Improved syringe and gasket system

Abstract

A process for producing improved washers for use in matched syringe and plunger systems, preferably pre-filled plastic syringe systems. In particular, a process for manufacturing and inspecting discontinuous channels in or through a gasket film by laser processing. The gasket is useful in mating syringe and plunger systems, providing high and consistent container closure integrity (CCI), as well as consistent loosening and sliding forces over time, and sealability.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 316,611, filed on March 4, 2022, the disclosure of which is hereby incorporated by reference herein in its entirety. Background Art

[0003] The present disclosure relates to a matched syringe and plunger system, in particular to a gasket to be used in a syringe, and an improved process for making and inspecting laser cuts in the gasket. This application incorporates by reference the PCT International Application No. PCT / US2019 / 065099 filed on December 6, 2019 and U.S. Patent No. 7,985,188B2 published on July 26, 2011 in its entirety. More specifically, this application incorporates by reference U.S. Patent No. 7,985,188B2, which discloses a syringe barrel lubricated by applying a PECVD coating of SiOxCy or SiOxCyHz, and methods for making, testing and using such syringe barrels.

[0004] Pre-filled parenteral containers, such as syringes or barrels and plunger systems, have been developed to facilitate rapid and accurate dosing of sterile products (e.g., saline solutions, dyes for injection, pharmaceutically active preparations, etc.), minimize dosing errors, reduce the risk of biological contamination, enhance convenience and ease of use, prevent product overflow, etc. (see, e.g., Yoshino et al., J Pharm Sci. 2014; 103 (5): 1520-8). Pre-filled parenteral containers are usually sealed with a rubber gasket fixed to the plunger at the distal end, which provides closure integrity during the storage period of the contents of the container. In order to use the pre-filled syringe, the packaging and cap are removed, a hypodermic needle or another delivery catheter is optionally attached to the distal end of the barrel, the delivery catheter or hypodermic needle is moved to the use position (e.g., by inserting it into the tissue of the subject or into the device to flush with the contents of the syringe), and the plunger is advanced in the barrel to inject the contents of the barrel into the application point.

[0005] The seal provided by the rubber gasket in the barrel of the syringe generally involves pressing the rubber of the gasket against the barrel. Typically, the maximum diameter of the rubber gasket is larger in diameter than the minimum inner diameter of the barrel. Therefore, when the injection product is to be dispensed from the syringe, in order to displace the rubber gasket and its attached plunger, it is necessary to overcome this pressure of the rubber gasket. In addition, not only is it typically necessary to overcome this pressure provided by the rubber seal when initially moving the gasket fixed to the plunger, but it is also necessary to continue to overcome this force when the rubber gasket is displaced along the barrel during the dispensing of the injection product. The need for a relatively increased force to advance the gasket and plunger in the syringe may increase the difficulty of the user administering the injection product from the syringe. This is particularly problematic for automatic injection systems, in which the syringe is placed in an automatic injection device and the gasket is advanced by a fixed spring. Therefore, the main considerations for using a gasket fixed to the plunger in a prefilled parenteral container include: (1) container closure integrity ("CCI", as defined below) and liquid / gas tightness; and (2) the plunger force required to dispense the contents of the syringe (as defined below).

[0006] In practice, maintaining CCI / liquid or gas tightness and providing the desired plunger force are often competing considerations. In other words, the tighter the fit between the gasket and the inner surface of the container to maintain sufficient CCI / liquid or gas tightness, the greater the force required to advance the gasket in use, in the absence of other factors. In the field of syringes, it is important to ensure that the gasket fixed to the plunger can move at a substantially constant speed and with a substantially constant and relatively small force when advancing in the barrel. In addition, the force required to start the plunger movement and then continue to advance the plunger should be small enough to enable the user to apply comfortably and to prevent vibrations or unnecessary high pressures that may cause discomfort to the patient.

[0007] In order to reduce friction and therefore improve the plunger force, conventionally the barrel contact engagement surface, the inner surface of the barrel or both of the gasket fixed to the plunger are lubricated. Liquid or gel-like flowable lubricants, such as free silicone oil (e.g., polydimethylsiloxane or "PDMS"), can provide a desired lubrication level between the plunger and the barrel to optimize the plunger force. PDMS is actually the standard flowable lubricant used in the industry. However, it is not desirable to use a flowable lubricant between the gasket and the barrel. One reason is that a flowable lubricant may mix and interact with the drug product in the syringe, thereby possibly degrading the drug or otherwise affecting its efficacy and / or safety. For example, when used as a lubricant, silicone oil may cause droplets, which may potentially lead to aggregation of sensitive biopharmaceuticals or turbidity of solutions (Bee JS et al., PDA J Pharm Sci Technol. 2014; 68(5): 494-503), or cause drug interactions and increased particle formation (Yamashita A et al., Adv Drug Deliv Rev. 2013; 65(1): 139-47). Monoclonal antibodies, conjugate vaccines, and protein formulations are particularly susceptible to silicone-induced protein aggregation and particle formation. (Majumdar et al., J Pharm Sci. 2011 July; 100(7): 2563-73). In addition, over time, silicone migration may affect the consistency of delivery because it may change the release force and sliding force (BLGF) and injection time (Thornton JD et al., 2015. ON drug delivery magazine, issue 61 (October 2015), pages 10-15). Subvisible particles resulting from the migration of silicone oil into drug formulations may introduce several product quality issues, such as exceeding the USP limit for particulate matter in parenteral containers, adsorption leading to structural instability in proteins, and / or immunogenic reactions due to protein aggregates or silicone oil / protein complexes induced by injection of silicone oil, which may reduce drug efficacy and / or cause potentially dangerous reactions in patients, making the product unsuitable for use (Thornton JD et al., 2015. ON drug delivery magazine, issue 61 (October 2015), pages 10-15). Therefore, lubricants may be problematic in situations where they are injected into patients along with drug products.

[0008] Additionally, when used with prefilled syringes, the flowable lubricant can migrate away from the gasket over time, resulting in a point where there is little or no lubrication between the gasket and the inner surface of the container. This can result in a phenomenon known as "stiction," which is industry jargon for adhesion between the gasket and the barrel that needs to be overcome to disengage the plunger and gasket and allow the plunger to begin moving. For these reasons, the industry requires an "oil-free" solution, i.e., a gasket without flowable lubricant between the gasket and the barrel, and in which such flowable lubricant is not present in the drug product stream.

[0009] As an alternative (or supplement) to a flowable lubricant, a gasket has been developed from a material with lubricating properties or a gasket has been developed to include a coating or film that reduces friction on its outer surface. Such fluoropolymer films (in some embodiments, laminates) can provide a barrier to minimize the interaction between the formulation and the plunger while maintaining the sealing integrity of the gasket (Christa Jansen-Otten 2019.Blog; Westpharma). For example: TERUMO's i-COATING, which is cited in Canadian Patent No. 1,324,545, which is incorporated herein by reference in its entirety; WLGore expanded PTFE membrane on a rubber stopper, which is disclosed in EP2493534B1, which is incorporated herein by reference in its entirety; and WEST's CZ plunger. However, such gaskets may also have poor gas barrier properties due to film wrinkling, defects in the film, and / or film delamination from the rubber gasket, which have experienced CCI failure. Therefore, for pre-filled syringes containing products that are sensitive to certain gases, a separate conventional fluoropolymer film laminate gasket may not be a viable solution. Furthermore, such syringe and gasket systems have poor CCI.

[0010] Furthermore, in such pre-filled syringe systems, the gasket is in contact with the packaged sterile product during administration and drug storage. The interaction between the sterile product and its packaging can have a significant impact on the purity and degradation of the formulation and the safety of the patient to whom the product is administered (Christa Jansen-Otten 2019. Blog; Westpharma). Therefore, choosing the right gasket for a syringe system, especially a pre-filled syringe system, is an important consideration for the pharmaceutical and biopharmaceutical industries.

[0011] U.S. Patent Application No. 15 / 445,108, which is incorporated herein by reference in its entirety, mentions a laminated gasket for use in a medical syringe. This gasket includes a body made of an elastic material, and a film disposed on the surface of the body. In a syringe system, the syringe generally includes a syringe barrel and a plunger that can reciprocate in the syringe barrel. The gasket is attached to the distal end of the plunger. In this application, the gasket is further subjected to a laser processing process by applying a laser beam to the circumferential surface portion obliquely relative to the circumferential surface portion of the gasket while rotating the circumferential surface portion of the gasket around the central axis of the gasket, thereby circumferentially forming an annular groove in at least the surface portion of the film on the gasket. This laser-cut groove or channel improves the slidability and sealability of the laminated gasket in the syringe while maintaining the elasticity of the gasket and minimizing liquid leakage from the pre-filled syringe. In addition, the laser-cut groove forms a trench-like structure on the rib of the gasket, wherein the micro-protrusions rise above the film surface to improve the slidability and sealability of the laminated gasket in the syringe. However, this method of laser machining has several disadvantages because the laser cut grooves in the gasket increase the risk of defects forming in the gasket, which may lead to micro-protrusion defects and cause gasket failure, which in some embodiments may lead to a failure of container closure integrity.

[0012] In the gasket disclosed in U.S. Patent Application No. 15 / 445,108, the laser cut groove or channel of the gasket is formed in the entire circumferential surface portion of the film of the gasket, so that the groove is continuous. However, such continuous grooves in the gasket have experienced failures of CCI due to roundness. Roundness can affect the uniformity of the tiny protrusions; for example, when the gasket is rotated during the laser process, the depth of the protrusions can vary based on the position of the gasket. When the gasket is rotated, in the case of imperfect centering, this method of laser processing can also result in an elliptical cut that has a deeper groove at one point along the circumference of the gasket and a shallower groove at another point, which results in poor gas barrier properties. Therefore, conventional laser cut gaskets alone are not a viable solution for pre-filled syringes that contain products that are sensitive to certain gases. In addition, such syringes and gasket systems have poor CCI.

[0013] Additionally, the specific laser used to form the grooves can result in unevenly cut grooves based on the laser beam profile. For example, a laser beam with a Gaussian laser beam profile provides a bell-shaped intensity profile whose spatial intensity distribution results in wasted energy at the "tail" of the beam profile when the intensity is below the ablation threshold and is only sufficient to melt / heat the material (Hoang et al., Micromachines, February 2020, 11(221)).

[0014] In the process mentioned in U.S. Patent Application No. 15 / 445,108, the internal cavity of the gasket (or plunger) is then rotated during the laser cutting process. However, this method of fixing the gasket (plunger) during the laser process has several disadvantages because the wall of the gasket (plunger) may deform or sag when the gasket (plunger) is rotated to form the laser cut groove. This causes the laser cut or groove on the gasket (plunger) film to be less consistent. Injector systems including gaskets (plungers) produced by the process of U.S. Patent Application No. 15 / 445,108 are also more prone to liquid or gas leaks and have poor CCI. Summary of the invention

[0015] There is a need for a process for producing two or more non-continuous channels on the surface of a gasket (or plunger) having a film on its outer surface, and an improved gasket for use in a syringe gasket system for delivering, for example, a drug product to a subject in need thereof. The resulting gasket has improved prevention of liquid or gas leakage and has excellent CCI when used in a matching syringe and plunger system. A syringe assembled with the improved gasket of the present disclosure has improved protection for the product contained therein and is characterized by improved product shelf life.

[0016] In some embodiments, the present application provides a process for making two or more non-continuous channels in or through a film located on the outer surface of a gasket used in a matching syringe and plunger gasket system (in some embodiments, the two or more non-continuous channels extend into the gasket itself), which process results in excellent container closure integrity and sealability with minimal liquid / gas leakage.

[0017] In some embodiments, the disclosure of the present application provides a gasket with a discontinuous channel for use in a matching syringe-plunger system. A plurality of discontinuous channels may be included in a film located on at least a portion of the circumferential outer surface portion of the gasket, or in some embodiments pass through the film. A plurality of discontinuous channels of some embodiments also include a non-channel portion disposed around the circumferential outer surface portion of the gasket. The discontinuous channels may be substantially parallel to each other, wherein each channel includes a non-channel portion that is not aligned with each other in some embodiments. The silicone-free syringe and gasket system (preferably a prefilled plastic syringe system) of some embodiments of the present disclosure has excellent container closure integrity (CCI), avoids high loosening forces and liquid / gas leakage, produces consistent delivery performance over time, provides protection for packaged products, minimizes the interaction of the gasket with the product, and maintains efficacy and sterility during the storage period of the product, and has an improved product storage period. The syringe and gasket system of some embodiments also produces reduced sub-visible particles, and can protect the complex or sensitive biological products contained in the syringe from aggregation and particle formation caused by silicone oil. In some embodiments, the present disclosure also provides a process for creating non-continuous channels in a gasket and a membrane on its outer surface by laser cutting.

[0018] In some embodiments, the present disclosure also provides a process for producing a silicone oil-free syringe and gasket system having less than 300 particles of 2 microns or larger measured using light obscuration (LO) or microflow imaging (MFI). In some embodiments, the syringe system of the present disclosure incorporates a process for improving the sealability provided by a built-in lubricating film on the gasket, which eliminates the need to use a lubricated syringe barrel. In some embodiments, the present disclosure includes a description of a prior art manufacturing process control and essentially 100% inspection system that provides strict dimensional control of the gasket and corresponding syringe and channel, thereby achieving highly consistent compression of the assembled syringe and gasket system optimized for container closure integrity and plunger force.

[0019] In some embodiments, the present disclosure is directed to a process for forming a plurality of non-continuous channels in or through a membrane located on at least a portion of a circumferential outer surface of a gasket, the gasket comprising a body and an internal cavity defined by an inner surface of the gasket and including an open end, the process comprising:

[0020] (a) inserting one end of a mandrel into the open end of the cavity;

[0021] (b) positioning the mandrel and the washer relative to a laser; and

[0022] (c) applying a laser beam emitted from the laser to a plurality of locations on the surface of the film while rotating the mandrel and the gasket along the longitudinal axis of the mandrel to form the plurality of non-continuous channels, wherein:

[0023] Each non-continuous channel is substantially parallel to the other non-continuous channels, and each non-continuous channel of the plurality of non-continuous channels extends partially around the circumferential outer surface of the gasket. In some embodiments, a non-channel portion interrupts each non-continuous channel and is positioned along the circumferential outer surface portion of the gasket so that the non-channel portion is not aligned with another non-channel portion of the immediately adjacent one or more non-continuous channels.

[0024] In some embodiments, the process includes monitoring a plurality of selected locations using a laser micrometer by monitoring the precise location where the laser beam is applied, and adjusting the laser beam based on the monitoring.

[0025] In some embodiments, the thickness of the film on at least a portion of the circumferential outer surface portion of the gasket is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

[0026] In some embodiments, the membrane is configured to slide along the barrel of a syringe and is chemically stable.

[0027] In some embodiments, the film is capable of preventing migration of components from the elastomeric material of the gasket.

[0028] In some embodiments, the process includes securing the washer to the mandrel. For example, in some embodiments, the washer is secured to the mandrel by a press-fit assembly.

[0029] In some embodiments, at least a portion of the mandrel inserted into the interior cavity of the gasket has a diameter that is greater than an inner diameter of the interior cavity prior to insertion of the mandrel.

[0030] In some embodiments, the plurality of discontinuous channels include two discontinuous channels axially spaced apart from each other. In some embodiments, each of the plurality of discontinuous channels includes an axially opposite first sidewall and a second sidewall and a bottom surface. In some embodiments, each of the plurality of discontinuous channels includes an axial width between the sidewalls, the axial width being selected from 1-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns. In some embodiments, each of the plurality of discontinuous channels includes a radial depth selected from 0-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns. In some embodiments, each of the plurality of discontinuous channels includes a laser cutting depth selected from 20-80 microns, 30-60 microns, 40-50 microns, 50-60 microns, 40-45 microns, 45-50 microns, 50-55 microns, and 55-60 microns.

[0031] In some embodiments, one or more of the plurality of non-continuous channels extend through the membrane into the circumferential outer surface of the gasket.

[0032] In some embodiments, the plurality of non-continuous channels each comprises a radial depth greater than a thickness of the film on the surface of the gasket.

[0033] In some embodiments, the plurality of non-continuous channels includes a circumferentially extending first lip positioned adjacent to a first sidewall of the channel and extending radially above the membrane.

[0034] In some embodiments, the plurality of non-continuous channels further comprises a second circumferentially extending lip, the second circumferentially extending lip being positioned adjacent to the second sidewall and extending radially above the membrane. In some embodiments, the first lip comprises a first peak height selected from 10-100 microns, 15-60 microns, 20-50 microns, or 30-40 microns, and wherein the second lip comprises a second peak height selected from 10-100 microns, 15-60 microns, 20-50 microns, or 30-40 microns.

[0035] In some embodiments, the first lip of each of the plurality of non-continuous channels comprises a first peak width selected from 200-1,000 microns, 275-550 microns, 300-400 microns, or 450-500 microns, and wherein the second lip of each of the plurality of non-continuous channels comprises a second peak width selected from 200-1,000 microns, 275-550 microns, 300-400 microns, or 450-500 microns.

[0036] In some embodiments, each lip comprises film material that is displaced from the channel by the laser beam when forming the channel.

[0037] In some embodiments, the gasket is positionable in a tubular syringe barrel to form a seal between an inner surface of the barrel and at least one lip.

[0038] In some embodiments, the position of the laser relative to the mandrel and washer is controlled by a servo motor.

[0039] In some embodiments, the membrane comprises a fluoropolymer membrane. In some embodiments, the fluoropolymer membrane comprises polytetrafluoroethylene (PTFE). In some embodiments, the elastomeric material comprises brominated butyl rubber.

[0040] In some embodiments, the process includes treating the inner surface of the film to promote adhesion to the outer surface before applying to the outer surface of the gasket. For example, in some embodiments, the inner surface of the film is corona treated or chemically treated.

[0041] In some embodiments, the dimensional tolerance of the gasket is selected from ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±3 microns.

[0042] In some embodiments, the gasket has less than 300 particles 2 microns in size or larger as measured using light obscuration (LO) or microfluidic imaging (MFI).

[0043] In some embodiments, the present disclosure relates to a matched syringe and plunger system comprising:

[0044] (a) Tubular body;

[0045] (b) a plunger located within the tubular barrel and movable longitudinally within the barrel; and

[0046] (c) a gasket coupled to an end of the plunger, wherein the gasket comprises a body made of an elastomeric material having a circumferential surface portion, a membrane located on at least a portion of the circumferential outer surface portion of the gasket, and an internal cavity defined by an inner surface portion of the gasket and including an open end,

[0047] (d) a plurality of non-continuous channels in or through the membrane, each non-continuous channel being substantially parallel to the other non-continuous channels, each non-continuous channel of the plurality of non-continuous channels extending around the circumferential outer surface of the gasket and having a non-channel portion interrupting the non-continuous channel,

[0048] The non-channel portion of each non-continuous channel is positioned along a circumferential outer surface portion of the gasket so that the non-channel portion is not aligned with the non-channel portion of one or more adjacent non-continuous channels. In some embodiments, the matched syringe and plunger system is characterized by an improvement in longer shelf life.

[0049] In some embodiments, the thickness of the film on at least a portion of the circumferential outer surface portion of the gasket is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

[0050] In some embodiments, the film has one or more of good slidability and chemical stability. In some embodiments, the film is configured to slide along the barrel of a syringe and is chemically stable.

[0051] In some embodiments, the film is capable of preventing migration of components from the elastomeric material of the gasket.

[0052] In some embodiments, the gasket is attached to the plunger by a press-fit assembly.

[0053] In some embodiments, the tubular barrel contains an injectable fluid in contact with the gasket.

[0054] In some embodiments, the syringe and plunger system is capable of maintaining container closure integrity (CCI) over a two-year storage period as measured by one or both of a liquid migration test method and a helium leak detection test method. In some embodiments, the syringe and plunger system comprises a container closure integrity (CCI) with a defect rate of no more than 6σ.

[0055] In some embodiments, the plunger and the washer comprise a breakaway force between 4 and 20 Newtons (N).

[0056] In some embodiments, the plunger and the washer comprise a sliding force between 4 and 20 Newtons (N).

[0057] In some embodiments, the break-loose force or glide force varies by less than about 10%-30% over a two year storage life when exposed to conditions between 2°C and 8°C.

[0058] In some embodiments, the break-loose force or glide force varies by less than about 20%-40% over a two year storage life when exposed to conditions between 20°C and 25°C.

[0059] In some embodiments, the tubular barrel comprises a wall having an inner surface coated with a lubricating layer having an atomic ratio of 1 Si atom: 0.5 to 2.4 O atoms: 0.6 to 3 C atoms as measured by X-ray photoelectron spectroscopy (XPS).

[0060] In some embodiments, the tubular barrel comprises a wall having an inner surface characterized by a three-layer coating, wherein the three layers comprise a bond coating, a barrier coating, and a pH protective coating; wherein

[0061] (a) the bond coating comprises SiOxCy or SiNxCy, wherein x is from about 0.5 to about 2.4, and y is from about 0.6 to about 3, the bond coating having an outer surface facing the inner surface of the wall, and the bond coating having an inner surface facing the lumen of the tubular barrel;

[0062] (b) the barrier coating comprises SiOx, wherein x is from 1.5 to 2.9, the barrier coating has a thickness from 2 to 1000 nm, the barrier coating has an outer surface facing the inner surface of the bond coating, and the barrier coating has an inner surface facing the lumen of the syringe barrel; and

[0063] (c) the pH protective coating comprises SiOxCy or SiNxCy, wherein x is from about 0.5 to about 2.4, and y is from about 0.6 to about 3, the pH protective coating having an outer surface facing the inner surface of the barrier coating and an inner surface facing the inner cavity of the tubular barrel.

[0064] In some embodiments, the tubular barrel includes a lubricating layer having an outer surface facing the inner surface of the pH protective coating and an inner surface facing the lumen of the tubular barrel. In some embodiments, the lubricating layer can reduce one or both of the static friction and sliding friction of a gasket in the barrel, for example, compared to one or both of the static friction and sliding friction of a gasket in a tubular barrel without the lubricating layer.

[0065] In some embodiments, the membrane comprises a fluoropolymer membrane. In some embodiments, the fluoropolymer membrane comprises polytetrafluoroethylene (PTFE).

[0066] In some embodiments, the plurality of non-continuous channels improves the container closure integrity (CCI) of the system when assembled to form a pre-filled syringe, compared to an otherwise substantially similar pre-filled syringe that does not include the plurality of non-continuous channels produced by the process. In some embodiments, the improvement in CCI is measured by a vacuum decay leak detection method. In some embodiments, the improvement is measured by a liquid CCI test method.

[0067] In some embodiments, the tubular barrel includes a wall, the wall including an inner surface defining a generally cylindrical inner cavity, the barrel having an inner diameter; the gasket includes a front face, a side surface, a rear portion, and an outer diameter; the gasket is configured to be received in a tubular syringe barrel, wherein the gasket outer diameter is located within the barrel inner diameter and is movable relative to the barrel inner diameter; and the tubular barrel and gasket of the system are each sized to provide a spacing between the minimum barrel inner diameter and the maximum gasket outer diameter when assembled, wherein the spacing deviates from the nominal spacing by no more than: ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±2 microns.

[0068] In some embodiments, the present disclosure relates to a gasket comprising

[0069] (a) a body comprising an elastomeric material and having a circumferential surface portion and an internal cavity, the cavity being defined by an inner surface portion of the gasket and being open-ended at one end;

[0070] (b) a membrane located on at least a portion of a circumferential outer portion of the gasket; and

[0071] (c) a plurality of non-continuous channels in or through the membrane and extending around a circumferential outer surface portion of the gasket and having respective non-channel portions interrupting each respective non-continuous channel,

[0072] The corresponding non-channel portion of each non-continuous channel is positioned along a circumferential outer surface portion of the gasket such that the corresponding non-channel portion is not aligned with an adjacent non-channel portion.

[0073] In some embodiments, the gasket exhibits one or more of the following properties:

[0074] (i) Maintain container closure integrity (CCI) over a two-year storage period as measured by one or more of the liquid migration and helium leak detection test methods;

[0075] (ii) a container closure integrity (CCI) defect rate not exceeding 6σ when assembled in a matched syringe and plunger system;

[0076] (iii) a breakaway force of between 4 and 20 Newtons (N), alternatively between 4 and 10 Newtons (N), alternatively between 4 and 8 Newtons (N), when assembled in a matching syringe and plunger system;

[0077] (iv) when assembled in a matching syringe and plunger system, the sliding force is between 4 and 20 Newtons (N), alternatively between 4 and 10 Newtons (N), alternatively between 4 and 8 Newtons (N); and

[0078] The break-loose force or sliding force varies by less than about 10%-30% over a two year shelf life. BRIEF DESCRIPTION OF THE DRAWINGS

[0079] According to one or more various embodiments, the present disclosure is described in detail with reference to the following drawings. The drawings are provided for illustrative purposes only and depict only typical or exemplary embodiments. These drawings are provided to facilitate understanding of the concepts disclosed herein and should not be considered to limit the breadth, scope or applicability of these concepts. It should be noted that for clarity and ease of description, these drawings are not necessarily drawn to scale.

[0080] Figure 1 A cross-sectional view of a syringe 10 is shown that includes a syringe barrel 12 assembled with a gasket 14 attached to a plunger 26 according to some embodiments of the present disclosure.

[0081] Figure 2 Some embodiments of the present disclosure are shown Figure 1 A detailed view of a syringe.

[0082] Figure 3A Shown along Figure 2 A schematic cross-sectional view taken along section line 3A-3A shows a gasket core 18, a membrane 16, and a first non-continuous channel 20 in the surface of the membrane (in some embodiments, the channel 20 extends through the membrane into the outer surface of the gasket (not shown)) and a second non-continuous channel 21 in the surface of the membrane and substantially parallel to the first non-continuous channel 20 (in some embodiments, the channel 21 extends through the membrane into the outer surface of the gasket (not shown)).

[0083] Figure 3B Shows Figure 3A , showing an embodiment of a first non-continuous channel 20 and a first non-continuous channel 21 extending around the circumferential outer surface of the gasket core 18 and substantially parallel to the first non-continuous channel 20 and each of the lips 22 and 24 on the respective sides of the channel 20.

[0084] Figure 3CA top view of the gasket 14 is shown along with an approximate geometric distribution of a first non-continuous channel 20 extending around the circumferential outer surface of the gasket core 18 and an approximate geometric distribution of a second non-continuous channel 21 extending around the circumferential outer surface of the gasket core 18. Each non-continuous layer includes a non-channel portion (21a, 20a) associated with the non-continuous layer. The non-channel portions (21a, 20a) are not aligned with each other on the circumferential outer surface portion of the gasket.

[0085] Figure 3D A top view of a gasket 14 and an approximate geometric distribution of three non-continuous channels 20, 21, 23 extending around the circumferential outer surface of a gasket core 18 are shown. The three non-continuous channels 20, 21, 23 are axially spaced from each other and arranged so that the non-continuous channel 20 is close to the top of the plunger relative to the other two non-continuous channels 21 and 23, the non-continuous channel 21 is adjacent to the non-continuous channel 20 and is away from the top of the plunger relative to the non-continuous channel 20, and the non-continuous channel 23 is adjacent to the non-continuous channel 21 and is away from the top of the plunger relative to the non-continuous channel 21. Each of the non-continuous channels 20, 21, 23 includes a non-channel portion (20a, 21a, 23a) associated with the non-continuous channel 20, 21, 23. The non-channel portions (20a, 21a, 23a) are positioned so that they are misaligned with the non-channel portions of adjacent non-continuous channels along the circumferential outer surface portion of the gasket.

[0086] Figure 4A The assembly of the gasket 14 and the mandrel 28 inserted into the internal cavity of the gasket is shown. The figure also depicts the application of a laser beam obliquely to the outer portion of the film 16 located on the circumferential outer surface portion of the gasket 14 fixed on the mandrel 28, while the mandrel 28 and the gasket 14 are rotated along the longitudinal axis of the mandrel to produce a non-continuous channel 20 in the film 16 located on the circumferential outer portion of the gasket 14.

[0087] Figure 4B According to some embodiments of the present disclosure, Figure 4A 4B-4B, showing a mandrel 28 secured in the interior cavity of the gasket, a membrane 16, a first non-continuous channel 20 and a second non-continuous channel 21 in the outer surface of the membrane 16 located on a circumferential outer surface portion of the gasket 20. In other embodiments, the first non-continuous channel 20 and the second non-continuous channel 21 extend through the membrane and into the outer surface of the gasket.

[0088] Figure 5A A gasket 14 is shown having a membrane 16 with a first non-continuous channel 20 therein, according to some embodiments of the present disclosure.

[0089] Figure 5B Some embodiments of the present disclosure are shown Figure 5A , showing an embodiment of a first non-continuous channel 20 in the surface of the membrane with lips 22 and 24 on respective sides of the first non-continuous channel 20, and various dimensions (peak width, axial width, laser cut depth, and radial depth) of the first non-continuous channel 20 and lips 22 and 24. In other more preferred embodiments, the first non-continuous channel 20 extends into the outer surface of the gasket (not shown).

[0090] Figure 6 An image of an example of a gasket (Sample 40110) having a non-continuous channel 20 extending around the circumferential outer surface of the gasket core according to some embodiments of the present disclosure is shown.

[0091] Figure 7 An image of an example of a gasket (Sample 40125) having a non-continuous channel 20 extending around the circumferential outer surface of the gasket core according to some embodiments of the present disclosure is shown. DETAILED DESCRIPTION

[0092] The following reference numerals are used in the drawings according to any of the embodiments:

[0093] 10 Syringes

[0094] 12 Syringe barrel

[0095] 14 Washer

[0096] 16 Membrane

[0097] 18 Washer core

[0098] 20 First non-continuous channel

[0099] 20a First non-channel portion

[0100] 21 Second non-continuous channel

[0101] 21a Second non-channel part

[0102] 22 First lip of channel

[0103] 23 Third non-continuous channel

[0104] 23a Third non-channel part

[0105] 24 Second lip of channel

[0106] 26 Plunger

[0107] 28 Mandrel

[0108] In the context of this disclosure, the following definitions and abbreviations are used:

[0109] According to any embodiment, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality, unless otherwise specified. Whenever a parameter range is indicated, it is intended to disclose the parameter values ​​given as the limits of the range and all parameter values ​​falling within the range. References to "about" values ​​or parameters herein include (and describe) embodiments involving the value or parameter itself. For example, a description referring to "about X" includes a description of "X". Numerical ranges include numbers defining the range. As used herein, the term "about" allows a variation of ±10% within the range of significant digits.

[0110] Where aspects or embodiments are described in terms of Markush groups or other alternative groups, the present application encompasses not only the entire group listed as a whole, but also each member of the individual groups and all possible subgroups of the main group, as well as the main group without one or more of the group members. The present application also contemplates one or more of the group members being explicitly excluded from any of the group members in the embodiments of the present disclosure.

[0111] Exemplary methods and materials are described herein, but methods and materials similar or equivalent to those described herein can also be used in the practice or testing of various aspects and embodiments. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0112] In order to make the present disclosure more easily understood, certain terms are first defined. These definitions should be understood in conjunction with the remainder of the present disclosure and are understood by those of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.

[0113] As used herein, the term "syringe" is broadly defined as including barrels, injection pens and other types of barrels or reservoirs suitable for assembling with one or more other components to provide a functional syringe. "Syringe" is also broadly defined as including related products provided for the mechanism of distributing contents, such as automatic syringes. Preferably, "syringe" can include pre-filled syringes. "Syringe" as used herein can also be applied to vaccine distribution syringes, which include a product space for accommodating vaccine or immune antigen and product composition. "Syringe" as used herein can also be applied to diagnosis, for example, including a sampling device for a medical barrel pre-filled with a diagnostic agent (for example, a contrast agent), etc. In a broad sense, "syringe" as used herein is any medical barrel, which acts as a container / dispenser for a flowable product when assembled with one or more other components (for example, a gasket and a plunger). Although the present disclosure is not necessarily limited to syringes of a specific volume, it is envisioned that the inner cavity of the syringe has a void volume of, for example, 0.5 to 50 mL, optionally 1 to 10 mL, optionally 0.5 to 5 mL, optionally 1 to 3 mL. The syringe of the present disclosure includes a hollow cylindrical syringe barrel 12, a plunger 26 combined with the syringe barrel and reciprocatably movable in the syringe barrel 12, and a gasket 14 attached to the distal end of the plunger 26. Figure 1 .

[0114] As used herein, the term "gasket" in the context of the present disclosure is a shaped piece or ring made of an elastomeric material, which can be used to mechanically seal the space between two opposing inner surfaces of a syringe barrel. A gasket is also referred to as a plunger. The shape of the gasket is preferably cylindrical with a short axis. The gasket has a circumferential surface portion to maintain substantially air-tight and liquid-tight contact with the inner circumferential surface of the syringe barrel. The gasket of the present disclosure is a gasket comprising a main body made of an elastic material and a membrane located on at least the circumferential surface of the main body, the gasket having a circumferential surface portion and an internal cavity (IC) located at its center, the cavity being defined by the inner surface of the gasket and being open at one end. See Figure 2 and Figure 3A In a preferred embodiment, the internal cavity of the gasket is not threaded.

[0115] "Elastic material" can be a rubber or an elastomer. Specifically, preferred rubber types include butyl rubber, chlorinated butyl rubber and brominated butyl rubber. Other types of elastic materials can include thermosetting rubbers and dynamically crosslinkable thermoplastic elastomers with crosslinking sites (which makes them heat resistant). These polymer components of such elastomers include ethylene-propylene-diene rubber and butadiene rubber.

[0116] As used herein, the term "film" is a material located at least on the circumferential outer surface portion of the main body of the gasket. Preferably, it is coated on or located on substantially all outer surfaces of the gasket. The film can have an optional thickness of less than about 100 microns (μm or micron), optionally about 10-30 microns, about 15-35 microns or about 20-50 microns. Most preferably, the thickness of the film is about 20 microns. A variety of different materials can be used for film, such as inert fluoropolymers, including fluorinated ethylene propylene (FEP), ethylene tetrafluoroethylene (ETFE), polytetrafluoroethylene (PTFE), ethylene perfluoroethylene propylene (EFEP), ethylene trifluorochloroethylene (ECTFE), polychlorotrifluoroethylene (PCTFE), perfluoroalkoxy (PFA) and other coatings. Preferably, the film is an ultra-high molecular weight polyethylene film (UHMWPE) or a fluoropolymer film. Fluoropolymer films such as polytetrafluoroethylene (PTFE) are preferred because they have excellent slidability and chemical stability. The type of film provided on the surface of the main body of the gasket is not particularly limited as long as the film can prevent migration of substances from the crosslinked rubber (main body) and has slidability, ie, a smaller friction coefficient than the main body of the gasket.

[0117] Optionally, the membrane may comprise CPT fluoropolymer. CPT is a modified perfluoroalkoxy (PFA) that typically involves the addition of PCTFE side chains to the PFA backbone during polymerization.

[0118] Optionally, additives can also be added to the film material for the film, such as additives that can improve the adhesion of the film to the lower part of the gasket to form a liquid sealing section and / or reduce the friction between the section and the side wall of the syringe barrel. In addition, according to certain embodiments, an adhesion-promoting coating or process, such as corona treatment or chemical treatment, can be adopted. Corona treatment or air plasma is a surface modification technology that uses low-temperature corona discharge plasma to impart changes in surface properties. Corona plasma is generated by applying high voltage to an electrode with a sharp tip. For some applications, it may be necessary to coextrude different materials to form a film. For example, a coextruded film combination can include cycloolefin copolymer (COC) and Aclar, polyethylene (PE) and Aclar, and FEP and PE, and other combinations.

[0119] As used herein, the term "mandrel" refers to a device or tool that can be attached to a base at its distal end, which keeps the body of the mandrel stable and fixed, but allows the mandrel to rotate along its longitudinal axis. The proximal portion of the mandrel has a shape similar to the male mold portion of a two-part mold, which can be inserted into and fixed in the internal cavity of the gasket (corresponding female mold portion). In some embodiments, the mandrel is a shaped rod of metal or steel, such as a cylindrical rod. The proximal end of the mandrel can be continuous with the body of the mandrel, or can have a circumferential portion that is smaller or larger than the distal section of the mandrel. In a preferred embodiment, the proximal end of the mandrel is fixed to the gasket using a "press-fit assembly", in which the gasket is fixed to the mandrel by friction after the parts are pushed together, rather than by any other fastening means (such as upper screws). In some embodiments, the diameter of at least a portion of the mandrel portion inserted into the internal cavity of the gasket is greater than the inner diameter of the cavity. "Securing the washer" to the mandrel means ensuring that the washer is secured or fastened to the proximal end of the mandrel so as not to skew, become loose, or move independently of the mandrel. The washer secured to the mandrel will maintain the shape of its inner and outer walls and will not collapse or deform during the laser cutting process. "Positioning the mandrel and securing the washer proximate to the laser" means securing the base of the mandrel at a desired position relative to the laser beam so that the base of the mandrel will be in a rigid, non-moving position during the laser beam process of the present disclosure. However, the mandrel will still be able to rotate along its longitudinal axis. See Figure 4A .

[0120] As used herein, the term "channel" refers to a cut in a film located on the surface of the gasket by laser cutting. The term "channel" can be used interchangeably with the term "cut". In the present disclosure, the term "cutting" can also refer to a process of using one or more laser beams to produce a notch or separation of a film located on at least a circumferential outer surface portion of the gasket. In some embodiments, a channel is cut in a surface portion of the film. In a more preferred embodiment, the channel extends through the film into the outer surface of the gasket. One or more such channels can be produced, each of which surrounds a portion of the gasket. Each channel has a non-channel portion that does not form a channel / cut. For example, the channel can surround the gasket 350 degrees, and the non-channel portion can surround the remaining 10 degrees of a 360-degree circle on the gasket. When there are more than one channel, they are preferably spaced axially from each other. The non-channel portions of more than one channel are not aligned on the gasket. For example, the non-channel portion can be arranged on one side of the gasket, and the second non-channel portion can be arranged on the other side of the gasket. Each channel has two lips. The term "lip" refers to the structure created by the accumulation of film material along either side of the channel created by laser beam cutting. Channel lips 22 and 24 are Figure 3B and Figure 5BEach lip is a raised rib that is positioned to seal against the inner surface of the cylinder. Thus, each channel has two lips including two sealing ribs or peaks. In this disclosure, the terms "lip", "rib", "peak" and "microprotrusion" are interchangeable.

[0121] The laser cuts and resulting channels are characterized by various dimensions, including laser cut depth, radial depth, peak width, axial width, and peak height. "Laser cut depth" is measured from the surface of the uncut gasket film down to the lowest point of the valley of the channel. See Figure 5B The laser cutting depth of the one or more channels is independently selected from the following ranges: 30-60 microns, 40-50 microns, 50-60 microns, 40-45 microns, 45-50 microns, 50-55 microns, and 55-60 microns. The "radial depth" is measured from the uncut outer surface of the gasket up to the lowest valley in the channel. See Figure 5B The radial depth of one or more channels can be independently selected from the following ranges: 0 to 100 microns, 5 to 50 microns, 10 to 30 microns, and 15 to 25 microns. The "peak width" is the distance between the two peaks of the two lips on either side of the channel. The peak width is measured from the top of the peak. See Figure 5B The peak width may be one of the following ranges: 200-1,000 microns, 275-550 microns, 300-400 microns, and 450-500 microns.

[0122] The circumferential non-continuous channels of the present disclosure have axially opposed "first and second sidewalls" and a "bottom surface". The bottom surface of the channel can be a membrane surface, or more preferably a gasket surface, depending on the thickness of the membrane and the depth of the cut. The "axial width" is the width across the bottom surface of the channel measured from the first sidewall of the channel to the second sidewall. In other words, the "axial width" is measured at a baseline level, i.e., at the level of the laser uncut outer surface of the membrane or gasket, across its width from one end of the channel to the other end of the channel. One or more channels independently have an axial width between the sidewalls in one of the following ranges: 1 to 100 microns, 5 to 50 microns, 10 to 30 microns, and 15 to 25 microns.

[0123] "Peak height" is measured along the central axis of the peak, i.e., perpendicular to the surface of the film, from the surface of the uncut gasket film up to the highest peak of the lip produced by the laser beam. The peak height of the lip on one or more channels is independently selected from one of the following ranges: 10-100 microns, 15-60 microns, 20-50 microns and 30-40 microns.

[0124] As used herein, the term "container closure integrity" or "CCI" refers to the ability of a container closure system (e.g., a plunger attached to a gasket disposed in a syringe barrel (preferably a prefilled syringe barrel)) to provide protection and maintain efficacy and sterility during the storage period of a sterile product contained in a container. In some embodiments, container closure integrity is associated with the sealability of the syringe system of the present disclosure. By providing a physical break in the film that prevents defects in the film (such as delamination, tearing, or wrinkling) from adversely affecting the sealing integrity between the gasket and the syringe, one or more channels generated by a laser in the film are intended to enhance the CCI of the plunger to which the gasket is attached when assembled into a prefilled syringe. It is necessary to substantially maintain container closure integrity (CCI) throughout the storage period of the syringe of the present disclosure. CCI is an important characteristic of a prefilled syringe for a parenteral drug product contained in a syringe. An important element of CCI is to maintain a sterile barrier. The improved process for generating one or more channels on the film of the present disclosure reduces the possibility of CCI failure (sterility breach), and / or is conducive to a longer storage period.

[0125] As used herein, the term "break-away force" refers to the force required to initiate the movement of a plunger attached to a gasket in a syringe, such as a prefilled syringe. It is the maximum force required to break the static friction of the gasket attached to the plunger. In the context of the present disclosure, break-away force is synonymous with "plunger force", "plunger disengagement force", "disengagement force", "starting force" and "Fi".

[0126] As used herein, the term "sliding force" refers to the force required to maintain the plunger movement in the syringe barrel (when the plunger is attached to the gasket of the present disclosure), for example, during aspiration or dispensing, once static friction has been overcome. In the context of the present disclosure, sliding force is synonymous with "push force", "plunger sliding force", "maintenance force" and "Fm".

[0127] As used herein, the terms "break-loose force", "sliding force" are collectively referred to as "BLGF force", i.e., various forces of the plunger of the present disclosure and the attached gasket. The BLGF force can be measured using any test known in the art, such as ISO 7886-1:1993. For example, the BLGF force can be tested by filling the syringe of the present disclosure with 1 ml of liquid (such as water) and then vacuum loading the stopper. The plunger force can be tested at 300 mm / min with a plastic threaded (or threadless) rod. In the present disclosure, the improved process of creating a channel on the surface of the gasket prevents the plunger force from aging (i.e., the break-loose force increases over time). The matching syringe-plunger system of the present disclosure maintains a break-loose force and a sliding force between 4 and 20 Newtons (N), optionally between about 4 and 10 Newtons (N), or between about 4 and 8 Newtons (N). Most preferably, the sliding force is between about 4 and 8 Newtons (N) and changes less than about 10%-30% within a two-year storage life. The process of the present disclosure provides consistent break-loose and glide forces by combining manufacturing process controls and a 100% inspection system.

[0128] As used herein, the term "static friction" is an industry term that refers to the phenomenon of adhesion between the plunger (attached to the gasket) and the syringe barrel, which needs to be overcome to disengage the plunger attached to the barrel and allow the plunger to begin moving. The term "sliding friction" or "dynamic friction" refers to the resistance generated by two objects sliding relative to each other. Sliding friction is intended to prevent objects from moving. In the present disclosure, the lubricating layer in the syringe barrel can reduce one or both of the static friction and sliding friction of the gasket in the barrel as needed or as the case may be compared to one or both of the static friction and sliding friction of the gasket in the barrel in the absence of the lubricating layer.

[0129] As used herein, the term "dimensional tolerance", "dimensional accuracy" or "dimensional consistency" is the degree of control over the size of a part (Technical Department Quality Management (2000) 142-158). Dimensional tolerance is the permissible variation limit of the physical dimensions of the various parts of the present disclosure (such as gaskets and syringe barrels). "Tolerance" is the permissible variation of any given dimension of a gasket or syringe barrel of the present disclosure that allows the syringe system to work properly. In other words, dimensional tolerance is the permissible variation of the dimensions of a syringe or gasket of the present disclosure that does not compromise one or more of the following properties: container closure integrity, BLGF force, sealability, leakage characteristics, slidability, etc. The dimensional tolerance of the gasket that can be used in the process of the present disclosure is selected from ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns or ±3 microns. The term "nominal spacing" in the syringe system of the present disclosure relates to dimensional tolerance. In the barrel and gasket of the system of the present invention, the dimensions are set to provide a spacing between the minimum barrel inner diameter and the maximum gasket outer diameter when assembled, and the deviation from the nominal spacing does not exceed: ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns or ±2 microns.

[0130] Some embodiments of the present disclosure will now be described more fully with reference to the accompanying drawings. However, the present disclosure can be embodied in a variety of different forms and should not be construed as being limited to the embodiments set forth herein. On the contrary, these embodiments are merely examples, which have the full scope indicated by the claim language. Throughout the text, similar numbers refer to similar or corresponding elements.

[0131] Exemplary Syringe and Plunger System Embodiments

[0132] exist Figure 1 , an exemplary embodiment of a matching syringe and plunger system of the present disclosure is shown, which includes a gasket 14 and a plunger 26 constructed according to one aspect of the present disclosure. The terms "distal" and "proximal" generally refer to a spatial or positional relationship relative to a given reference point, wherein "proximal" is a position at or relatively closer to the reference point, and "distal" is a position farther from the reference point. For example, as applied to the plunger 26 herein, the relevant reference point is the bottom end of the plunger 26 attached to the gasket 14, i.e., the distal end. For example, as applied to the syringe barrel 12 herein, the relevant reference point is the bottom end of the barrel 12 attached to the delivery catheter or hypodermic needle, i.e., the distal end.

[0133] The syringe 10 has a generally conventional construction and material, preferably plastic, and includes a hollow barrel 12 having a central longitudinal axis A. The barrel has an inner surface 14 and is configured to contain an injectable liquid therein. A hypodermic needle or delivery catheter is located at the distal end of the barrel and is in fluid communication therewith. A plunger 26 also has a generally conventional construction and material. A gasket 14 of the present disclosure is attached to the distal end of the plunger.

[0134] Figure 2 Shows Figure 1 Detailed partial view of a syringe of , showing the inner diameter (ID) of the barrel 12 and the outer diameter (OD) of the gasket 14, which are matched within a predetermined tolerance therebetween, and also showing the membrane 16 on the outer surface of the gasket core 18, the first non-continuous channel 20 extending around the circumferential outer surface of the gasket core 18, and the second non-continuous channel 21 extending around the circumferential outer surface of the gasket core 18 and generally parallel to the first non-continuous channel 20. Figure 3B As shown in FIG. 1 , the channel has lips 22 and 24 .

[0135] Exemplary Laser Process Embodiments

[0136] Figure 4A FIG. 1 is a diagram of a laser processing process according to an embodiment of the present disclosure. Figure 4A , a laser beam is applied to a circumferential surface portion of the gasket 14 fixed on the mandrel 28 at a desired angle. The angle at which the laser beam is applied may be 5 to 90 degrees with respect to the surface portion of the gasket. In order to form a channel in at least a portion of the circumferential surface portion of the gasket, a laser beam source is fixed relative to the circumferential surface portion of the gasket 14, wherein the film 16 is located on the outer surface of the gasket, and a laser beam is applied to the circumferential surface portion while the gasket 14 fixed to the mandrel 28 is rotated about its longitudinal axis. Thus, the laser beam can be applied to any angular position of the circumferential surface portion at a predetermined incident angle α (e.g., 5° to 90°), thereby uniformly forming a channel.

[0137] When the laser beam is applied obliquely to the circumferential surface portion, the washer can be rotated in a direction so that the circumferential surface portion moves away from the laser beam application position (at Figure 4A , washer rotates clockwise).

[0138] Figure 3C A top view of a gasket 14 having a first non-continuous channel 20 and a second non-continuous channel 21 is shown. The top view is intended to illustrate the location of the non-channel portion of each non-continuous channel in a plurality of non-continuous channels. In some embodiments, one or more non-channel portions in a single channel. Figure 3C , the non-channel portion of the first non-continuous channel is not aligned with the non-channel portion of the second non-continuous channel. Figure 3CThe non-channel portion of the first non-continuous channel is shown positioned 180 degrees from the non-channel portion of the adjacent non-continuous channel around the circumference of the gasket, but the non-channel portion can also be positioned around the circumference of the gasket as long as the adjacent non-channel portions are not aligned, for example, the non-channel portion of the first non-continuous channel can be positioned in a range of 90 degrees to 270 degrees from the adjacent non-channel portion around the circumference of the gasket, wherein the adjacent non-channel portions are not aligned. In a preferred embodiment, the non-channel portion of the first non-continuous channel can be positioned about 180 degrees from the adjacent non-channel portion around the circumference of the gasket.

[0139] In another embodiment, each non-continuous channel can include a plurality of non-channel portions arranged around a circumference, so that the non-continuous channel can be a "dashed line" of channel and non-channel portions. Adjacent non-continuous channels can also be "dashed" channels of channel and non-channel portions. As long as adjacent non-channel portions are not aligned, the channel and non-channel portions of adjacent non-continuous channels can be positioned around the circumference of the gasket. For example, the non-channel portion can be out of phase with the adjacent non-channel portion.

[0140] Figure 3D A top view of a gasket 14 having a first non-continuous channel 20, a second non-continuous channel 21, and a third non-continuous channel 23 is shown. The top view is intended to illustrate the location of the non-channel portion of each non-continuous channel 20, 21, 23 of the plurality of non-continuous channels. Each channel extends around the circumferential surface of the gasket, and each channel has a portion that does not include the channel. The three non-continuous channels 20, 21, 23 are axially spaced apart from each other and are arranged such that the non-continuous channel 20 is close to the top of the plunger relative to the other two non-continuous channels 21 and 23, the non-continuous channel 21 is adjacent to the non-continuous channel 20 and is away from the top of the plunger relative to the non-continuous channel 20, and the non-continuous channel 23 is adjacent to the non-continuous channel 21 and is away from the top of the plunger relative to the non-continuous channel 21. Reference Figure 3D The non-channel portions (20a, 21a, 23a) are positioned so that they are not aligned with the non-channel portions of adjacent non-continuous channels along the circumferential outer surface portion of the gasket. In some embodiments, the non-channel portion of a non-continuous channel can be aligned with the non-channel portion of a non-adjacent non-continuous channel.

[0141] In some embodiments, the laser beam is applied through a beam expander via multiple steering mirrors and then through a shaping optical device to convert the laser beam profile from a Gaussian spatial intensity profile to a flat-top spatial intensity profile. In a flat-top spatial intensity profile, uniform spatial intensity can improve processing conditions at the laser spot and generally lead to higher geometric accuracy and repeatability, lower surface roughness, and higher laser microstructuring quality. A camera is used for fine positioning and monitoring the process.

[0142] By thus performing the laser machining process of this embodiment of the present disclosure, the channel is substantially uniformly formed in the film and more preferably extends into the circumferential surface portion of the gasket, and at the same time the outer edge portions 22 and 24 ( Figure 5B ).

[0143] Exemplary Gasket Manufacturing and Laser Cutting Process

[0144] In some embodiments of the present disclosure, the gasket comprises two materials: a bromobutyl rubber-based gasket and a membrane, preferably a PTFE membrane, located on the outer surface. Examples of bromobutyl rubber include: Sumitomo LAG 5010-50 and West 4023. The PTFE membrane in the preferred embodiment substantially covers the outer surface of the gasket. Gasket manufacturing includes the following processes, which belong to some embodiments of the present disclosure:

[0145] (a) Molding: The PTFE membrane is treated to promote adhesion to the brominated butyl rubber of the gasket. A typical treatment is corona treatment. In some embodiments, chemical treatments may also be used. The PTFE membrane is placed into a multi-cavity gasket mold. The brominated butyl rubber is poured / injected into the multi-cavity mold. The mold is closed and the PTFE membrane and brominated butyl rubber are formed into a gasket. The mold is opened and the gasket is removed from the mold. The gasket produced in this way has a substantially uniform wall thickness and includes rubber and PTFE. The gasket is trimmed via punching to remove excess material. In some embodiments, the multi-cavity mold produces a gasket without threads in the internal cavity.

[0146] (b) Laser cutting of PTFE or other membranes: The improved process of the present disclosure includes the following steps:

[0147] (1) inserting a portion of one end of a mandrel into the open end of the gasket cavity of the gasket manufactured in step (a); (2) positioning the mandrel and the gasket near a laser; and (3) applying a laser beam emitted from a precision laser to one or more selected locations on a surface portion of the membrane located on a circumferential outer surface portion of the gasket while rotating the mandrel and the gasket along the longitudinal axis of the mandrel to form a plurality of non-continuous channels in the membrane that extend partially around the circumferential outer surface of the gasket. The process produces a plurality of non-continuous channels in the PTFE or other membrane in a circumferential direction on the outer surface of the gasket. The precision of the channels produced by the laser beam is directly related to the fixation of the gasket on the mandrel, the position of the laser beam, and the dimensional tolerances of the gasket used in the process.

[0148] The resulting channel creates a physical separation in the PTFE or other membrane on the gasket. Specifically, without being bound by theory, it is believed that the laser treatment melts the PTFE or other membrane and pushes the PTFE material to either side of the channel. During the laser treatment, the PTFE or other membrane material "pile up" on either side of the channel, creating two sealing ribs or peaks (tiny protrusions). The PTFE or other membrane sealing ribs on either side of the channel are able to maintain the CCI - both a liquid barrier and a sterile barrier. Assuming the PTFE membrane is uniform in thickness and "defect-free", the height and angle of the sealing ribs are dependent on the alignment and position control of the laser beam (relative to the rotating gasket on the mandrel). The largest sources of variation in the sealing ribs are due to the PTFE or other membrane: (1) thickness variation on the membrane and (2) defects in the membrane (e.g., blockages).

[0149] In addition, the fluoropolymer film is usually stretched during the manufacturing process when the initial film is formed. This stretching process forms microchannels or micropores in the film (the terms "microchannels" or "micropores" are used interchangeably in this specification), and their size and dimensions vary depending on specific manufacturing conditions. These microchannels or micropores are considered to provide a path in the inner cavity of the syringe containing the material of the filled syringe from the rear portion of the gasket of the pre-filled syringe (which is outside the sealing portion of the syringe) along the fluoropolymer or other film at least in some cases. This reduces the CCI of the matching syringe-plunger system and shortens the shelf life.

[0150] Although cutting multiple non-continuous channels in or through the film can alleviate some of the degradation of container closure integrity and the reduced shelf life caused by these microchannels, the process of creating the channels itself may also cause CCI and other problems of shelf life degradation. For example, without wishing to be bound by theory, unless the gasket is properly secured during the laser cutting process, the gasket may sag or otherwise deform on its outer surface, causing inconsistencies and variations in the channels. In addition, unless the gasket and channels are carefully and individually inspected after production, the failure rate of the gasket when used in a syringe plunger system will be unacceptable.

[0151] The improved process, gasket and syringe-plunger system and gasket of the present disclosure overcome these problems.In addition, the strict inspection process of the present disclosure ensures that the failure rate of the gasket is low when used in the syringe-plunger system.

[0152] Improved gasket inspection system: Inspection of gasket properties after gasket manufacture and in some embodiments after the laser treatment process of the present disclosure includes, but is not limited to, the following: (1) dimensional inspection of the overall height and outer diameter of the gasket; (2) camera inspection of the shape of the sealing rib; (3) camera inspection of the laser cut, for example, to verify the peak and laser cut dimensions (peak height, peak width, axial width, laser cut depth, and radial depth (if present)); and (4) camera inspection of the PTFE film for signs of wrinkling, tearing, or debonding from the rubber (insufficient adhesion). Further tests are also performed to inspect the properties of the syringe and gasket system of the present disclosure, for example, container closure integrity testing (CCIT), plunger breakaway and glide force testing, sterility assurance, and sub-visible particle testing.

[0153] Gasket inspection (punching and micro-protrusions): Vision systems are used to inspect plungers inline (100% inspection). An example of a high-speed inspection system for plungers is manufactured by Simac (Netherlands). The camera inspection system has the following attributes: (1) 13 plungers / second; (2) supports a variety of plunger colors; (3) performs top bottom, external and internal surface inspection; (4) inspects for micro-protrusions; (5) inspects for stamping and forming failures; (6) 100% quality control with a minimum defect detection of 100 μm. Rejected parts are sorted in separate containers and statistically tracked. Acceptable parts are accurately counted and automatically packaged.

[0154] Dimensional Measurements with a Laser Micrometer: The dimensional consistency of each finished gasket of the present disclosure is measured. Preferably, this is an in-line system. In a preferred embodiment, a scanning laser micrometer is used to perform these measurements. An example of a scanning laser micrometer is the LS-3000 series manufactured by Keyence. A scanning laser micrometer uses a rotating optical element to reflect or refract a laser beam that passes through a measurement area and across the path of the object to be measured. The part blocks the laser, creating a shadow that persists for a certain time proportional to the size of the part. Optics in the receiver collect the unobstructed laser light and focus it on a phototube. The output of the phototube is analyzed by electronics to detect the exact time when the laser crosses the edge of each part. Software converts the timing data into meaningful measurements.

[0155] Classification: Using the dimensional measurements, the washers of the present disclosure can be classified to ensure that each washers has a specific dimensional tolerance. The tolerance can be ±100 microns, more specifically ±50 microns, more specifically ±35 microns, more specifically ±25 microns, more specifically ±20 microns, more specifically ±15 microns, more specifically ±10 microns, more specifically ±5 microns, more specifically ±3 microns.

[0156] Pre-filled syringe barrel dimensions are measured in a similar manner so that an accurate and consistent fit between the syringe and the gasket is achieved. This enables accurate control of gasket compression in the assembled syringe. Quality attributes of the assembled syringe include, but are not limited to: (1) container closure integrity measured by dye intrusion, (2) container closure integrity measured by vacuum decay method, (3) plunger force curve (Fi / Fm) consistency (aging and batch-to-batch variation).

[0157] In some embodiments, the gaskets of the present disclosure maintain container closure integrity with a defect failure rate of at least 6σ. System elements may include: 100% inspection of molded plungers; 100% inspection of laser cuts or channels in plunger fluoropolymer; 100% inspection of plunger diameter; 100% measurement of syringe barrel ID; and low draft angle syringe barrels.

[0158] In some embodiments, in the context of the improved laser process of the present disclosure, there is 100% inspection of (a) the depth around the perimeter of the gasket fixed on the stainless steel mandrel; (b) the shape of the edge of the film formed by the laser cut or channel using a servo motor to control the laser movement. In some embodiments, plasma and / or chemical treatment is used to optimize the adhesion of the film to the rubber gasket.

[0159] The test of container closure integrity (CCI) can be completed using a vacuum decay leak detection method, in which a vacuum is maintained inside the test volume, and the pressure rise is measured over time. A sufficiently large pressure rise is an indication of the presence of flow into the system, which is evidence of a leak. Optionally, the vacuum decay test is implemented in two separate cycles. The first cycle is dedicated to detecting large leaks in a very short duration. The vacuum extracted in the first cycle is relatively weak, because if a serious leak is detected, a large pressure differential is not required to detect a large pressure rise. The use of the first cycle as described helps to shorten the total test time in the presence of a serious leak. If no leak is detected in the first cycle, the second cycle is run, which complies with the ASTM F2338-09 standard test method for non-destructive detection of leaks in packaging by a vacuum decay method. The second cycle starts with a system evaluation to reduce the signal-to-noise ratio in the pressure rise measurement. A relatively strong vacuum is extracted over a long period of time in the second cycle to increase the chance of detecting a pressure rise in the system.

[0160] Example: Liquid CCI Test Method

[0161] In an illustrative example, in some embodiments, the syringe and gasket system of the present invention is filled with water and the stopper is vacuum loaded. The Luer end or needle end of the syringe is stored at 4°C with the syringe facing up. Each syringe is removed at a specific time point (e.g., 0 days, 1 day, 4 days, 7 days, 1 month, and 3 months), allowed to reach room temperature, and then visually inspected for signs that water has entered the space between the ribs of the stopper. A text description of each failure is recorded, and a photo of each failure is taken. The leakage characteristics of the syringe of the present invention are compared with the leakage characteristics of other syringes with gasket films (e.g., laminated films). Compared with syringes produced by the improved laser and inspection process of the present invention, the syringe of the present invention has excellent CCI over time.

[0162] Below, please find Table 1 of the initial Liquid CCI data collected for two variations of gaskets (Samples 40110 and 40125) and the uncut gasket. While this data shows no Liquid CCI failures, data was collected at time points up to 1 month. Additional Liquid CCI test data will be collected long term to demonstrate the superior performance of the syringe and gasket system.

[0163]

[0164] Table 1 Liquid CCI data for gasket samples 40110, 40125 and the uncut version.

[0165] like Figure 6-7 As shown in the figure, the #40125 plug ( Figure 7 ) than the non-continuous channels formed in the #40110 plug ( Figure 6 ) is wider and shallower. This difference is due to the spindle speed during laser processing. The channel was formed at 30 degrees / second in #40125, while the channel was formed at 60 degrees / second in #40110. In both processes, the laser beam was a Gaussian beam and was at normal incidence.

[0166] The foregoing is merely an illustration of the principles of the present disclosure, and various modifications may be made by those skilled in the art without departing from the scope of the present disclosure. The above embodiments are presented for illustrative purposes rather than limiting purposes. The present disclosure may also take many forms other than those explicitly described herein. Therefore, it should be emphasized that the present disclosure is not limited to the methods, systems, and devices explicitly disclosed, but is intended to include variations and modifications thereof within the spirit of the following claims.

Claims

1. A process for forming a plurality of non-continuous channels in or through a membrane located on at least a portion of a circumferential outer surface of a gasket, the gasket comprising a body and an internal cavity defined by an inner surface of the gasket and including an open end, the process comprising: (a) inserting one end of a mandrel into the open end of the internal cavity; (b) positioning the mandrel and the washer relative to the laser; as well as (c) applying a laser beam emitted from the laser to a plurality of locations on the surface of the film while rotating the mandrel and the gasket along the longitudinal axis of the mandrel to form the plurality of non-continuous channels, wherein: Each non-continuous channel is roughly parallel to the other non-continuous channels. Each non-continuous channel of the plurality of non-continuous channels extends partially around the circumferential outer surface of the gasket.

2. A process according to claim 1, wherein a non-channel portion interrupts each non-continuous channel and is positioned along the circumferential outer surface of the gasket so that the non-channel portion is not aligned with another non-channel portion of one or more adjacent non-continuous channels.

3. The process according to claim 1, further comprising: monitoring a plurality of selected locations using a laser micrometer by monitoring the location where the laser beam is applied, and The laser beam is adjusted based on the monitoring.

4. The process of claim 1, wherein the thickness of the film on at least a portion of the circumferential outer surface portion of the gasket is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

5. The process according to any one of claims 1 or 2, wherein the membrane is configured to slide along the barrel of a syringe and is chemically stable.

6. The process of any one of claims 1-5, wherein the gasket comprises an elastomeric material, and wherein the membrane is capable of preventing migration of components from the elastomeric material of the gasket.

7. The process of any one of claims 1-6, wherein the process further comprises securing the washer to the mandrel.

8. The process of claim 7, wherein the gasket comprises an elastomeric material, wherein the gasket is secured to the mandrel by a press-fit assembly.

9. The process of claim 8, wherein at least a portion of the mandrel inserted into the interior cavity of the gasket has a diameter that is greater than the inner diameter of the interior cavity prior to insertion of the mandrel.

10. The process of any one of claims 1-9, wherein the plurality of non-continuous channels comprises two non-continuous channels axially spaced from each other.

11. The process of any one of claims 1-10, wherein each non-continuous channel of the plurality of non-continuous channels comprises axially opposed first and second sidewalls and a bottom surface.

12. The process of claim 11, wherein each non-continuous channel of the plurality of non-continuous channels comprises an axial width between the sidewalls, the axial width being selected from the group consisting of 1-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns.

13. The process of any one of claims 1-12, wherein each non-continuous channel of the plurality of non-continuous channels comprises a radial depth selected from the group consisting of 0-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns.

14. The process of any one of claims 1-13, wherein each of the plurality of non-continuous channels comprises a laser cutting depth selected from 20-80 microns, 30-60 microns, 40-50 microns, 50-60 microns, 40-45 microns, 45-50 microns, 50-55 microns, and 55-60 microns.

15. The process of any one of claims 1-14, wherein one or more of the plurality of non-continuous channels extend through the membrane into the circumferential outer surface of the gasket.

16. The process of any one of claims 15, wherein the plurality of non-continuous channels each comprises a radial depth greater than the thickness of the film on the surface of the gasket.

17. The process of any one of claims 1-12, wherein the plurality of non-continuous channels comprises a circumferentially extending first lip positioned adjacent to a first sidewall of the channel and extending radially above the membrane.

18. The process of any one of claims 17, wherein the plurality of non-continuous channels further comprises a second circumferentially extending lip positioned adjacent the second sidewall and extending radially above the membrane.

19. The process of any one of claims 18, wherein the first lip comprises a first peak height selected from 10-100 microns, 15-60 microns, 20-50 microns, or 30-40 microns, and wherein the second lip comprises a second peak height selected from 10-100 microns, 15-60 microns, 20-50 microns, or 30-40 microns.

20. The process of any one of claims 17-19, wherein the first lip of each of the plurality of non-continuous channels comprises a first peak width selected from 200-1,000 microns, 275-550 microns, 300-400 microns, or 450-500 microns, and wherein the second lip of each of the plurality of non-continuous channels comprises a second peak width selected from 200-1,000 microns, 275-550 microns, 300-400 microns, or 450-500 microns.

21. A process according to any one of claims 17 to 20 wherein each lip comprises film material displaced from the channel by the laser beam when the channel is formed.

22. The process of any one of claims 17-21, wherein the gasket is positionable in a tubular syringe barrel to form a seal between an inner surface of the barrel and at least one lip.

23. The process of any one of claims 1-22, wherein the position of the laser relative to the mandrel and washer is controlled by a servo motor.

24. The process of any one of claims 1-23, wherein the membrane comprises a fluoropolymer membrane.

25. The process of claim 24, wherein the fluoropolymer membrane comprises polytetrafluoroethylene (PTFE).

26. The process of any one of claims 1-25, wherein the elastomeric material comprises bromobutyl rubber.

27. The process of any one of claims 1-26, further comprising treating the inner surface of the film prior to application to the outer surface of the gasket to promote adhesion to the outer surface.

28. The process of claim 27, wherein the inner surface of the film is corona treated or chemically treated.

29. The process of any one of claims 1-28, wherein the gasket has a dimensional tolerance selected from ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±3 microns.

30. The process of any one of claims 1-27, wherein the gasket has less than 300 particles of 2 microns in size or larger as measured using light obscuration (LO) or microfluidic imaging (MFI).

31. A matched syringe and plunger system comprising: (a) Tubular body; (b) a plunger located within the tubular barrel and movable longitudinally within the barrel; as well as (c) a gasket coupled to an end of the plunger, wherein the gasket includes a body made of an elastomeric material having a circumferential surface portion, a membrane located on at least a portion of the circumferential outer surface of the gasket, and an internal cavity defined by an inner surface of the gasket and including an open end, (d) a plurality of non-continuous channels in or through the membrane, each non-continuous channel being substantially parallel to the other non-continuous channels, each non-continuous channel of the plurality of non-continuous channels extending around the circumferential outer surface of the gasket and having a non-channel portion interrupting the non-continuous channel, The non-channel portion of each non-continuous channel is positioned along a circumferential outer surface portion of the gasket such that the non-channel portion is not aligned with the non-channel portions of one or more immediately adjacent non-continuous channels.

32. The matched syringe and plunger system of claim 31 , wherein the thickness of the film on at least a portion of the circumferential outer surface portion of the gasket is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

33. The matched syringe and plunger system of claim 32, wherein the membrane is configured to slide along the barrel of the syringe and is chemically stable.

34. A matched syringe and plunger system according to any one of claims 31-33, wherein the membrane is capable of preventing migration of components from the elastomeric material of the gasket.

35. The matched syringe and plunger system of claim 31 , wherein the gasket is attached to the plunger by a press-fit assembly.

36. The matched syringe and plunger system of claim 31 , wherein the tubular barrel contains an injectable fluid in contact with the gasket.

37. The matched syringe and plunger system of any one of claims 31-36, capable of maintaining container closure integrity (CCI) over a two year storage period as measured by one or both of a liquid migration test method and a helium leak detection test method.

38. The matched syringe and plunger system of any one of claims 31-36, comprising a container closure integrity (CCI) with a defect rate not exceeding 6 sigma.

39. The matched syringe and plunger system of any one of claims 31-36, wherein the plunger and the gasket comprise a breakaway force between 4 and 20 Newtons (N).

40. The matched syringe and plunger system of any one of claims 31-36, wherein the plunger and the gasket comprise a sliding force between 4 and 20 Newtons (N).

41. The matched syringe and plunger system of claim 32 or 33, wherein the break-away or glide force varies by less than about 10%-30% over a two year storage life when subjected to conditions between 2°C and 8°C.

42. The matched syringe and plunger system of claim 33 or 34, wherein the break-away or glide force varies by less than about 20%-40% over a two year storage life when subjected to conditions between 20°C and 25°C.

43. The matched syringe and plunger system of any one of claims 31-42, wherein the tubular barrel comprises a wall having an inner surface coated with a lubricating layer having an atomic ratio of 1 Si atom: 0.5 to 2.4 O atoms: 0.6 to 3 C atoms as measured by X-ray photoelectron spectroscopy (XPS).

44. The matched syringe and plunger system of claims 31-42, wherein the tubular barrel comprises a wall having an inner surface characterized by a three-layer coating, wherein the three layers comprise a bond coating, a barrier coating, and a pH protective coating; in (a) the bond coating comprises SiOxCy or SiNxCy, wherein x is from about 0.5 to about 2.4, and y is from about 0.6 to about 3, the bond coating having an outer surface facing the inner surface of the wall, and the bond coating having an inner surface facing the lumen of the tubular barrel; (b) the barrier coating comprises SiOx, wherein x is 1.5 to 2.9, the barrier coating has a thickness of 2 to 1000 nm, the barrier coating has an outer surface facing the inner surface of the bond coating, and the barrier coating has an inner surface facing the lumen of the tubular barrel; and (c) the pH protective coating comprises SiOxCy or SiNxCy, wherein x is from about 0.5 to about 2.4, and y is from about 0.6 to about 3, the pH protective coating having an outer surface facing the inner surface of the barrier coating and an inner surface facing the inner cavity of the tubular barrel.

45. The matched syringe and plunger system of claim 44, wherein the tubular barrel further comprises a lubricious layer having an outer surface facing the inner surface of the pH protective coating and an inner surface facing the lumen of the tubular barrel.

46. ​​A matching syringe and plunger system according to claims 43 or 44, wherein the lubricating layer is capable of reducing one or both of the static friction and sliding friction of a gasket in the barrel compared to one or both of the static friction and sliding friction of a gasket in a tubular barrel without the lubricating layer.

47. The matched syringe and plunger system of any one of claims 31-46, wherein the membrane comprises a fluoropolymer membrane.

48. The matched syringe and plunger system of any one of claims 31-47, wherein the fluoropolymer membrane comprises polytetrafluoroethylene (PTFE).

49. A matching syringe and plunger system according to any one of claims 31-48, wherein the multiple non-continuous channels improve the container closure integrity (CCI) of the system when assembled to form a prefilled syringe, compared to an otherwise substantially similar prefilled syringe that does not include the multiple non-continuous channels produced by the process.

50. The matched syringe and plunger system of any one of claims 31-49, characterized in that Improvements for longer shelf life.

51. The matched syringe and plunger system of claim 49 or 50, wherein the improvement in CCI is measured by a vacuum decay leak detection method.

52. The matched syringe and plunger system of claim 49 or 50, wherein the improvement is measured by the Liquid CCI test method.

53. The matched syringe and plunger system of any one of claims 31-52, wherein The tubular barrel includes a wall including an inner surface defining a generally cylindrical lumen, the barrel having an inner diameter; The gasket includes a front face, a side surface, a rear portion, and an outer diameter; The gasket is configured to be received within a tubular syringe barrel, wherein the gasket outer diameter is within the barrel inner diameter and is movable relative to the barrel inner diameter; and The tubular barrel and gasket of the system are each sized to provide a spacing between the minimum barrel inner diameter and the maximum gasket outer diameter when assembled, wherein the spacing deviates from the nominal spacing by no more than: ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns or ±2 microns.

54. A gasket comprising (a) a body comprising an elastomeric material and having a circumferential surface portion and an internal cavity, the cavity being defined by an inner surface portion of the gasket and being open-ended at one end; (b) a membrane located on at least a portion of a circumferential outer portion of the gasket; as well as (c) a plurality of non-continuous channels in or through the membrane and extending around a circumferential outer surface portion of the gasket and having respective non-channel portions interrupting each respective non-continuous channel, The corresponding non-channel portion of each non-continuous channel is positioned along a circumferential outer surface portion of the gasket such that the corresponding non-channel portion is not aligned with an adjacent non-channel portion.

55. The gasket of claim 54, wherein the gasket exhibits one or more of the following properties: (i) Maintain container closure integrity (CCI) over a two-year storage period as measured by one or more of the liquid migration and helium leak detection test methods; (ii) a container closure integrity (CCI) defect rate not exceeding 6σ when assembled in a matched syringe and plunger system; (iii) a breakaway force of between 4 and 20 Newtons (N), alternatively between 4 and 10 Newtons (N), alternatively between 4 and 8 Newtons (N), when assembled in a matching syringe and plunger system; (iv) when assembled in a matching syringe and plunger system, the sliding force is between 4 and 20 Newtons (N), alternatively between 4 and 10 Newtons (N), alternatively between 4 and 8 Newtons (N); and The break-loose force or sliding force varies by less than about 10%-30% over a two year shelf life.

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