gap length of 2.3 mm was also below the USP limit of 6,000 subvisible particles on average, as shown in FIG. Figure 2 However, when the air gap length was increased to 3.5 mm, the subvisible particle count per container of syringe 10 exceeded the USP limit of 6,000 subvisible particles for several samples tested, further indicating that larger air gap lengths generally produce more subvisible particles than smaller air gap lengths.

[0036] Table 1: Particle counts per container and sample number according to air gap length

[0037]

[0038]

[0039] As demonstrated in Table 1 above, the effect of air gap length on average particle generation is proportionally related, indicating that larger air gap lengths produce significantly more particles than smaller air gap lengths. However, each data set still captures samples exceeding the USP limit of 6,000, but with less frequency as the air gap length decreases.

[0040] Reference now Figure 3 , depicts a graph showing sub-visible particle counts as a function of air gap length. The average particle count relative to the associated air gap was well approximated by a linear fit (R2=0.9996). Therefore, subsequent studies assumed a larger air gap length of 3.5 mm 23 as the worst case for sub-visible particle generation. The 3.5 mm air gap syringe system produced an average of 7,231 particles with a standard deviation of 4,567, while the 1.40 mm produced an average of 2,372 particles with a standard deviation of 2,388. This is an average reduction of 4,859 particles, showing that particle generation is reduced by about 67% and the standard deviation is reduced by 48% from a 3.5 mm air gap to a 1.4 mm air gap.

[0041] Reference now Figure 4 , depicts a graphical representation of the amount (e.g., thickness) of silicone oil 18 disposed on the inner surface 12c of the syringe barrel 12 as a function of distance from the flange 13 of the syringe barrel 12. The thick black line in the figure depicts the silicone distribution data for a syringe having an amount of 0.7 mg of silicone oil, and the lighter line depicts the silicone distribution data for a syringe having an amount of 0.5 mg of silicone oil 18. For example, the silicone distribution data (including the thickness of that amount of silicone oil 18) is significantly more uniform as the amount of silicone oil 18 applied to the inner surface 12c across the length of the syringe barrel 12 is reduced, such as at various distances from the flange 13. The reduced amount of silicone oil 18 applied is shown to produce a reduction in silicone oil particles in the drug product 16 while still providing an acceptable sliding force value for the syringe 10.

[0042] Reference now Figure 5 For example, the amount of silicone oil 18 applied to the inner surface 12c of the syringe barrel 12 greatly affects the generation of subvisible particles, such as during shipping of the syringe 10. Generally, an increase in the amount of silicone oil 18 can help reduce the plunger sliding force value in the syringe 10. Likewise, for example, an increase in the amount of silicone oil 18 can also result in an increase in the amount of silicone oil particles present after shipping the syringe 10, such as in a PFS 91.5 hour post-shipping simulation, thereby preventing the syringe 10 from meeting the subvisible particle requirement. Figure 5 , for example, when the syringe 10 included an amount of 0.7 mg of silicone oil 18, the syringe produced an average of 7,315 particles with a standard deviation of 4,096, which is an amount above the desired sub-visible particle limit of, for example, 6,000 particle counts per container. However, when the syringe 10 included an amount of 0.5 mg of silicone oil 18, the syringe 10 produced an average of 1,580 particles with a standard deviation of 696, which is well below the desired sub-visible particle limit. When reducing the amount of silicone oil 18 from 0.7 mg to 0.5 mg, there was a reduction of 5,735 particles on average, indicating a 78% reduction in particle generation.

[0043] Reference now Figure 6 , depicts a graph demonstrating the effect of a silicone oil nozzle on sub-visible particle generation in a syringe 10 of the present disclosure. In the production of the syringe 10, a variety of silicone oil application techniques may be utilized to achieve a target silicone oil distribution and amount as well as varying tolerances. In one example, a production line for a syringe 10 having a reservoir 14 with a fill volume of 3.0 mL is capable of using two nozzle systems to apply the amount of silicone oil 18 to the inner surface 12c of the syringe barrel 12. One nozzle system (e.g., IVEK, either industrial line or benchtop production scale) is a continuous airflow submersible nozzle system, and the other nozzle system is an intermittent airflow submersible nozzle, such as Bausch+Strobel, which is industrial line production scale. The sample being tested included 0.5 mg of silicone oil 18. As Figure 6 As depicted in FIG. 1 , a continuous airflow submersible nozzle system (e.g., an IVEK nozzle) shows improvements over an intermittent airflow submersible nozzle (e.g., a Bausch+Strobel system) with respect to subvisible particle generation. However, for example, both nozzle systems applying a 0.5 mg amount of silicone oil to the inner surface 12c of the syringe barrel 12 demonstrated that the particle size remained below the USP for a particle size of 10 μm. <787> Limit value, such as less than 6,000 particles per container, such as Figure 6 as shown in the results.

[0044] As mentioned above about Figure 1 As explained with reference to the syringe 10 of FIG. 1 , the reservoir 14 of the syringe barrel 12 can have a larger fill volume, such as a fill volume in the range of about 1.0 mL to 3.0 mL, while still meeting the required subvisible particle limit. For example, and with reference to Figure 7 , generally lower fill volumes exhibit lower silicone particle generation. Thus, for example, a fill volume of 3.0 mL of syringe 10 produces the highest subvisible particle generation, such as after shipping of syringe 10, compared to a lower fill volume of 1.0 mL that produces the lowest subvisible particle generation. More specifically, and as Figure 7 , the syringe 10 with a 3.0 mL fill volume produced an average of 1,580 particles with a standard deviation of 696, while the syringe 10 with a 1.0 mL fill volume produced an average of 703 particles with a standard deviation of 339. This is a reduction of 876 particles on average, showing, for example, a 55% reduction in particle generation and a 51% reduction in standard deviation from a 3.0 mL fill volume to a 1.0 mL fill volume.

[0045] Reference now Figure 8, depicting the suspension packaging system 100 of the present disclosure. The suspension packaging system 100 includes a housing 110 having an inner wall 112 forming an inner region 114. The suspension packaging system 100 further includes a packaging material placed in the housing 110, adjacent to the inner wall 112 and / or at least partially around the inner wall. In this example, a packaging material 116 is provided substantially around the entire inner wall 112 of the housing 110. Further, and in this example, there are four inner walls 112a, 112b, 112c, 112d, which form the housing 110 of a rectangular shape. However, it will be appreciated that the housing 110 and therefore the inner wall 112 can take the form of various other shapes (such as, circular and / or cylindrical), and still fall within the scope of the present disclosure. For example, if the shape of the housing 110 is circular, the shape of the inner wall 112 is also cylindrical, and the packaging material 116 is provided substantially around the entire circumference of the inner wall 112. As will be appreciated, the packaging material 116 may include one or more of padding, foam, bubble wrap, small pieces of Styrofoam, and / or cushioning plastic materials, for example, and still fall within the scope of the present disclosure.

[0046] like Figure 8 As further depicted in FIG. 1 , the suspension packaging system 100 also includes and / or is configured to receive a carton 118 including syringes 10, and typically a plurality of syringes 10 are placed in the carton 118. When so configured, the carton 118 is limited to contacting only the packaging material 116 (e.g., during transportation and / or movement of the carton 118), thereby reducing the amount of sub-visible particles generated in the syringes 10 during movement. During testing, the standard conventional packaging system produced an average of 1,580 particles / container with a standard deviation of 696, while Figure 8 The suspension packaging system 100 of ® produced an average of 566 particles per container with a standard deviation of 405. This is an average reduction of 1,015 particles per container, thereby showing, for example, a 64% reduction in particle generation and a 42% reduction in standard deviation over a standard conventional packaging system.

[0047] In view of at least the foregoing, various methods of limiting subvisible particles in the syringe 10 and the system 100 will be appreciated. For example, in one example, an exemplary method of limiting subvisible particles in a syringe 10 partially filled with a drug product 16 includes applying the amount of silicone oil 18 to a syringe barrel 12 of the syringe 10, such as along the length of the syringe barrel 10, the syringe barrel 10 including a proximal end 12a, a distal end 12b, and a reservoir 14, as explained above. The drug product 16 is disposed in the distal end 14b of the reservoir 14 at the distal end 12b of the syringe barrel 12, and the amount of silicone oil is in a range of about 0.4 mg to about 0.6 mg, thereby reducing the amount of subvisible particles generated based on the amount of silicone oil 18 applied. In one example, applying the amount of silicone oil 18 includes applying the amount of silicone oil 18 to the syringe barrel 12, wherein the fill volume of the reservoir 14 is in a range of about 1.0 mL to about 3.0 mL. In another example, applying the amount of silicone oil 18 to the syringe barrel 12 includes: applying the amount of silicone oil 18 to the inner surface 12c of the syringe barrel 12 and applying it along the length of the syringe barrel, the amount of silicone oil 18 facilitating movement of the plunger portion 20 during injection of the drug product 16 in the syringe 10 while reducing the amount of sub-visible particles generated in the syringe 10.

[0048] The method further includes placing the carton 118 including the syringes 10 in a suspension packaging system 100 configured to reduce generation of sub-visible particles in the syringes 10 during transport. The suspension packaging system 100 includes a packaging material 116 that is at least partially spaced around the carton 118 including the syringes 10, thereby limiting contact of the carton 118 including the syringes 10 with the packaging material 116. In one example, limiting contact of the carton 118 including the syringes 10 with the packaging material 116 includes limiting contact of the carton 118 with one or more of a dunnage, foam, bubble wrap, or a cushioning plastic material, thereby maintaining a position of the carton 118 within the suspension packaging system 100 during movement of the suspension packaging system 100 and / or the carton 118.

[0049] The method may also include placing the plunger portion 20 into the syringe barrel 12 to a depth D within the syringe barrel 12, such that the plunger portion 20 is spaced apart from the drug product 16. In some examples, placing the plunger portion 20 into the syringe barrel 12 includes placing the stopper 20 into the syringe barrel 12 to a depth D within the syringe barrel 12, the stopper 20 being spaced apart from the drug product 16. The method may still further include creating an air gap 22 between the plunger portion 20 disposed within the syringe barrel 12 and the drug product 16, and the air gap length 23 of the air gap is in the range of about 1.2 mm to about 3.5 mm, in one example, the air gap length 23 is 1.4 mm. In another example, the air gap length 23 is 2.3 mm, and in another example, the air gap length 23 is 3.5 mm.

[0050] Another exemplary method of limiting subvisible particles in a syringe 10 partially filled with a drug product 16 includes applying the amount of silicone oil 18 to a syringe barrel 12 of the syringe 10, the syringe barrel 12 including a proximal end 12a, a distal end 12b, and a reservoir 14. The drug product 16 is placed in the distal end 14b of the reservoir 14, at the distal end 12b of the syringe barrel 12, and the amount of silicone oil 17 is in the range of about 0.4 mg to about 0.6 mg. The method also includes placing a plunger portion 20 into the syringe barrel 12 to a depth D within the syringe barrel 12 and creating an air gap 22 between the plunger portion 20 and the drug product 16, the air gap length 23 of the air gap 22 being in the range of about 1.2 mm to about 3.5 mm.

[0051] In some examples of this method, applying the amount of silicone oil 18 to the syringe barrel 12 again includes: applying the amount of silicone oil 18 to the syringe barrel 12, wherein the fill volume of the reservoir 14 is in the range of about 1.0 mL to about 3.0 mL. In one example, for example, the fill volume is 3.0 mL, as explained above. In addition, applying the amount of silicone oil 18 to the syringe barrel 12 can further include: applying the amount of silicone oil 18 to the inner surface 12c of the syringe barrel 12, thereby facilitating the movement of the plunger portion 20 during the injection of the drug product of the syringe and reducing the amount of sub-visible particles generated in the syringe 10.

[0052] Further, placing the plunger portion 20 into the syringe barrel includes placing the stopper 20 into the syringe barrel 12 to a depth D within the syringe barrel 12, the stopper 20 being spaced apart from the drug product 16. Additionally, creating an air gap 22 between the plunger portion 20 and the drug product 16 may include creating an air gap 22 between a distal-most point of the plunger portion 20 and a meniscus 25 of the drug product 16 disposed in the distal end 12b of the reservoir 12. Still further, after creating the air gap 22 between the plunger portion 20 and the drug product 16, the method may further include placing the syringe 10 in a carton 118 and then placing the carton 118 in a suspension packaging system 100 configured to reduce generation of sub-visible particles in the syringe 10 during movement of the carton 118. Furthermore, placing the carton 118 in the suspension packaging system 100 may include placing the carton 118 within a housing 110 of the suspension packaging system 100 and positioning the packaging material 116 within the housing 110 at least partially around the carton 118 including the syringe 10, thereby limiting contact of the carton 118 with the packaging material 116 during movement. The packaging material 116 may include one or more of padding, foam, or a cushioning plastic material.

[0053] Various experiments related to the syringe 10, system 100 and method of the present disclosure described above were carried out to confirm various results and advantages of the present disclosure. More specifically, when performing the experiment, the exemplary sample syringe used included an OMPI 3.0mL syringe and a Daikyo-Seiko 3.0mL Flurotec coated Plungee. For example, the sample syringe was filled with 3.1mL of drug product and completed using the automated stopper placement technology described above. The sample syringe was then packaged as a prefilled syringe into a package consisting of three (3) times fourteen (14) counted rondo disks packaged into a standard carton for a syringe system. The sample syringe was then subjected to transport simulation, and then manually extruded and sub-visible particle counts were measured according to MET-404639 (HIAC) and MET-403619 (MFI). Additionally, other methods of SbVP quantification were used, such as the Microscopic Particle Count Test (MET-401787) for quantifying liquid-borne subvisible particulate matter and the HORIZON Aura system from Halo Labs. This series of studies used a transport test sequence that is typically performed as part of a Transport Operational Qualification (TOQ) study. This included a "91.5 hour" simulated transport test in which the syringe was subjected to many repeated drops, significant vibrations, and pressure changes that mimicked the transport factors that would occur during actual transport of the syringe. For example, a significant increase in subvisible particles in the syringe that exceeded acceptable limits occurred after such agitation. For this study, the circulation chamber was programmed to maintain a constant 18°C ​​for the duration of the simulation, as this was intended to simulate the transport of the sample prior to the subvisible particle test, and was not intended to test the ability of the insulated transport to maintain 2°C to 8°C. An overview of the data from the experiments performed is provided in Table 2 below.

[0054] Table 2: Overview of experiments performed on sample syringes

[0055]

[0056]

[0057] As demonstrated in Table 2, for example, a sample syringe having a fill volume of 3 mL, an air gap length of 3.5 mm, and a silicone oil amount of 0.5 mg had no samples that failed the subvisible particle limit requirement.

[0058] Further, while various attributes were investigated as potentially relevant to reducing particle count to mitigate and / or limit subvisible particle generation in syringes, the following attributes demonstrated the greatest reduction in particle count: (1) silicone amount; (2) packaging configuration; (3) air gap length; and (4) fill volume. For example, Table 3 below lists the attributes that had the greatest impact and were therefore used in the systems and methods of the present disclosure. Attributes that were found to have no impact on particle generation are also included in this table.

[0059] Table 3: Magnitude of effect of experimental attributes based on particle count reduction

[0060]

[0061] In view of at least the foregoing, the following various advantages of the systems and methods of the present disclosure will be appreciated. The syringe 10 and related methods apply and maintain an optimal amount of silicone oil 18 across the desired length of the syringe barrel 12 to maintain lubricity so as to facilitate movement of the plunger portion 20 (e.g., during injection) while reducing subvisible particles in the syringe 10, thereby meeting the required subvisible particle limit. In addition, placing the packaging material 116 around the carton 118 of the suspension packaging system 100 that includes the syringe 10 mitigates and / or reduces the impact on the syringe 10 during transportation and particularly during any drops (which are found to often generate the most subvisible particles), thereby limiting subvisible particles in the syringe 10. In addition, reducing and / or making the air gap length 22 within the range of about 1.2 mm and about 3.5 mm results in a smaller surface area of ​​the syringe barrel 12 to move liquid within the syringe 10, for example, resulting in a reduction in the amount of siliconized surface area of ​​the syringe barrel 12 exposed to the drug product 16. Further, for example, due to the reduced air gap length 22 and the surface area of ​​the syringe barrel 12, the amount of liquid movement to potentially remove some of the silicone oil 18 from the inner surface of the syringe barrel 12 is smaller, thereby resulting in maintaining a more uniform amount of silicone oil 18 on the inner surface 12c of the syringe barrel 12. Still further, by having the reservoir 14 have a lower fill volume in the range of about 1.0 mL to about 3.0 mL, the plunger portion 20 moves to a reduced depth D within the syringe barrel 12, for example, thereby again reducing the exposed surface area within the syringe barrel 12. The amount of sub-visible particles caused by the amount of silicone oil 18 is therefore also reduced.

[0062] Furthermore, by implementing the silicone oil 18 amounts described above within the syringe barrel 12 of the syringe 10 and placing the syringes 10 having such silicone oil 18 characteristics within a carton 118, and placing the carton 118 within the packaging material 116 of the suspension packaging system 100, a 94% reduction in average subvisible particle generation in the syringe 10 was achieved along with an 84% standard deviation. Additionally, the subvisible particle counts were consistently below the limits defined for the novel features of the present disclosure (e.g., explained above).

[0063] The above description describes various devices, assemblies, parts, subsystems and methods used in relation to drug delivery devices. These devices, assemblies, parts, subsystems, methods or drug delivery devices may further include or be used together with drugs, including but not limited to those drugs identified below and their generic counterparts and biosimilar counterparts. As used herein, the term drug can be used interchangeably with other similar terms, and can be used to refer to any type of medicament or therapeutic material, including traditional and non-traditional drugs, nutritional supplements, supplements, biologics, bioactive agents and compositions, macromolecules, biosimilars, bioequivalents, therapeutic antibodies, polypeptides, proteins, small molecules and generics. Non-therapeutic injectable materials are also covered. The drug can be in liquid form, in lyophilized form or in a form reconstructed by lyophilized form. The following example drug list should not be considered to be all-inclusive or restrictive.

[0064] The drug will be contained in a reservoir. In some cases, the reservoir is a primary container that is filled or pre-filled with the drug for treatment. The primary container can be a vial, cartridge, or pre-filled syringe.

[0065] In some embodiments, the reservoir of the drug delivery device can be filled with colony stimulating factors (e.g., granulocyte colony stimulating factor (G-CSF)), or the device can be used with these colony stimulating factors. Such G-CSF agents include, but are not limited to (Pegfilgrastim, Pegylated filgrastim, Pegylated G-CSF, Pegylated hu-Met-G-CSF) and (filgrastim, G-CSF, hu-MetG-CSF), (Pegfilgrastim-cbqv), (LA-EP2006; pegfilgrastim-bmez) or FULPHILA (pegfilgrastim-bmez).

[0066] In other embodiments, the drug delivery device may contain or be used with an erythropoiesis stimulating agent (ESA), which may be in liquid or lyophilized form. ESA is any molecule that stimulates erythropoiesis. In some embodiments, 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 the receptor and causing receptor dimerization). Erythropoiesis stimulating proteins include erythropoietin and its variants, analogs or derivatives, which bind to and activate the erythropoietin receptor; antibodies that bind to and activate the erythropoietin receptor; or peptides that bind to and activate the erythropoietin receptor. Erythropoiesis stimulating proteins include but are not limited to (Epoetin α), (darbepoetin alfa), (Epoetine δ), (methoxy polyethylene glycol-epoetin beta), MRK-2578, INS-22, (Epoetin ζ), (Epoetin β), (Epoetin ζ), (Epoetin α), Epoetin α hexal, (Epoetin α), (Epoetine θ), (Epoetine θ), (Epoetin theta), Epoetin alpha, Epoetin beta, Epoetin iota, Epoetin omega, Epoetin delta, Epoetin zeta, Epoetin theta and Epoetin delta, pegylated erythropoietin, carbamylated erythropoietin, and molecules or variants or analogs thereof.

[0067] Among the specific displayed proteins are the specific proteins set forth below, including fusions, fragments, analogs, variants or derivatives thereof: OPGL-specific antibodies, peptibodies, related proteins and the like (also referred to as RANKL-specific antibodies, peptibodies, and the like), including fully humanized and human OPGL-specific antibodies, particularly fully humanized monoclonal antibodies; myostatin binding proteins, peptibodies, related proteins and the like, including myostatin-specific peptibodies; IL-4 receptor-specific antibodies, peptibodies, related proteins and the like, particularly those that inhibit activity mediated by IL-4 and / or IL-13 binding to the receptor; interleukin 1 receptor 1 ("IL1-R1")-specific antibodies, peptibodies, related proteins and the like; Ang2-specific antibodies, peptibodies, related proteins and the like; NGF-specific antibodies, peptibodies, related proteins and the like; CD22-specific antibodies, peptibodies, related proteins and the like, particularly 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 dimers of human-mouse monoclonal hLL2γ chain disulfides linked to human-mouse monoclonal hLL2κ chains, such as the human CD22-specific fully humanized antibody in epratuzumab (CAS Reg. No. 501423-23-0); IGF-1 receptor-specific antibodies, peptibodies and related proteins, etc., including but not limited to anti-IGF-1R antibodies; B-7-related protein 1-specific antibodies, peptibodies, related proteins, etc. ("B7RP-1" and 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 that bind to epitopes in the first immunoglobulin-like domain of B7RP-1, including but not limited to those that inhibit the interaction of B7RP-1 with its natural receptor ICOS on activated T cells; IL-15-specific antibodies, peptibodies, related proteins, etc., such as, in particular, humanized monoclonal antibodies, including but not limited to HuMax IL-15 antibodies and related proteins, such as, for example, 145c7; IFNγ-specific antibodies, peptibodies, related proteins, and the like, including but not limited to human IFNγ-specific antibodies, and including but not limited to fully human anti-IFNγ antibodies; TALL-1-specific antibodies, peptibodies, related proteins, and the like, as well as other TALL-specific binding proteins; parathyroid hormone ("PTH")-specific antibodies, peptibodies, related proteins, and the like; thrombopoietin receptor ("TPO-R")-specific antibodies, peptibodies, related proteins, and the like; hepatocyte growth factor ("HGF")-specific antibodies, peptibodies, related proteins, and the like, 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, peptide bodies, related proteins, etc.; activin A specific antibodies, peptide bodies, proteins, etc.; TGF-β specific antibodies, peptide bodies, related proteins, etc.; amyloid-β specific antibodies, peptide bodies, related proteins, etc.; c-Kit specific antibodies, peptide bodies, related proteins, etc., including but not limited to proteins that bind to c-Kit and / or other stem cell factor receptors; OX40L specific antibodies, peptide bodies, related proteins, etc., including but not limited to proteins that bind to OX40L and / or other ligands of OX40 receptors; (alteplase, tPA); (Darbepoetin alfa) erythropoietin [30-asparagine, 32-threonine, 87-valine, 88-asparagine, 90-threonine], darbepoetin alfa, novel erythropoiesis-stimulating protein (NESP); (epoetin alfa, or erythropoietin); GLP-1, (interferon beta-1a); (tositumomab, anti-CD22 monoclonal antibody); (interferon-β); (alemtuzumab, anti-CD52 monoclonal antibody); (Epoetin delta); (bortezomib); MLN0002 (anti-?4β7 mAb); MLN1202 (anti-CCR2 chemokine receptor mAb); (etanercept, TNF receptor / Fc fusion protein, TNF blocker); (Epoetin alpha); (cetuximab, anti-EGFR / HER1 / c-ErbB-1); (Somatropin, human growth hormone); (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb); Kanjinti TM (Trastuzumab-anns) anti-HER2 monoclonal antibody, a biosimilar of trastuzumab or another product containing trastuzumab for the treatment of breast or gastric cancer; (Somatropin, human growth hormone); (adalimumab); (panitumumab), (Dinosutumab), (Dinosutumab), RANK ligand immunoglobulin G2 human monoclonal antibody, (etanercept, TNF-receptor / Fc fusion protein, TNF blocker), (romiplostim), rilotumumab, ganitumab, conatumumab, brodalumab, insulin in solution; (interferon alfacon-1); (Nesiritide; recombinant human B-type natriuretic peptide (hBNP)); (Anakinra); (sargramostim, rhuGM-CSF); (epatuzumab, anti-CD22 mAb); Benlysta TM (lymphostat B, belimumab, anti-BlyS mAb); (tenecteplase, a t-PA analog); (methoxypolyethylene glycol-epoetin beta); (gemtuzumab ozogamicin); (efalizumab); (certolizumab pegol, CDP 870); Soliris TM (eculizumab); pexelizumab (anti-C5 complement); (MEDI-524); (ranibizumab); (17-1A, edrecolomab); (lerdelimumab); TheraCim hR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4); (IDM-1); (B43.13); (viciluzumab); cantuzumab mertansine (huC242-DM1); (Epoetin beta); (Opreleukin, human interleukin-11); Orthoclone (Muromonab-CD3, anti-CD3 monoclonal antibody); (Epoetin alpha); (Infliximab, anti-TNF? monoclonal antibody); (abciximab, anti-GP lIb / Ilia receptor monoclonal antibody); (anti-IL6 receptor mAb); (bevacizumab), HuMax-CD4 (zanolimumab); MvasiTM (bevacizumab-awwb); (rituximab, anti-CD20 mAb); (erlotinib); -(Interferon alfa-2a); (basiliximab); (lumiracoxib); (palivizumab); 145c7-CHO (anti-IL15 antibody, see U.S. Patent No. 7,153,507); (natalizumab, anti-?4 integrin mAb); (MDX-1303, anti-anthrax protective antigen mAb); ABthrax TM ; (omalizumab); ETI211 (anti-MRSA mAb); IL-1trap (Fc portion of human IgG1 and extracellular domain of IL-1 receptor components (type I receptor and receptor accessory protein)); VEGF trap (Ig domain of VEGFR1 fused to IgG1 Fc); (daclizumab); (daclizumab, anti-IL-2R?mAb); (ibritumomab tiuxetan); (ezetimibe); (atacicept, TACI-Ig); anti-CD80 mAb (galiximab); anti-CD23 mAb (ruximab); BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist); CNTO 148 (golimumab, anti-TNF? mAb); HGS-ETR1 (mapatumumab; human anti-TRAIL receptor-1 mAb); HuMax-CD20 (ocrelizumab, anti-CD20 human mAb); HuMax-EGFR (zalutumumab); M200 (volociximab, anti-?5?1 integrin mAb); MDX-010 (ipilimumab, anti-CTLA-4 mAb and VEGFR-1 (IMC-18F1); anti-BR3 mAbs; anti-C. difficile toxin A and toxin BC mAbs 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 idiopathic pulmonary fibrosis stage I fibrinogen (FG-3019); anti-CTLA4 mAb; anti-eotaxin 1 mAb (CAT-213); anti-FGF8 mAb; anti-ganglioside GD2 mAb; anti-ganglioside GM2 mAb; anti-GDF-8 human mAb (MYO-029); anti-GM-CSF receptor mAb (CAM-3001); anti-HepC mAb (HuMax HepC); anti-IFN? 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 / hCG? mAb (MDX-1307); anti-mesothelin dsFv-PE38 conjugate (CAT-5001);Anti-PD1 mAb (MDX-1106 (ONO-4538)); anti-PDGFR? 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). ;

[0068] In some embodiments, the drug delivery device may contain or be used with a sclerostin antibody for the treatment of postmenopausal osteoporosis and / or fracture healing, such as, but not limited to, lomosozumab, bruxozumab, or BPS 804 (Novartis), Evenity TM (Lomosozumab-aqqg), another product comprising lomosozumab, and in other embodiments, comprising 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 (evolocumab) and (alirocumab). In other embodiments, the drug delivery device can contain or be used with: rituximab, bisalom, trebananib, ganitazumab, canatumumab, motesanib diphosphate, brodalumab, vidupiprant, or panitumumab. In some embodiments, the reservoir of the drug delivery device can be filled with a drug for treating melanoma or other cancers. (talimogene laherparepvec) or another oncolytic HSV, or the device can be used with it, the other oncolytic HSV includes but is not limited to OncoVEXGALV / CD; OrienX010; G207, 1716; NV1020; NV12023; NV1034; and NV1042. In some embodiments, the drug delivery device can 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 can include or be used with: for the treatment of migraine (erenumab-aooe), anti-human CGRP-R (calcitonin gene-related peptide type 1 receptor) or another product containing erenumab. Antagonistic antibodies to human calcitonin gene-related peptide (CGRP) receptor (such as but not limited to erenumab) and bispecific antibody molecules targeting CGRP receptor and other headache targets can also be delivered using the drug delivery device of the present disclosure. Additionally, bispecific T cell engagers Molecules (such as but not limited to, (blinatumomab)) can be used in or with the drug delivery device of the present disclosure. In some embodiments, the drug delivery device can include or be used with an APJ macromolecular agonist, such as but not limited to apelin or its analogs. In some embodiments, a therapeutically effective amount of anti-thymic stromal lymphopoietin (TSLP) or TSLP receptor antibody is used in or with the drug delivery device of the present disclosure. In some embodiments, the drug delivery device can include AvsolaTM (infliximab-axxq), anti-TNF? monoclonal antibody, In some embodiments, the drug delivery device may include a biosimilar of infliximab (Janssen Biotech, Inc.) or another product containing infliximab or used together with it. (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-phenylbutyramido)-4-methylpentanamide, or another product comprising or for use with carfilzomib. In some embodiments, the drug delivery device may comprise a drug for treating various inflammatory diseases. (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 or used together with it. In some embodiments, the drug delivery device may contain or be used together with ParsabivTM (velacaptide HCl, KAI-4169) or another product containing velacaptide HCl for the treatment of secondary hyperparathyroidism (sHPT), such as hemodialysis for patients with chronic kidney disease (KD). In some embodiments, the drug delivery device may contain ABP 798 (rituximab), / MabTheraTM In some embodiments, the drug delivery device may contain or be used with a VEGF antagonist (e.g., a non-antibody VEGF antagonist) and / or a VEGF-Trap (e.g., aflibercept (Ig domain 2 of VEGFR1 and Ig domain 3 of VEGFR2 fused to the Fc domain of IgG1)). In some embodiments, the drug delivery device may contain or be used with ABP 959 (eculizumab), In some embodiments, the drug delivery device may include or be used with a biosimilar candidate drug of 1% or more of a monoclonal antibody that specifically binds to complement protein C5. In some embodiments, the drug delivery device may include or be used with Lobifupu α (formerly AMG 570), which is a novel bispecific antibody-peptide conjugate that simultaneously blocks ICOSL and BAFF activity. In some embodiments, the drug delivery device may include or be used with Omekadimecarb (a small molecule selective cardiac myosin activator), or myotrope that directly targets the cardiac contractile mechanism, or another product containing a small molecule selective cardiac myosin activator. In some embodiments, the drug delivery device may include or be used with Sotolacib (formerly AMG 510), a small molecule inhibitor of KRASG12C, or another product containing a small molecule inhibitor of KRASG12C. In some embodiments, the drug delivery device may include or be used 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 to interleukin-15 (IL-15), or another product that contains a human monoclonal antibody that binds to interleukin-15 (IL-15). In some embodiments, the drug delivery device may contain or be used with AMG 890, a small interfering RNA (siRNA) that lowers lipoprotein (a) (also referred to as Lp(a)), or another product that contains a small interfering RNA (siRNA) that lowers lipoprotein (a). In some embodiments, the drug delivery device may contain ABP 654 (human IgG1κ antibody), In some embodiments, the drug delivery device may comprise AmjevitaTM or AmgevitaTM (formerly ABP 501) (monoclonal anti-TNF human IgG1), In some embodiments, the drug delivery device may comprise AMG 160, or a half-life extended (HLE) anti-prostate specific membrane antigen (PSMA) x anti-CD3 (bispecific T cell engager) construct or use it together. In some embodiments, the drug delivery device may include AMG 119 or another product containing delta-like ligand 3 (DLL3) CAR T (chimeric antigen receptor T cell) cell therapy or use it together. In some embodiments, the drug delivery device may include AMG 119 or another product containing delta-like ligand 3 (DLL3) CAR T (chimeric antigen receptor T cell) cell therapy or use it together. In some embodiments, the drug delivery device may include AMG 133 or another product containing gastric inhibitory peptide receptor (GIPR) antagonists and GLP-1R agonists or use it together. In some embodiments, the drug delivery device may include AMG 171 or another product containing growth differentiation factor 15 (GDF15) analogs or use it together. In some embodiments, the drug delivery device may include AMG 176 or another product containing small molecule inhibitors of myeloid cell leukemia 1 (MCL-1) or use it together. In some embodiments, the drug delivery device may comprise AMG 199 or a bispecific T cell engager construct comprising a half-life extended (HLE) In some embodiments, the drug delivery device may contain or be used with another product of the invention. In some embodiments, the drug delivery device may contain or be used with AMG256 or another product (comprising an anti-PD-1 x IL21 mutant protein and / or an IL-21 receptor agonist) designed to selectively turn on 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 a product comprising anti-CD33 x anti-CD3 In some embodiments, the drug delivery device may contain or be used with another product of a (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with AMG 404 or another product (comprising a human anti-programmed cell death-1 (PD-1) monoclonal antibody) being studied for the treatment of patients with solid tumors. In some embodiments, the drug delivery device may contain or be used with AMG 427 or a half-life extended (HLE) anti-fms-like tyrosine kinase 3 (FLT3) x anti-CD3 In some embodiments, the drug delivery device may contain AMG430 or another product containing an anti-Jagged-1 monoclonal antibody or be used with it. In some embodiments, the drug delivery device may contain AMG 506 or another product (containing a multispecific FAP x4-1BB-targeting 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 the use 2+1 technology design. In some embodiments, the drug delivery device may contain AMG 562 or contain half-life extended (HLE) CD19 x CD3 In some embodiments, the drug delivery device may contain or be used with another product comprising a (bispecific T cell engager) construct. In some embodiments, the drug delivery device may contain or be used with another product comprising Efavaleukin alpha (formerly AMG 592) or an IL-2 mutein Fc fusion protein. In some embodiments, the drug delivery device may contain or be used with another product comprising a CD3 x epidermal growth factor receptor vIII (EGFRvIII) In some embodiments, the drug delivery device may comprise AMG 673 or comprise half-life extended (HLE) anti-CD33 x anti-CD3 In some embodiments, the drug delivery device may comprise AMG 701 or comprise half-life extended (HLE) anti-B cell maturation antigen (BCMA) x anti-CD3 In some embodiments, the drug delivery device may comprise AMG 757 or comprise half-life extended (HLE) anti-delta-like ligand 3 (DLL3) x anti-CD3 In some embodiments, the drug delivery device may comprise AMG 910 or comprise a half-life extended (HLE) epithelial cell tight junction protein (claudin) 18.2x CD3 Another product of the (bispecific T cell engager) construct is used together with it.

[0069] Although the drug delivery devices, assemblies, components, subsystems, and methods have been described in terms of exemplary embodiments, they are not limited thereto. The detailed description is to be construed as exemplary only and does not describe every possible embodiment of the present disclosure. Numerous alternative embodiments may be implemented using current technology or technology developed after the filing date of this patent application, and these embodiments will still fall within the scope of the claims defining the invention(s) disclosed herein.

[0070] Those skilled in the art will recognize that a wide variety of modifications, changes and combinations may be made to the embodiments described above without departing from the spirit and scope of the invention(s) disclosed herein, and that such modifications, changes and combinations will be deemed to be within the scope of the inventive concept(s).

Claims

1. A method of limiting subvisible particles in a syringe partially filled with a drug product, the method comprising: applying an amount of silicone oil to a syringe barrel of a syringe, the syringe barrel comprising a proximal end, a distal end, and a reservoir, wherein a drug product is disposed in the distal end of the reservoir at the distal end of the syringe barrel, and the amount of silicone oil is in a range of about 0.4 mg to about 0.6 mg; placing a plunger portion into the syringe barrel to a depth within the syringe barrel, the plunger portion being spaced apart from the drug product; and An air gap is created between the plunger portion and the drug product, the air gap having an air gap length in the range of about 1.2 mm to about 3.5 mm.

2. The method of claim 2, wherein: Applying an amount of silicone oil to the syringe barrel includes applying the amount of silicone oil to the syringe barrel, wherein the reservoir has a fill volume in a range of about 1.0 mL to about 3.0 mL.

3. The method according to claim 1 or 2, wherein: Applying an amount of silicone oil to the syringe barrel includes applying the amount of silicone oil to an inner surface of the syringe barrel along the length of the syringe barrel, thereby facilitating movement of the plunger during injection of a drug product in the syringe and reducing the amount of subvisible particles generated in the syringe.

4. The method according to any one of claims 1 to 3, wherein: Placing the plunger portion into the syringe barrel includes placing a stopper into the syringe barrel to a depth within the syringe barrel, the stopper being spaced apart from the drug product.

5. The method according to any one of claims 1 to 4, wherein: Creating an air gap between the plunger portion and the drug product includes creating the air gap between a distal-most point of the plunger portion and a meniscus of the drug product disposed in the distal end of the reservoir.

6. The method according to any one of claims 1 to 5, wherein: After creating an air gap between the plunger portion and the drug product, the method further includes placing the syringe in a carton and placing the carton in a suspension packaging system configured to reduce generation of sub-visible particles in the syringe during shipping of the carton.

7. The method of claim 6, wherein: Placing the carton in a suspension packaging system includes placing the carton within a housing of the suspension packaging system and positioning packaging material within the housing at least partially around the carton including the syringe, thereby limiting contact of the carton with the packaging material during movement, the packaging material including one or more of padding, foam, bubble wrap, or a cushioning plastic material.

8. A method of limiting subvisible particles in a syringe partially filled with a drug product, the method comprising: applying an amount of silicone oil to a syringe barrel of a syringe, the syringe barrel comprising a proximal end, a distal end, and a reservoir, wherein a drug product is disposed in the distal end of the reservoir at the distal end of the syringe barrel, and the amount of silicone oil is in a range of about 0.4 mg to about 0.6 mg; placing the syringe in a carton; and The carton is placed in a suspension packaging system configured to reduce generation of sub-visible particles in the syringe during shipping, the suspension packaging system comprising packaging material surrounding the carton including the syringe, thereby limiting contact between the carton and the packaging material.

9. The method of claim 9, wherein: Limiting contact of the carton with packaging materials includes limiting contact of the carton with one or more of dunnage, foam, bubble wrap, or cushioning plastic material to maintain the position of the carton within the suspension packaging system during transport.

10. The method according to any one of claims 8 or 9, further comprising: A plunger portion is placed into the syringe barrel to a depth within the syringe barrel where the plunger portion is spaced apart from the drug product.

11. The method of claim 10, wherein: Placing the plunger portion into the syringe barrel includes placing a stopper into the syringe barrel to a depth within the syringe barrel, the stopper being spaced apart from the drug product.

12. The method of any one of claims 10 or 11, further comprising: An air gap is created between a plunger portion disposed within the syringe barrel and the drug product, the air gap having an air gap length in a range of about 1.2 mm to about 3.5 mm.

13. The method according to any one of claims 8 to 12, wherein: Applying an amount of silicone oil includes applying the amount of silicone oil to the syringe barrel, wherein the reservoir has a fill volume in a range of about 1.0 mL to about 3.0 mL.

14. The method according to any one of claims 8 to 13, wherein: Applying an amount of silicone oil to the syringe barrel includes applying the amount of silicone oil to the inner surface of the syringe barrel, the amount of silicone oil facilitating movement of the plunger during injection of a drug product in the syringe while reducing the amount of subvisible particles generated in the syringe.

15. A syringe partially filled with a drug product, the syringe comprising: a syringe barrel comprising a proximal end, a distal end, and a reservoir, wherein a drug product is disposed in the distal end of the reservoir at the distal end of the syringe barrel, the syringe barrel having an amount of silicone oil in a range of about 0.4 mg to about 0.6 mg, the amount of silicone oil being configured to limit an amount of subvisible particles generated in the syringe barrel; a plunger portion disposed at a depth within the syringe barrel, the plunger portion being spaced apart from the drug product; and An air gap is disposed between the plunger portion and the drug product, the air gap having an air gap length in a range of about 1.2 mm to about 3.5 mm.

16. The syringe of claim 15, the syringe barrel further comprising an inner surface and a length, and the amount of silicone oil is disposed on the inner surface along the length of the syringe barrel.

17. A syringe according to any one of claims 15 or 16, wherein The fill volume of the reservoir of the syringe barrel is in the range of about 1.0 mL to about 3.0 mL.

18. The syringe according to any one of claims 15 to 17, wherein The plunger portion is a stopper.

19. The syringe according to any one of claims 15 to 18, wherein The air gap length comprises the distance between the distal-most point of the plunger portion and the meniscus of the drug product disposed in the distal end of the reservoir.

20. A suspension packaging system, comprising: a housing having an inner wall defining an interior region; a packaging material disposed within the housing, adjacent to the inner wall and / or at least partially surrounding the inner wall; as well as A carton comprising the syringe of claim 15, the carton being placed within the packaging material and being restricted from contact with the packaging material, thereby reducing the amount of subvisible particles generated in the syringe during shipping.

Images