Improved Syringe and Gasket System

Abstract

A process for manufacturing a gasket with an improved channel for use in an adapted syringe and plunger system, preferably a prefilled plastic syringe system, is disclosed. Specifically, the process involves forming and inspecting a continuous channel in a gasket film by laser processing. The gasket has high and consistent container closure integrity (CCI), consistent sliding yield and equilibrium stress over time, and sealability, making it useful for adapted syringe and plunger systems.

Description

[Technical field]

[0001] This application incorporates by reference in its entirety U.S. Provisional Patent Application No. 62 / 776,958, filed December 7, 2018; U.S. Provisional Patent Application No. 62 / 788,168, filed January 4, 2019; U.S. Provisional Patent Application No. 62 / 789,366, filed January 7, 2019; U.S. Provisional Patent Application No. 62 / 825,166, filed March 28, 2019; and U.S. Patent No. 7,985,188 B2, issued July 26, 2011. This application specifically incorporates by reference U.S. Patent No. 7,985,188 B2 for its disclosure of, among other things, a syringe barrel lubricated by application of a PECVD coating of SiOxCy or SiOxCyHz, and methods of making, testing, and using such a syringe barrel.

[0002] The present disclosure relates to adapted syringe and plunger systems, particularly gaskets used within syringes, and improved processes for forming and inspecting the laser cuts of the gaskets. [Background technology]

[0003] Prefilled parenteral containers, such as syringes or cartridges, and plunger systems have been developed to facilitate rapid and accurate administration of sterile products (e.g., saline, injection dyes, pharma- ceutical active preparations, etc.), minimize administration errors, reduce the risk of biological contamination, increase convenience and ease of use, and prevent overfilling of the product (Yoshino et al. J Pharm Sci. 2014; 103(5):1520-8). Prefilled parenteral containers are typically sealed with a rubber gasket that is secured to the plunger at the distal end, providing closure integrity over the shelf life of the contents of the container. To use a prefilled syringe, the package and cap are removed, an optional hypodermic needle or another delivery conduit is attached to the distal end of the barrel, the delivery conduit or syringe is moved to a use position (such as by insertion into a subject's tissue or a device that is rinsed with the contents of the syringe), and the plunger is advanced within the barrel to inject the contents of the barrel into the application point.

[0004] The seal provided by a rubber gasket in the barrel of a syringe usually involves the rubber of the gasket being pressed against the barrel. Usually, the maximum diameter of the rubber gasket is larger in diameter than the minimum inner diameter of the barrel. This pressing force of the rubber gasket must therefore be overcome in order to displace the rubber gasket and the plunger attached thereto when dispensing the injection product from the syringe. Moreover, this pressing force provided by the rubber seal usually not only needs to be overcome when initially moving the gasket fixed to the plunger, but this force must also continue to be overcome as the rubber gasket is displaced along the barrel during dispensing of the injection product. The relatively high force required to advance the gasket and plunger in the syringe can increase the user's difficulty in administering the injection product from the syringe. This is particularly problematic in automatic injection systems where the syringe is placed in an automatic injection device and the gasket is advanced by a fixed spring. Thus, primary considerations regarding the use of a gasket secured to a plunger in a prefilled parenteral container include: (1) Container Closure Integrity ("CCI", defined below) and liquid / air tightness; and (2) the plunger force (defined below) required to dispense the contents of the syringe.

[0005] In practice, maintaining CCI / liquid-tightness or air-tightness and providing a desirable plunger force tend to be competing considerations. In other words, the tighter the fit between the gasket and the inner surface of the container to maintain adequate CCI / liquid-tightness or air-tightness, in the absence of other factors, the greater the force required to advance the gasket during use. In the field of syringes, it is important to ensure that the gasket secured to the plunger can move at a substantially constant speed and with a substantially constant and relatively low force as it advances within the barrel. Furthermore, the force required to initiate plunger movement and then continue plunger advancement must be low enough to allow comfortable administration by the user and prevent rocking or unnecessarily high pressing forces that may cause discomfort to the patient.

[0006] To reduce friction and therefore improve plunger force, lubrication is conventionally applied to the barrel contact engagement surface of the gasket fixed to the plunger, the inner surface of the barrel, or both. A liquid or gel-like mobile lubricant, such as free silicone oil (e.g., polydimethylsiloxane or "PDMS"), can provide a desired level of lubrication between the plunger and the barrel to optimize the plunger force. In fact, PDMS is a standard mobile lubricant used in the industry. However, it is not desirable to use a mobile lubricant between the gasket and the barrel. One reason is that the mobile lubricant may mix and interact with the pharmaceutical product in the syringe, degrading the pharmaceutical product or affecting its efficacy and / or safety. For example, silicone oils, when used as lubricants, can generate droplets that can cause aggregation of sensitive biopharmaceuticals or clouding of the solution (Bee JS et al. PDA J Pharm Sci Technol. 2014; 68(5): 494-503), or can cause increased drug interactions and particle formation (Yamashita A et al. Adv Drug Deliv Rev. 2013; 65(1): 139-47). Monoclonal antibodies, conjugate vaccines, and protein formulations are particularly vulnerable to silicone-induced protein aggregation and particle formation. (Majumdar et al. J Pharm Sci. 2011 Jul; 100(7): 2563-73). Additionally, over time, silicone migration can affect delivery consistency. This is because it may change the sliding yield and sliding equilibrium stress (BLGF) as well as the injection time (Thornton JD et al., 2015. ON drug Delivery Magazine, Issue 61 (Oct 2015), pp 10-15).The invisible particles caused by the migration of silicone oil into the formulation may result in several product quality concerns, such as exceeding the USP limit for particles in parenteral containers, structural instability of proteins caused by adsorption, and / or immunogenic responses caused by silicone oil-induced protein aggregates or injection of silicone oil / protein complexes, which may reduce the efficacy of the drug 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 (Oct 2015), pp 10-15.). Thus, lubricants may be problematic when injected into patients together with the drug product.

[0007] Additionally, mobile lubricants, when used in prefilled syringes, can migrate away from the gasket over time, resulting in spots with little or no lubricant between the gasket and the inside surface of the container. This can result in a phenomenon called "sticktion," which is the industry term for adhesion between the gasket and barrel that must be overcome to break out the plunger and gasket and allow it to begin to move. For these reasons, there is a need in the industry for "oil-free" solutions, i.e., gaskets that do not contain mobile lubricants between the gasket and barrel, and where such mobile lubricants are not present in the pharmaceutical flow.

[0008] As an alternative (or in addition) to mobile lubricants, gaskets have been developed from materials with lubricating properties or to include friction-reducing coatings or films on their exterior surfaces. Such fluoropolymer films, in some embodiments laminates, can provide a barrier that minimizes interactions between the formulation and the plunger while maintaining the seal integrity of the gasket (Christa Jansen-Otten 2019.Blog; Westpharma). Examples: i-COATING by TERUMO, mentioned in Canadian Patent No. 1,324,545, incorporated herein in its entirety by reference; WLGore expanded PTFE film on rubber stoppers, disclosed in European Patent No. 2493534 B1, incorporated herein in its entirety by reference; and CZ plungers by WEST. However, such gaskets have experienced CCI failures due to film wrinkling, film defects and / or film peeling from the rubber gasket may also have poor gas barrier properties. Thus, conventional fluoropolymer film laminate gaskets alone may not be a viable solution for pre-filled syringes containing certain gas sensitive products, and further, such syringe and gasket systems have poor CCI.

[0009] Moreover, in such prefilled syringe systems, the gasket is in contact with the enclosed sterile product during administration and during drug storage. The interaction between the sterile product and its packaging can have a significant impact on the purity and degradation of the drug product and the safety of patients administered the product (Christa Jansen-Otten 2019.Blog;Westpharma). Therefore, the selection of suitable gaskets for syringe systems, especially prefilled syringe systems, is an important consideration for the pharmaceutical and biopharmaceutical industries.

[0010] US Patent Application No. 15 / 445,108, incorporated herein by reference in its entirety, discloses a laminated gasket for use in a medical syringe. Such a gasket includes a body made of an elastic material and a film provided on the surface of the body. In a syringe system, the syringe typically includes a syringe barrel and a plunger that is reciprocable within 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 treatment process by applying a laser beam to a circumferential surface portion of the gasket at an angle to the circumferential surface portion while rotating the circumferential surface portion of the gasket about the central axis of the gasket, thereby forming an annular groove in the circumferential direction on at least the surface portion of the film on the gasket. Such laser-cut grooves or channels improve the sliding and sealing of the laminated gasket in the syringe while maintaining the elasticity of the gasket and minimizing the leakage of liquid from the prefilled syringe.

[0011] In the process disclosed in U.S. Patent Application Serial No. 15 / 445,108, the internal cavity of the gasket includes threads for mounting a threaded plunger rod, which is then rotated during the laser cutting process. However, this method of fixing the gasket during the laser process has some drawbacks because the walls of the gasket may deform or sag while the gasket is rotated to form the laser cut grooves. This reduces the consistency of the laser cut or grooves in the gasket film. Syringe systems incorporating gaskets manufactured by the process of U.S. Patent Application Serial No. 15 / 445,108 are also more prone to liquid or gas leakage and have poor CCI. Summary of the Invention [Problem to be solved by the invention]

[0012] Thus, there is a need for an improved process for forming one or more channels on a surface of a gasket that has a film on its exterior surface, as well as an improved gasket for use in a syringe-gasket system, for example, for delivering pharmaceutical products to a subject in need. The resulting gasket provides improved protection against liquid or gas leakage and has excellent CCI when used with a compatible syringe and plunger system. Syringes assembled with the improved gaskets of the present disclosure provide improved protection of products contained therein and are characterized by improved product shelf life. [Means for solving the problem]

[0013] The present application provides an improved process for forming one or more continuous channels in a film present on the exterior surface of a gasket for use in an adapted syringe and plunger-gasket system, and in some embodiments extending into the gasket itself, which provides superior container closure integrity and seal and minimal liquid / gas leakage.

[0014] In some embodiments, the present disclosure provides a gasket with improved channels for use with adapted syringe-plunger systems. The silicone oil-free syringe and gasket system, preferably a prefilled plastic syringe system, of some embodiments of the present disclosure has excellent container closure integrity (CCI), high sliding yield stress and avoids liquid / gas leakage, provides consistent delivery performance over time, provides protection for the enclosed product, minimizes interaction with the product, maintains efficacy and sterility during the shelf life of the product, and has improved shelf life. The syringe and gasket system of some embodiments also reduces the generation of non-visible particles, and can protect complex or sensitive biological materials contained within the syringe from silicone oil-induced agglomeration and particulation. The present disclosure in some embodiments also provides an improved process for forming continuous channels in the gasket and the film present on its outer surface by laser cutting.

[0015] In some embodiments, the present disclosure also provides an improved process for manufacturing a silicone oil-free syringe and gasket system having less than 300 particles of 2 microns or greater size measured using light obscuration (LO) or microflow imaging (MFI). Additionally, in some embodiments, the syringe system of the present disclosure incorporates a process that improves the seal provided by a built-in lubricating film on the gasket, eliminating the need to use a lubricated syringe barrel. In other embodiments, the present disclosure incorporates a state-of-the-art manufacturing process control and 100% inspection system that provides tight dimensional control of the gasket and corresponding syringe and channel, thereby allowing highly consistent compression of the assembled syringe and gasket system to be optimized for container closure integrity and plunger force.

[0016] Particular embodiments of the present disclosure are described in the following numbered paragraphs: 1. A process for forming one or more continuous channels in a film present on at least a circumferential outer surface portion of a gasket, the gasket comprising a body made of a resilient material, the body having a circumferential surface portion and an interior cavity at its center, the cavity being defined by an inner surface portion of the gasket and open at one end, the process comprising: (a) inserting a portion of one end of a mandrel into an open end of a cavity; (b) securing the gasket to the mandrel; (c) placing the mandrel and the secured gasket adjacent to a laser; and (d) applying a laser beam emitted from the laser to one or more selected locations on a surface portion of the film residing on a circumferential outer surface portion of the gasket while rotating the mandrel and the secured gasket along the longitudinal axis of the mandrel to form one or more channels in the film, the channels extending completely around the circumferential outer surface of the gasket; A process including. 2. The process of paragraph 1, wherein the thickness of the film on the surface of the gasket prior to step (d) is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns. 3. The process of paragraph 1 or 2, wherein the film has one or more of good slip properties and chemical stability. 4. The process of any one of paragraphs 1-2, wherein the film is capable of preventing migration of components from the elastic material of the gasket. 5. The process of any one of paragraphs 1-4, wherein the gasket is secured to the mandrel by a press-fit assembly. 6. The process of paragraph 5, wherein the diameter of at least a portion of the mandrel portion that is inserted into the internal cavity of the gasket is greater than the inner diameter of the cavity. 7. The process of any one of paragraphs 1-6, wherein when multiple channels are formed, the channels are axially spaced apart. 8. The process of any one of paragraphs 1-7, wherein the one or more channels have axially opposed first and second sidewalls and a floor. 9. The process of any one of paragraphs 1-8, wherein the one or more channels each independently have an axial width between sidewalls selected from 1 to 100 microns, 5 to 50 microns, 10 to 30 microns, and 15 to 25 microns. 10. The process of any one of paragraphs 1-9, wherein the one or more channels each independently have a radial depth selected from 0 to 100 microns, 5 to 50 microns, 10 to 30 microns, and 15 to 25 microns. 11. The process of any one of paragraphs 1-10, wherein the one or more channels each independently have a laser cut 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. 12. The process of any one of paragraphs 1-11, wherein one or more channels extend through the film into an exterior portion of the gasket. 13. The process of any one of paragraphs 1-12, wherein the one or more channels comprise a first circumferentially extending lip disposed adjacent a first sidewall of the channel and extending radially above the film. 14. The process of paragraph 13, wherein the one or more channels further comprise a second circumferentially extending lip disposed adjacent the second sidewall and extending radially above the film. 15. The process of paragraph 13 or 14, wherein the first and second lips independently have a peak height selected from 10 to 100 microns, 15 to 60 microns, 20 to 50 microns, or 30 to 40 microns. 16. The process of any one of paragraphs 13-15, wherein the first and second lips of each of the one or more channels independently have a peak width selected from 200 to 1,000 microns, 275 to 550 microns, 300 to 400 microns, or 450 to 500 microns. 17. The process of any one of paragraphs 13-16, wherein each lip comprises a film material. 18. The process of any one of paragraphs 13-16, wherein each lip comprises film material displaced from the channel by the laser beam as the channel is formed. 19. The process of any one of paragraphs 13-18, wherein at least one lip can be positioned within the tubular syringe barrel to form a seal against an inner surface of the barrel. 20. The process of any one of paragraphs 1 to 19, wherein the position of the laser relative to the mandrel and fixed gasket is controlled by a servo motor. 21. The process of any one of paragraphs 1 to 20, wherein the film is a fluoropolymer film. 22. The process of paragraph 21, wherein the fluoropolymer film is polytetrafluoroethylene (PTFE). 23. The process of any one of paragraphs 1-22, wherein the elastic material comprises bromobutyl rubber. 24. The process of any one of paragraphs 1 to 23, wherein the inner surface of the film is treated before being applied to the outer surface portion of the gasket to promote adhesion to said outer surface portion. 25. The process of paragraph 24, wherein the inner surface of the film is corona treated. 26. The process according to paragraph 24, wherein the inner surface of the film is chemically treated. 27. The process of any one of paragraphs 1 to 26, wherein the dimensional tolerances of gaskets usable in the process are selected from ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±3 microns. 28. The process of any one of paragraphs 1-27, wherein the gasket has less than 300 particles equal to or greater than 2 microns in size as measured using light obscuration (LO) or microflow imaging (MFI). 29. An adapted syringe and plunger system, comprising: (a) Tubular syringe barrel; (b) a plunger disposed inside the syringe barrel and longitudinally reciprocatable within the barrel; and (c) a gasket attached to the distal end of the plunger, the gasket including a body made of a resilient material, the body having a circumferential outer surface portion and an internal cavity at its center, the cavity being defined by an inner surface portion of the gasket and open at one end, the gasket comprising: (i) inserting a portion of one end of a mandrel into an open end of a cavity; (ii) securing the gasket to the mandrel; (iii) placing the mandrel and the secured gasket adjacent to a laser; and (iv) applying a laser beam emitted from the laser to one or more selected locations on a surface portion of the film present on a circumferential outer surface portion of the gasket while rotating the mandrel and the secured gasket along the longitudinal axis of the mandrel to form one or more continuous channels in the film, the channels extending completely around the circumferential outer surface of the gasket; 16. An adapted syringe and plunger system characterized by one or more continuous channels formed according to a process including: 30. The system of paragraph 29, wherein the gasket is attached to the plunger by a press-fit assembly. 31. The system of paragraph 30, wherein the syringe barrel contains an injectable fluid distal to the gasket. 32. The system of any one of paragraphs 29 to 31, having a container closure integrity (CCI) of less than or equal to 32.6 sigma. 33. A system according to any one of paragraphs 29 to 32, wherein the plunger and attached gasket have a sliding yield stress of between 4 and 20 Newtons (N). 34. A system according to any one of paragraphs 29 to 33, wherein the plunger and attached gasket have a sliding equilibrium stress of between 4 and 20 Newtons (N). 35. The system of paragraphs 33 or 34, wherein the change in sliding yield stress or sliding equilibrium stress is less than about 10-30% over a two-year shelf life. 36. The system of any one of paragraphs 29-35, wherein the syringe barrel includes a wall having an inner surface coated with a lubricating layer having an atomic ratio of 1 atom of Si:0.5-2.4 atoms of O:0.6-3 atoms of C as measured by X-ray photoelectron spectroscopy (XPS). 37. The syringe barrel further comprises a three-layer coating between the inner surface of the wall and the lubricious coating, the three layers comprising a tie coating, a barrier coating, and a pH protective coating; (a) Tie coating is SiO x C y or SiN x C y wherein x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, the tie coating having an outer surface facing the inner surface of the wall and an inner surface facing the lumen of the syringe barrel; (b) Barrier coating is SiO x wherein x is between 1.5 and 2.9, the barrier coating is between 2 and 1000 nm thick, has an outer surface facing the inner surface of the tie coating, and has an inner surface facing the lumen of the syringe barrel; (c) pH protective coating is SiO x C y or SiN x C y wherein x is from about 0.5 to about 2.4 and y is from about 0.6 to about 3, and the pH protective coating has an outer surface facing the inner surface of the barrier coating and an inner surface facing the lumen of the syringe barrel. 37. A system according to paragraph 36. 38. The system of paragraphs 36 or 37, wherein the lubricating layer is capable of reducing one or both of the sticktion and sliding friction of the gasket in the barrel compared to one or both of the sticktion and sliding friction of the gasket in the barrel without the lubricating layer. 39. The system of any one of paragraphs 29 to 38, wherein the film is a fluoropolymer film. 40. The system of any one of paragraphs 29 to 39, wherein the fluoropolymer film is polytetrafluoroethylene (PTFE). 41. The system of any one of paragraphs 29 to 40, wherein one or more of the channels improve container closure integrity of the syringe components when assembled to form a prefilled syringe, when compared to an otherwise substantially similar prefilled syringe that does not include channels formed by the process. 42. The system of paragraph 41, wherein the improvement is a longer shelf life. 43. The system of paragraph 41 or 42, wherein the improvement is measured by a vacuum collapse leak detection method. 44. The system of paragraph 41 or 42, wherein the improvement is measured by a liquid CCI test method. 45. A syringe barrel having a wall including an inner surface defining a generally cylindrical lumen, the barrel having an inner diameter; the gasket having a leading surface, a side surface, a following portion, and an outer diameter; the gasket is configured to be received within any barrel with an outer diameter of the gasket disposed within and movable relative to an inner diameter of the barrel; the barrel and gasket of the system, when assembled, are each sized to provide a spacing between the minimum barrel inner diameter and the maximum gasket outer diameter that deviates no more than ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±2 microns from the nominal spacing; 45. An adapted syringe and plunger system according to any one of paragraphs 29 to 44. 46. ​​A gasket comprising: (a) a body made of a resilient material, the body having a circumferential surface portion and an interior cavity, the cavity being defined by an interior surface portion of a gasket, the body being open at one end; (b) a film present on at least an outer circumferential portion of the gasket; (c) one or more continuous channels in the film, the channels extending around an entire circumferential outer surface of the object; The gasket has the following features: (i) Container Closure Integrity (CCI) when assembled into a matched syringe and plunger system with a failure rate of 6 sigma or less; (ii) a sliding yield stress of 4 to 20 Newtons (N) when assembled into an adapted syringe and plunger system; (iii) a sliding equilibrium stress of 4 to 20 Newtons (N) when assembled into an adapted syringe and plunger system; having one or more of: A gasket whose sliding yield stress or sliding equilibrium stress changes by less than about 10-30% over a two year shelf life. [Brief description of the drawings]

[0017] [Figure 1] A cross-sectional view of the syringe 10 is shown including the syringe barrel 12 assembled with the gasket 14 attached to the plunger 26. [Diagram 2] 1 shows a fragmentary detailed view of the syringe of FIG. 1 , showing the inside diameter (ID) of barrel 12 and the outside diameter (OD) of gasket 14 fitted to be within a predetermined tolerance therebetween, and also shows film 16 on the exterior surface of gasket core 18, and a continuous channel 20 in the film present on a circumferential exterior portion of gasket core 18, which surrounds gasket 14. The channel has lips 22 and 24 as shown in FIG. 3B. [Figure 3A]A schematic cross-sectional view taken along section line 3A-3A in FIG. 2 is shown, showing gasket core 18 within the interior cavity (IC), film 16, and channels 20 in the surface of the film (in some embodiments, channels 20 extend through the film into the outer surface of the gasket (not shown)) and surrounding a circumferential outer surface portion of gasket 14. [Figure 3B] A fragmentary detail view of the structure of FIG. 3A is shown illustrating one embodiment of a channel 20 and lips 22 and 24 on either side of the channel 20. [Figure 4A] 2 shows the assembly of gasket 14 and mandrel 28 inserted into the interior cavity of the gasket. The figure also shows the application of a laser beam at an angle to an outer portion of film 16 present on a circumferential outer surface portion of gasket 14 secured to mandrel 28 while mandrel 28 and gasket 14 rotate along the longitudinal axis of the mandrel to form continuous channels 20 in film 16 present on a circumferential outer portion of gasket 20. [Figure 4B] 4A shows a schematic cross-sectional view of one embodiment of a gasket taken along section line 4B-4B, illustrating a mandrel 28 secured to the gasket interior cavity, film 16, and channels 20 in the exterior surface of film 16 that reside in and surround a circumferential exterior portion of gasket 20. In other embodiments, the channels extend through the film into the exterior surface of the gasket. [Figure 5A] A gasket 14 is shown with a film 16 having channels 20 within the film 16 . [Figure 5B] 5A shows a fragmentary detail view of the structure, illustrating an embodiment of a channel 20 in the surface of a film with lips 22 and 24 on either side of the channel 20, and with various dimensions (peak width, axial width, laser cut depth, and radial depth) of the channel 20 and lips 22 and 24. In another more preferred embodiment, the channel 20 extends into the exterior surface of a gasket (not shown). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The following reference characters are used in the drawings according to any embodiment:

[0019] [Table 1]

[0020] definition In the context of this disclosure, the following definitions and abbreviations are used:

[0021] The term "comprising" according to any embodiment does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality, unless otherwise indicated. Whenever a parameter range is given, it is intended to disclose the parameter value given as the limit of the range and all values ​​of the parameter that are within said range. Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter itself. For example, a description that refers to "about X" includes the description of "X". Numerical ranges include the numerical values ​​that define the range. As used herein, the term "about" allows for a variation of ±10% within significant digits.

[0022] When aspects or embodiments are described in terms of a Markush group or other alternative grouping, the application includes not only the entire group listed as a whole, but each member of the group individually, and all possible subgroups of the main group, and the main group lacking one or more of the group members. The application also envisions the explicit exclusion of any one or more of the group members in the embodied disclosure.

[0023] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can 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.

[0024] In order to make this disclosure easier to understand, certain terms are defined first. These definitions should be read in light of the remainder of this disclosure as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Additional definitions are set forth throughout the detailed description.

[0025] As used herein, the term "syringe" is broadly defined to include cartridges, injection pens, and other types of barrels or reservoirs adapted to be assembled with one or more other components to provide a functional syringe. "Syringe" is also broadly defined to include related articles such as auto-injectors that provide a mechanism for dispensing contents. Preferably, "syringe" may include pre-filled syringes. "Syringe" as used herein may also refer to vaccine dispensing syringes with a product space that contains a vaccine. "Syringe" as used herein may also have applications in diagnostics, e.g., sampling devices including medical barrels pre-filled with diagnostic agents (e.g., contrast agents), etc. In general, "syringe" as used herein is any medical barrel that, when assembled with one or more other components (e.g., gaskets and plungers), functions as a container / dispenser of a fluent product. Although the present disclosure is not necessarily limited to a syringe of a particular volume, syringes having a lumen having a void volume of, for example, 0.5-50 mL, optionally 1-10 mL, optionally 0.5-5 mL, optionally 1-3 mL are contemplated. The syringe of the present disclosure includes a hollow cylindrical syringe barrel 12, a plunger 26 coupled with the syringe barrel and reciprocatable within the syringe barrel 12, and a gasket 14 attached to a distal end of the plunger 26. See FIG. 1.

[0026] As used herein, the term "gasket" in the context of the present disclosure is a molded part or ring made of an elastomeric material that can be used to mechanically seal the space between two opposing inner surfaces of a syringe barrel. The gasket is preferably cylindrical with a short axis. The gasket has a circumferential surface portion that is maintained in 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 that includes a body made of an elastomeric material and a film that is present on at least the circumferential surface of the body, the gasket having a circumferential surface portion and an internal cavity (IC) at its center, the cavity being defined by the inner surface of the gasket and open at one end. See Figures 2 and 3A. In a preferred embodiment, the internal cavity of the gasket is not threaded.

[0027] An "elastomeric material" may be a rubber or elastomer. Particularly preferred types of rubber include butyl rubber, chlorinated butyl rubber, and brominated butyl rubber. Other types of elastomeric materials may include thermoset rubbers and dynamically crosslinkable thermoplastic elastomers that have crosslinking sites that make them heat resistant. These polymeric components of such elastomers include ethylene-propylene-diene rubber and butadiene rubber.

[0028] As used herein, the term "film" refers to a material present on at least a circumferential outer surface portion of the body of the gasket. Preferably, it coats or is present on substantially all of the outer surface of the gasket. The film may have an optional thickness of less than about 100 micrometers (μm or microns), optionally about 10-30 microns, about 15-35 microns, or about 20-50 microns. Most preferably, the film is about 20 microns thick. A variety of different materials can be used for the film, such as inert fluoropolymers including, for example, fluorinated ethylene propylene (FEP), ethylene tetrafluoroethylene (ETFE), polytetrafluoroethylene (PTFE), ethylene perfluoroethylene propylene (EFEP), ethylene chlorotrifluoroethylene (ECTFE), polychlorotrifluoroethene (PCTFE), perfluoroalkoxy (PFA), among other coatings. Preferably, the film is an ultra-high molecular weight polyethylene film (UHMWPE) or a fluoropolymer film. A fluoropolymer film such as polytetrafluoroethylene (PTFE) is preferred due to its excellent slipperiness and chemical stability. The type of film provided on the surface of the gasket body is not particularly limited, as long as the film can prevent the transfer of material (body) from the crosslinked rubber and has slipperiness, i.e., a small coefficient of friction compared to the gasket body.

[0029] Optionally, the film may include a CPT fluoropolymer. CPT is a modified perfluoroalkoxy (PFA), which generally involves the addition of PCTFE side chains to a PFA backbone during polymerization.

[0030] Optionally, additives can be added to the film material of the film, for example additives that can improve the adhesion of the film to the underlying portion of the gasket to create a liquid sealing section and / or reduce friction between the section and the sidewall of the syringe barrel. Additionally, according to certain embodiments, adhesion promoting coatings or processes can be used, such as, for example, corona treatment or chemical treatment. Corona treatment or air plasma is a surface modification technique that uses low-temperature corona discharge plasma to alter the properties of a surface. Corona plasma is generated by applying high voltage to a sharp-tipped electrode. In some applications, it may be desirable to co-extrude different materials to form a film. For example, co-extruded film combinations can include cyclic olefin copolymer (COC) with Aclar, polyethylene (PE) with Aclar, and FEP with PE, among other combinations.

[0031] As used herein, the term "mandrel" refers to a device or tool that may be attached at its distal end to a base that 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 portion of a two-part mold that can be inserted and secured into the internal cavity of the gasket (the corresponding female portion). In some embodiments, the mandrel is a formed bar of metal or steel, such as a cylindrical rod. The proximal end of the mandrel may be continuous with the body of the mandrel or may have a smaller or larger circumferential portion than the distal section of the mandrel. In a preferred embodiment, the proximal end of the mandrel is secured to the gasket using a "press-fit assembly," where the gasket is secured to the mandrel by friction rather than other fastening means (such as threading) after the parts are forced together. In some embodiments, the diameter of at least a portion of the mandrel portion that is inserted into the internal cavity of the gasket is larger than the inner diameter of the cavity. "Fixing the gasket" relative to the mandrel refers to the gasket being securely fixed or bonded to the proximal end of the mandrel so that it will not come apart, loosen, or move independently of the mandrel. A gasket fixed to the mandrel will maintain the shape of its inner and outer walls and will not collapse or deform during the laser cutting process. "Placing" the mandrel and fixed gasket near the laser refers to fixing the base of the mandrel in a desired position relative to the laser beam, so that the base of the mandrel is in a stationary position that does not move during the laser beam process of the present disclosure. However, the mandrel can still rotate along its longitudinal axis. See FIG. 4A.

[0032] As used herein, the term "channel" refers to the cutting of the film on the surface of the gasket by laser cutting. The term channel can be used interchangeably with the term "cut". In this disclosure, the term "cut" can also refer to the process of forming a score or separation in the film present at least in the circumferential outer surface portion of the gasket using one or more laser beams. In some embodiments, the channel is cut at the 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 formed, each of which surrounds the gasket. When multiple channels are present, they are preferably axially spaced from each other. Each channel has two lips. The term "lip" refers to the structure formed by the buildup of film material along both sides of the channel formed by the laser beam cutting. Channel lips 22 and 24 are shown in Figures 3B and 5B. Each lip is a raised rib arranged to seal against the inner surface of the barrel. Thus, each channel has two lips with two sealing ribs or peaks. In this disclosure, the terms "lip", "rib", "peak" and "microprojection" are interchangeable.

[0033] The laser cut and resulting channels are characterized by various dimensions, including laser cut depth, radial depth, peak width, axial width, and peak height. The "laser cut depth" is measured from the surface of the uncut gasket film to the lowest point of the trough of the channel. See FIG. 5B. The laser cut depth of the channel or channels is independently selected from the following ranges: 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. The "radial depth" is measured from the uncut outer surface of the gasket to the lowest trough of the channel. See FIG. 5B. The radial depth of the channel or channels may be independently selected from the following ranges: 0-100 microns, 5-50 microns, 10-30 microns, and 15-25 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 can be in one of the following ranges: 200-1,000 microns, 275-550 microns, 300-400 microns, and 450-500 microns.

[0034] The circumferentially continuous channels of the present disclosure have axially opposed "first and second sidewalls" and a "floor". The floor of the channel can be either the film surface or, more preferably, the gasket surface, depending on the thickness of the film and the depth of the cut. The "axial width" is measured from the first sidewall to the second sidewall of the channel across the width of the floor of the channel. In other words, the "axial width" is measured across the width from one end of the channel to the other end of the channel at the baseline level, i.e., the level of the non-laser cut outer surface of the film or gasket. One or more channels independently have an axial width between one of the sidewalls in the following ranges: 1-100 microns, 5-50 microns, 10-30 microns, and 15-25 microns.

[0035] "Peak height" is measured from the surface of the uncut gasket film along the central axis of the peak, i.e., perpendicular to the surface of the film, to the highest peak of the lip formed by the laser beam. The peak height of the lip or lips of the channel is independently selected from one of the following ranges: 10-100 microns, 15-60 microns, 20-50 microns, and 30-40 microns.

[0036] 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 shelf life of a sterile product contained in the container. In some embodiments, container closure integrity is related to the hermeticity of the syringe system of the present disclosure. The one or more channels formed by the laser in the film are intended to enhance the CCI of the plunger attached to the gasket when assembled into a prefilled syringe by providing a physical break in the film that prevents film defects (such as delamination, cracks, or wrinkles) from adversely affecting the seal integrity between the gasket and the syringe. Container closure integrity (CCI) should be substantially maintained throughout the shelf life of the syringe of the present disclosure. CCI is an important characteristic of prefilled syringes for parenteral pharmaceutical products contained within the syringe. One important element of CCI is maintaining a sterile barrier. The improved process of the present disclosure for forming one or more channels on a film reduces the likelihood of failure (breakdown of sterility) of the CCI and / or promotes a longer shelf life.

[0037] As used herein, the term "sliding yield stress" refers to the force required to initiate the movement of a plunger attached to a gasket in a syringe, such as a prefilled syringe. This is the maximum force required to break the static friction of the gasket attached to the plunger. In the context of this disclosure, sliding yield stress is synonymous with "plunger force", "plunger breakout force", "breakout force", "initiation force" and "Fi".

[0038] As used herein, the term "glide force" refers to the force required to maintain motion of a plunger (when the plunger is attached to a gasket of the present disclosure) within a syringe barrel after static friction has been overcome, e.g., during aspiration or dispensing. Glide force is synonymous with "push force," "plunger slide force," "retention force," and "Fm" in the context of this disclosure.

[0039] As used herein, the terms "sliding yield stress" and "sliding equilibrium stress" are collectively referred to as "BLGF forces", i.e., the various forces of the plunger and attached gasket of the present disclosure. The BLGF forces can be measured using any test known in the art, such as ISO 7886-1:1993. For example, the BLGF forces can be tested by filling a syringe of the present disclosure with 1 ml of liquid (such as water) and then applying a vacuum load to the stopper. The plunger forces can be tested with a plastic threaded rod at 300 mm / min. In the present disclosure, an improved process of forming channels on the surface of the gasket prevents aging of the plunger forces (i.e., an increase in sliding yield stress over time). The adapted syringe-plunger system of the present disclosure maintains sliding yield stress and sliding equilibrium stress between 4-20 Newtons (N), which changes by less than about 10%-30% over a two-year shelf life. The disclosed process provides consistent sliding yield and sliding equilibrium stress by incorporating manufacturing process control and a 100% inspection system.

[0040] As used herein, the term "sticktion" refers to a phenomenon that is an industry term for adhesion between a plunger (attached to a gasket) and a syringe barrel that must be overcome to break out the plunger attached to the barrel and allow it to begin to move. The term "sliding friction" or "kinetic friction" refers to the resistance created by two objects sliding against each other. Sliding friction is intended to stop the movement of an object. In the present disclosure, a lubricating layer in a syringe barrel can reduce one or both of the sticktion and sliding friction of a gasket in a barrel compared to one or both of the sticktion and sliding friction of a gasket in a barrel without a lubricating layer.

[0041] As used herein, the terms "dimensional tolerance", "dimensional accuracy" or "dimensional consistency" are the degree of control over the dimensions of a part (Quality Control in the Technical Sector (2000) 142-158). Dimensional tolerances are the allowable limits of variation in the physical dimensions of various parts of the present disclosure, such as gaskets and syringe barrels. "Tolerance" is the acceptable variation for any given size of a gasket or syringe barrel of the present disclosure that allows for proper functioning of the syringe system. In other words, dimensional tolerances are the acceptable variation for the dimensions of a syringe or gasket of the present disclosure that does not impair one or more of the following characteristics: container closure integrity, BLGF force, sealability, leakage characteristics, slipperiness, etc. Dimensional tolerances between gaskets that can be used in the processes of the present disclosure are 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 presently disclosed syringe system relates to dimensional tolerances in which the barrels and gaskets of the presently disclosed system are each sized to provide spacing between the smallest barrel inner diameter and the largest gasket outer diameter that, when assembled, 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.

[0042] Detailed Description The present disclosure in several embodiments will now be more fully described with reference to the accompanying drawings. However, the present disclosure may be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein. Rather, these embodiments are examples, and the present disclosure has full scope as indicated by the language of the claims. Like numbers refer to like or corresponding elements throughout.

[0043] Laser Process Embodiments 4A is a diagram of a laser treatment process according to one embodiment of the present disclosure. Referring to FIG. 4A, a laser beam is applied to a circumferential surface portion of a gasket 14 secured to a mandrel 28 at a desired angle. To form channels in the circumferential surface portion of the gasket, a laser beam source is fixed relative to the circumferential surface portion of the gasket 14, with the film 16 on the outer surface of the gasket, and the laser beam is applied to the circumferential surface portion while the gasket 14 secured to the mandrel 28 rotates about its longitudinal axis. Thus, the laser beam can be applied at a predetermined angle of incidence α to any angular position of the circumferential surface portion, thereby uniformly forming channels.

[0044] While the laser beam is applied obliquely to the circumferential surface portion, the gasket rotates in a rotational direction and the circumferential surface portion moves away from the laser beam application location where the laser beam is applied (in FIG. 4A, the gasket rotates clockwise).

[0045] Thus, by performing the laser treatment process of this embodiment of the present disclosure, channels are formed substantially uniformly in the film, and more preferably extend within the circumferential surface portion of the gasket, while simultaneously forming the outer edge portions 22 and 24 (FIG. 5B).

[0046] Syringe and Plunger System Embodiments 1 shows one exemplary embodiment of an adapted syringe and plunger system of the present disclosure, including a gasket 14 and a plunger 26 constructed according to one aspect of the disclosure. The terms "distal" and "proximal" generally refer to a spatial or positional relationship relative to a given reference point, with "proximal" being at or relatively close to that reference point and "distal" being far from that reference point. When applied herein to the plunger 26, for example, the relevant reference point is the bottom end of the plunger 26, with the distal end attached to the gasket 14. When applied herein to the syringe barrel 12, for example, the relevant reference point is the bottom end of the barrel 12, with the distal end attached to the delivery conduit or syringe.

[0047] Syringe 10 is generally of conventional construction and materials, preferably plastic, and includes a hollow barrel 12 having a central longitudinal axis A. The barrel has an interior surface 14 and is configured to hold an injectable liquid therein. A syringe or delivery conduit is disposed at a distal end of the barrel and in fluid communication therewith. A plunger 26 is also generally of conventional construction and materials. A gasket 14 of the present disclosure is attached to the distal end of the plunger.

[0048] Gasket Manufacturing and Laser Cutting Process In some embodiments of the present disclosure, the gasket comprises two materials: a bromobutyl rubber based gasket and a film, preferably a PTFE film, present on the outer surface. Examples of bromobutyl rubber include Sumitomo LAG 5010-50 and West 4023. The PTFE film in a preferred embodiment substantially covers the outer surface of the gasket. Manufacturing the gasket involves the following process, which is relevant to some embodiments of the present disclosure: (a) Forming: The PTFE film is treated to promote adhesion with the bromobutyl rubber of the gasket. A typical treatment is corona treatment. In some embodiments, chemical treatments can also be used. The PTFE film is placed into a multi-cavity gasket mold. Bromobutyl rubber is poured / injected into the multi-cavity mold. The mold is closed and the PTFE film and bromobutyl rubber are formed into a gasket. The mold is opened and the gasket is removed from the mold. The gasket thus produced has a substantially uniform wall thickness and comprises rubber and PTFE. The gasket is trimmed by die cutting to remove excess material. In some embodiments, the multi-cavity mold produces a gasket that is not threaded into the internal cavities. (b) Laser cutting of PTFE or other film: The improved process of the present disclosure includes the steps of: (1) inserting a portion of one end of a mandrel into the open end of the gasket cavity of the gasket produced in step (a); (2) fastening the gasket to the mandrel; (3) positioning the mandrel and fastened gasket near a laser; and (4) applying a laser beam emitted from a precision laser to one or more selected locations on a surface portion of the film on the circumferential outer surface portion of the gasket while rotating the mandrel and fastened gasket along the longitudinal axis of the mandrel to form one or more continuous channels in the film, the channels extending around the entire circumference of the circumferential outer surface of the gasket. This process forms one or more continuous channels in the PTFE or other film in the circumferential direction of the outer surface of the gasket. The precision of the channels formed by the laser beam is directly related to the fastening of the gasket to the mandrel, the position of the laser beam, and the dimensional tolerances of the gasket used in the process.

[0049] The resulting channel or channels create a physical separation in the PTFE or other film on the gasket. In particular, without being bound by theory, it is believed that the laser process melts the PTFE or other film, forcing the PTFE material to either side of the channel. During the laser process, the PTFE or other film material is "piled up" on either side of the channel, forming two sealing ribs or peaks (microprotrusions). The PTFE or other film sealing ribs on either side of the channel can maintain CCI at both the liquid barrier and the sterility barrier. However, assuming the PTFE film 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 film, namely (1) film thickness variation and (2) film defects (e.g., occlusion).

[0050] Furthermore, fluoropolymer films are generally stretched during manufacturing when the initial film is formed. This stretching process creates microchannels or pores in the film (the terms "microchannel" or "micropore" are used interchangeably herein), which vary in size and dimension depending on the specific manufacturing conditions. It is believed that these microchannels or pores, at least in some instances, provide a path along the fluoropolymer or other film from behind the gasket of the prefilled syringe, which is outside the sealed portion of the syringe, to the lumen of the syringe that contains the material that fills the syringe. This reduces the CCI and shortens the shelf life of the adapted syringe-plunger system.

[0051] While cutting one or more channels into a film may mitigate some of the reduced container closure integrity and shelf life caused by these fine channels, the process of forming the channels itself may introduce other issues that reduce CCI and shelf life as well. 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 exterior surface causing channel misalignment and variation. Also, unless the gasket and channels are carefully and individually inspected after formation, the failure rate of the gasket when used in a syringe plunger system will be unacceptable.

[0052] The improved processes, gaskets and syringe-plunger systems of the present disclosure overcome these problems. Additionally, the rigorous inspection process of the present disclosure ensures that the gaskets have a low defect rate when used in syringe-plunger systems.

[0053] 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: (1) dimensional check of the overall height and outer diameter of the gasket; (2) camera inspection of the shape of the seal ribs; (3) camera inspection of the laser cut, e.g., checking 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 evidence of wrinkles, cracks, or delamination (lack of adhesion) to the rubber. Additional tests to inspect the properties of the syringe and gasket system of the present disclosure, such as container closure integrity testing (CCIT), plunger sliding yield and sliding balance stress testing, sterility assurance, and non-visible particle testing, are also performed.

[0054] Gasket inspection (die cut and micro-projections): A vision system is used to inspect plungers in-line (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 / sec; (2) supports a wide range of plunger colors; (3) performs top, bottom, outer, and inner inspection; (4) inspects micro-projections; (5) inspects stamping and form defects; (6) 100% quality control with minimum defect detection of 100 μm. Rejected parts are sorted into separate bins and statistically tracked. Good parts are accurately counted and automatically packed.

[0055] Dimensional Measurement by Laser Micrometer: Each finished gasket of the present disclosure is measured for dimensional consistency. 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 rotating optics to reflect or refract a laser beam through the measurement area and across the path of the object being measured. The part blocks the laser light, casting a shadow that lasts for a time proportional to the size of the part. Receiver optics collect the unblocked laser light and focus it onto a photocell. The output of the photocell is analyzed by electronics to detect the exact time the laser crosses the edge of each part. Software converts the timing data into a meaningful measurement.

[0056] Classification: Using the dimensional measurements, the gaskets of the present disclosure may be classified such that each gasket is guaranteed a particular dimensional tolerance, which may 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.

[0057] The dimensions of the prefilled syringe barrel are measured in a similar manner to ensure a precise and consistent fit between the syringe and gasket. This allows precise control of gasket compression of the assembled syringe. Quality attributes of the assembled syringe include, but are not limited to: (1) measurement of container closure integrity by dye intrusion; (2) measurement of container closure integrity by vacuum decay method; (3) consistency of plunger force profile (Fi / Fm) over time and lot-to-lot variation.

[0058] In some embodiments, the lubricated gaskets of the present disclosure maintain container closure integrity with a defect failure rate of at least 6 sigma.System elements can include: 100% inspection of molded plungers; 100% inspection of the fluoropolymer laser cut or channel of the plunger; 100% inspection of plunger diameter; 100% measurement of syringe barrel ID; and low draft syringe barrels.

[0059] In some embodiments of the improved laser process of the present disclosure, there is 100% inspection of: (a) the perimeter depth of the gasket secured to the stainless steel mandrel; (b) the shape of the film edge formed by the laser cut or channel using a servo motor to control the movement of the laser. In some embodiments, the adhesion of the film to the rubber gasket is optimized using plasma and / or chemical treatments.

[0060] Testing for container closure integrity (CCI) can be performed using a vacuum collapse leak detection method, where a vacuum is maintained in the test volume and a pressure rise is measured over time. A sufficiently large pressure rise indicates that there is flow into the system, which is evidence of a leak. Optionally, the vacuum collapse test is performed in two separate cycles. The first cycle is dedicated to detecting large leaks for a very short period of time. A relatively weak vacuum is pulled in the first cycle, as a large pressure difference is not needed to detect a large pressure rise if a gross leak is detected. Using the first cycle as described helps to reduce the total test time if a gross leak is present. If no leak is detected in the first cycle, a second cycle is performed, which conforms to the ASTM F2338-09 Standard Test Method for Nondestructive Detection of Leaks in Packages by Vacuum Collapse Method. The second cycle begins with an evaluation of the system to reduce the signal-to-noise ratio in the pressure rise measurement. A relatively strong vacuum is pulled for a longer period of time in the second cycle to increase the likelihood of detecting a pressure rise in the system. EXAMPLES

[0061] Example 1: Liquid CCI Test Method The syringe and gasket system of the present disclosure are filled with water and the stopper is exposed to a vacuum load. The syringes are stored at 4° C. up to the needle tip. Each syringe is removed at specific time points (0 days, 1 day, 4 days, 7 days, 1 month, and 3 months) and, after reaching room temperature, is visually inspected for signs of water getting into the space between the ribs of the stopper. A written description of each error is recorded and a photograph of each error is taken. The leakage characteristics of the syringe of the present disclosure are compared to the leakage characteristics of other syringes with gasket films (such as laminated films). The syringes of the present disclosure have superior CCI over time compared to syringes not manufactured with the improved laser and inspection process of the present disclosure.

Claims

1. 1. A process for forming one or more continuous channels in a film present on at least a circumferential outer surface portion of a gasket, said gasket including a body made of a resilient material, said body having a circumferential surface portion and an unthreaded internal cavity at its center, said cavity being defined by an inner surface portion of said gasket and open at one end, said process comprising: (a) inserting a portion of one end of a mandrel into an open end of the cavity; (b) securing the gasket to the mandrel with a press fit assembly; (c) placing the mandrel and secured gasket adjacent a laser; and (d) applying a laser beam emitted from the laser to one or more selected locations on a surface portion of the film present on the circumferential outer surface portion of the gasket while rotating the mandrel and the secured gasket along the longitudinal axis of the mandrel to form one or more continuous channels in the film, the channels extending completely around the circumferential outer surface of the gasket; A process including.

2. 10. The process of claim 1, wherein the thickness of the film on the surface of the gasket prior to step (d) is about 10-30 microns, about 15-35 microns, about 20-50 microns, or about 20 microns.

3. 3. The process of claim 1 or 2, wherein the film has one or more of good slip properties and chemical stability.

4. The process according to any one of claims 1 to 2, wherein the film is capable of preventing migration of mobile lubricant from the elastic material of the gasket.

5. The process of claim 4 , wherein a diameter of at least a portion of the mandrel portion inserted into the internal cavity of the gasket is greater than an inner diameter of the cavity.

6. A process according to any one of claims 1 to 5, wherein when a plurality of channels are formed, the channels are axially spaced apart.

7. The process of any one of claims 1 to 6, wherein the one or more channels have first and second axially opposed sidewalls and a floor.

8. 8. The process of any one of claims 1 to 7, wherein the one or more channels each independently have an axial width between sidewalls selected from 1 to 100 microns, 5 to 50 microns, 10 to 30 microns, and 15 to 25 microns.

9. 9. The process of any one of claims 1 to 8, wherein the one or more channels each independently have a radial depth selected from greater than 0 microns to 100 microns, from 5 to 50 microns, from 10 to 30 microns, and from 15 to 25 microns.

10. 10. The process of any one of claims 1 to 9, wherein the one or more channels each independently have a laser cut depth selected from 20 to 80 microns, 30 to 60 microns, 40 to 50 microns, 50 to 60 microns, 40 to 45 microns, 45 to 50 microns, 50 to 55 microns, and 55 to 60 microns.

11. The process of any one of claims 1 to 10, wherein the one or more channels extend through the film into the circumferential outer surface portion of the gasket.

12. 8. The process of claim 7, wherein the one or more channels comprise a circumferentially extending first lip disposed adjacent the first sidewall of the channel and extending radially above the film.

13. 13. The process of claim 12, wherein the one or more channels further comprise a circumferentially extending second lip disposed adjacent the second sidewall and extending radially above the film.

14. 14. The process of claim 12 or 13, wherein the first lip and / or the second lip independently have a peak height selected from 10 to 100 microns, 15 to 60 microns, 20 to 50 microns, or 30 to 40 microns.

15. 15. The process of any one of claims 12 to 14, wherein the first lip and / or the second lip of each of the one or more channels independently have a peak width selected from 200 to 1,000 microns, 275 to 550 microns, 300 to 400 microns, or 450 to 500 microns.

16. The process of any one of claims 12 to 15, wherein each lip comprises a film material.

17. A process according to any one of claims 12 to 15, wherein each lip comprises film material displaced from the channel by the laser beam as the channel is formed.

18. The process of any one of claims 12 to 17, wherein at least one lip is disposed within a tubular syringe barrel to form a seal against an inner surface of the barrel.

19. The process of any one of claims 1 to 18, wherein the position of the laser relative to the mandrel and fixed gasket is controlled by a servo motor.

20. The process of any one of claims 1 to 19, wherein the film is a fluoropolymer film.

21. 21. The process of claim 20, wherein the fluoropolymer film is polytetrafluoroethylene (PTFE).

22. The process of any one of claims 1 to 21, wherein the elastic material comprises bromobutyl rubber.

23. The process of any one of claims 1 to 22, wherein the inner surface of the film is treated prior to application to the circumferential outer surface portion of the gasket to promote adhesion to the circumferential outer surface portion.

24. 24. The process of claim 23, wherein the inner surface of the film is corona treated.

25. The process of claim 23 , wherein the inner surface of the film is chemically treated.

26. 26. The process of any one of claims 1 to 25, wherein dimensional tolerances of gaskets that can be used in the process are selected from: ±100 microns, ±50 microns, ±35 microns, ±25 microns, ±20 microns, ±15 microns, ±10 microns, ±5 microns, or ±3 microns.

27. 27. The process of any one of claims 1 to 26, wherein the gasket has less than 300 particles equal to or greater than 2 microns in size as measured using light obscuration (LO) or microflow imaging (MFI).

Images