Improved syringe and gasket system

Abstract

A method for producing a liner with improved channels for use in mating syringe and plunger systems, preferably for pre-filled plastic syringe systems. Specifically, an improved method for creating and inspecting continuous channels in a liner film by laser processing. The liner, used in mating syringe and plunger systems, exhibits high and consistent container closure integrity (CCI), consistent loosening and sliding forces over time, and provides a tight seal.

Description

[0001] This application is incorporated herein by reference in its entirety by U.S. Provisional Application No. 62 / 776,958, filed December 7, 2018; U.S. Provisional Application No. 62 / 788,168, filed January 4, 2019; U.S. Provisional Application No. 62 / 789,366, filed January 7, 2019; U.S. Provisional Application No. 62 / 825,166, filed March 28, 2019; and U.S. Patent No. 7,985,188 B2, granted July 26, 2011. More specifically, this application is incorporated herein by reference by U.S. Patent No. 7,985,188 B2, which discloses a syringe barrel or the like lubricated by a PECVD coating of SiOxCy or SiOxCyHz, and methods for manufacturing, testing, and using such a syringe barrel. Technical Field

[0002] This disclosure relates to a matching syringe and plunger system, particularly a liner to be used within the syringe, and an improved method for forming laser cuts in the liner and inspecting these laser cuts. Background Technology

[0003] Prefilled parenteral containers (e.g., syringes or cartridges) and plunger systems have been developed to facilitate rapid and accurate dosing of sterile products (e.g., saline solutions, dyes for injection, active pharmaceutical preparations, etc.), minimize dosing discrepancies, reduce the risk of biocontamination, improve convenience and ease of use, and prevent overfilling of products (Yoshino et al., JPharm Sci. 2014; 103(5):1520-8). Prefilled parenteral containers are typically sealed with a rubber liner that is attached to the plunger at the distal end, providing closure integrity for the shelf life of the container's contents. To use a prefilled syringe, the packaging and cap are removed, a hypodermic needle or another delivery catheter is optionally attached to the distal end of the cartridge, the delivery catheter or syringe is moved to the use position (e.g., by inserting it into the subject's tissue or into a device for flushing the contents of the syringe to be used), and the plunger is advanced into the cartridge to inject the contents of the cartridge into the application point.

[0004] The seal provided by the rubber liner in the syringe barrel typically involves rubber that presses against the barrel against the liner. Typically, the maximum diameter of the rubber liner is greater than the minimum inner diameter of the barrel. Therefore, displacing the rubber liner and its attached plunger when dispensing the injectable product from the syringe requires overcoming this pressing force from the rubber liner. Moreover, this pressing force, provided by the rubber seal, is typically overcome not only during the initial movement of the liner fixed to the plunger, but also during the dispensing of the injectable product as the liner is moved along the barrel. The need for a relatively increased force to advance the liner and plunger within the syringe can increase the difficulty for the user to administer the injectable product from the syringe. This is particularly problematic for automated injection systems, where the syringe is placed into the automatic injection device and the liner is advanced by a stationary spring. Therefore, the main considerations for using a liner attached to the plunger in a prefilled parenteral container include: (1) container closure integrity (“CCI”, as defined below) and liquid / air tightness; and (2) the plunger force required to dispense the contents of the syringe (as defined below).

[0005] In practice, maintaining CCI / liquid or airtightness and providing the desired plunger force are often conflicting considerations. In other words, barring other factors, the tighter the fit between the liner and the inner surface of the container to maintain sufficient CCI / liquid or airtightness, the greater the force required to advance the liner during use. In the syringe industry, it is important to ensure that the liner attached to the plunger moves at a substantially constant speed and with a substantially constant and relatively small force when advanced within the barrel. Furthermore, the force required to initiate plunger movement and then continue plunger advancement should be small enough to allow for comfortable administration by the user and to prevent shaking or unnecessarily high pressure that could cause patient discomfort.

[0006] To reduce friction and thus improve plunger force, lubrication is traditionally applied to the mating surfaces of the contact tube with the liner attached to the plunger, the inner surface of the tube, or both. Liquid or gel-like flowable lubricants, such as free silicone oils (e.g., polydimethylsiloxane or "PDMS"), can provide the desired level of lubrication between the plunger and the tube to optimize plunger force. PDMS is, in fact, a standard flowable lubricant used in industry. However, using flowable lubricants between the liner and the tube is not desirable. One reason is that flowable lubricants can mix with and interact with the drug product in the syringe, potentially degrading the drug or otherwise affecting its efficacy and / or safety. For example, silicone oils used as lubricants may generate droplets that could potentially lead to aggregation of sensitive biopharmaceuticals or turbidity of the solution (Bee JS et al., PDAJ Pharm Sci Technol. 2014; 68(5):494-503), or to 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., JPharmSci. July 2011; 100(7):2563-73). Additionally, silicone migration over time can affect delivery consistency as it may alter the release slip force (BLGF) and injection timing (Thornton JD et al., ON Drug Delivery Journal, Vol. 61 (October 2015), pp. 10-15). Microparticles migrating from silicone oil into pharmaceutical formulations can cause several product quality issues, such as exceeding the USP limit for particles in parenteral containers, structural instability of proteins due to adsorption, and / or immunogenic reactions caused by silicone oil-induced protein aggregates or silicone oil / protein complexes. These can reduce drug efficacy and / or cause potentially dangerous reactions in patients, rendering the product unsuitable for use (Thornton JD et al., ON Drug Delivery, Vol. 61 (October 2015), pp. 10-15). Therefore, lubricants may be problematic if injected into patients along with pharmaceutical products.

[0007] Additionally, when used with pre-filled syringes, the flowable lubricant may migrate away from the liner over time, leaving a small or no lubricated spot between the liner and the inner surface of the container. This can cause a phenomenon known as "sticktion," an industry term for adhesion between the liner and the cartridge, which needs to be overcome to allow the plunger and liner to detach and begin movement. For these reasons, there is an industry need for "oil-free" solutions, i.e., liners without flowable lubricant between the liner and the cartridge, where such flowable lubricant does not appear in the drug product flow.

[0008] As alternatives to (or other than) flowable lubricants, gaskets have been made of materials with lubricating properties or have a friction-reducing coating or film on their 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 gasket's sealing integrity (Christa Jansen-Otten 2019. Blog; Westpharma). Examples include TERUMO's i-COATING, mentioned in Canadian Patent No. 1,324,545, which is incorporated herein by reference in its entirety; WLGore expanded PTFE films on rubber stoppers disclosed in EP 2493534 B1, which is incorporated herein by reference in its entirety; and WEST's CZ plunger. However, such gaskets may fail due to CCI failure caused by membrane wrinkling, defects in the membrane, and / or delamination between the membrane and the rubber gasket, and may also have poor gas barrier properties. Therefore, conventional fluoropolymer film laminated liner alone may not be a viable solution for pre-filled syringes containing products sensitive to certain gases. Furthermore, such syringe and liner systems have poor CCI (Common Criteria and Quality).

[0009] Furthermore, in such prefilled syringe systems, the liner comes into contact with the sealed sterile product during administration and drug storage. The interaction between the sterile product and its packaging can significantly impact the purity and degradation of the formulation, as well as the safety of patients administering the product (Christa Jansen-Otten 2019. Blog; Westpharma). Therefore, selecting appropriate liners for syringe systems, particularly prefilled syringe systems, is an important consideration for the pharmaceutical and biopharmaceutical industries.

[0010] U.S. Patent Application No. 15 / 445,108 discloses a laminated liner for use in a medical syringe, the entire contents of which are incorporated herein by reference. This liner comprises a body made of an elastic material and a membrane disposed on the surface of the body. In a syringe system, the syringe typically includes a syringe barrel and a plunger reciprocating within the syringe barrel. The liner is attached to the distal end of the plunger. In this application, the liner is further subjected to a laser processing process by applying a laser beam at an angle relative to the circumferential surface portion of the liner while rotating the liner about its central axis, thereby forming an annular groove circumferentially in at least the surface portion of the membrane on the liner. This laser-cut groove or channel improves the slidability and sealability of the laminated liner within the syringe while maintaining the elasticity of the liner and minimizing fluid leakage in a pre-filled syringe.

[0011] In the method disclosed in U.S. Patent Application No. 15 / 445,108, the internal cavity of the liner contains threads to attach a threaded plunger rod, which is then rotated during the laser cutting process. However, this method of fixing the liner during the laser process has several drawbacks because the liner walls may deform or sag as the liner rotates to create the laser-cut grooves. This results in inconsistent laser cuts or grooves on the liner membrane. A syringe system incorporating a liner produced by the method of U.S. Patent Application No. 15 / 445,108 is also more prone to liquid or gas leakage and has poor CCI (Clean Injection Chronicity). Summary of the Invention

[0012] Therefore, there is a need for an improved method for creating one or more channels on the surface of a liner, with a membrane residing on the outer surface of the liner, and also for an improved liner for use in syringe-liner systems for delivering, for example, pharmaceutical products to a subject in need. The resulting liner improves the prevention of liquid or gas leakage and exhibits excellent CCI when used in a matched syringe-plunger system. A syringe assembled with the improved liner of this disclosure provides improved protection for the product contained therein and is characterized by an improved product shelf life.

[0013] This application provides an improved method for creating one or more continuous channels (in some embodiments, extending into the liner itself) in a membrane residing on the outer surface of a liner used in a mating syringe and plunger-liner system, which produces excellent container closure integrity and sealability with minimal liquid / gas leakage.

[0014] In some embodiments, the disclosure of this application provides liners with improved channels for use in matched syringe and plunger systems. Some embodiments of the silicone-free syringe and liner systems of this disclosure, preferably pre-filled plastic syringe systems, exhibit excellent container closure integrity (CCI), avoiding high loosening forces and liquid / gas leakage, producing consistent delivery performance over time, providing protection for the sealed product, minimizing interactions with the product, maintaining efficacy and sterility throughout the product's shelf life, and extending shelf life. Some embodiments of the syringe and liner systems result in particulate reduction and can protect complex or sensitive biological products contained within the syringe from silicone-induced aggregation and particulate formation. In some embodiments, this disclosure also provides an improved method for creating continuous channels in the liner and a membrane residing on its outer surface by laser cutting.

[0015] In some embodiments, this disclosure also provides an improved method for producing silicone-free syringe and liner systems, measured using light-blocking (LO) or microfluidic imaging (MFI) with fewer than 300 particles of 2 micrometers or larger. Further, in some embodiments, the syringe system of this disclosure incorporates a method for improving sealability provided by an integrated lubricating film on the liner, eliminating the need for a lubricated syringe barrel. In other embodiments, this disclosure incorporates prior art manufacturing process controls and 100% inspection systems that provide tight dimensional control over the liner and corresponding syringe and channel, thereby enabling highly consistent compression of the assembled syringe and liner system for container closure integrity and plunger force.

[0016] The specific features of this disclosure are set forth in the following numbered paragraphs:

[0017] 1. A method for creating one or more continuous channels in a membrane residing at least on a circumferential outer surface portion of a liner, the liner comprising a body made of an elastic material having a circumferential surface portion and an internal cavity at its center, the cavity being defined by an inner surface portion of the liner and open at one end, the method comprising the steps of:

[0018] (a) Insert a portion of one end of the mandrel into the opening of the cavity;

[0019] (b) Secure the pad to the mandrel;

[0020] (c) Positioning the mandrel and the fixed pad near the laser; and

[0021] (d) While rotating the mandrel and the fixed pad along the longitudinal axis of the mandrel, a laser beam emitted from the laser is applied to one or more selected locations on the surface portion of the film residing on the circumferential outer surface portion of the pad to create one or more continuous channels in the film that extend around the entire circumference of the circumferential outer surface of the pad.

[0022] 2. The method as described in paragraph 1, wherein prior to step (d), the thickness of the film on the surface of the pad is about 10-30 micrometers, about 15-35 micrometers, about 20-50 micrometers, or about 20 micrometers.

[0023] 3. The method as described in paragraph 1 or 2, wherein the membrane has one or more of good slidability and chemical stability.

[0024] 4. The method as described in any of paragraphs 1 to 2, wherein the membrane is capable of preventing the migration of components from the elastic material of the liner.

[0025] 5. The method as described in any of paragraphs 1 to 4, wherein the gasket is secured to the mandrel by press-fit assembly.

[0026] 6. The method as described in paragraph 5, wherein the diameter of at least a portion of the mandrel portion inserted into the inner cavity of the liner is greater than the inner diameter of the cavity.

[0027] 7. The method as described in any of paragraphs 1 to 6, wherein when more than one channel is generated, the channels are axially spaced apart.

[0028] 8. The method as described in any of paragraphs 1 to 7, wherein the one or more channels have axially opposed first and second sidewalls and a base plate.

[0029] 9. The method as described in any of paragraphs 1 to 8, wherein each of the one or more channels has an axial width selected from 1-100 micrometers, 5-50 micrometers, 10-30 micrometers, and 15-25 micrometers between the sidewalls.

[0030] 10. The method as described in any of paragraphs 1 to 9, wherein the one or more channels each independently have a radial depth selected from 0-100 micrometers, 5-50 micrometers, 10-30 micrometers, and 15-25 micrometers.

[0031] 11. The method as described in any one of paragraphs 1 to 10, wherein the one or more channels each independently have a laser cutting depth selected from 20-80 micrometers, 30-60 micrometers, 40-50 micrometers, 50-60 micrometers, 40-45 micrometers, 45-50 micrometers, 50-55 micrometers, and 55-60 micrometers.

[0032] 12. The method as described in any of paragraphs 1 to 11, wherein the one or more channels extend through the membrane into the outer surface portion of the liner.

[0033] 13. The method as described in any of paragraphs 1 to 12, wherein the one or more channels include a first circumferentially extending lip positioned adjacent to a first sidewall of the channel and extending radially over the membrane.

[0034] 14. The method as described in paragraph 13, wherein the one or more channels further include a second circumferentially extending lip, the second circumferentially extending lip being positioned adjacent to the second sidewall and extending radially over the membrane.

[0035] 15. The method as described in paragraph 13 or 14, wherein the first lip margin and the second lip margin independently have peak heights selected from 10-100 micrometers, 15-60 micrometers, 20-50 micrometers, or 30-40 micrometers.

[0036] 16. The method as described in any of paragraphs 13 to 15, wherein the first and second lip margins of each of the one or more channels independently have peak widths selected from 200-1,000 micrometers, 275-550 micrometers, 300-400 micrometers, or 450-500 micrometers.

[0037] 17. The method as described in any of paragraphs 13 to 16, wherein each lip includes a membrane material.

[0038] 18. The method as described in any of paragraphs 13 to 16, wherein each lip includes membrane material removed from the channel by the laser beam during the generation of the channel.

[0039] 19. The method as described in any of paragraphs 13 to 18, wherein at least one lip can be positioned within a tubular syringe barrel to form a seal against the inner surface of the barrel.

[0040] 20. The method as described in any one of paragraphs 1 to 19, wherein the position of the laser relative to the mandrel and the fixed pad is controlled by a servo motor.

[0041] 21. The method as described in any of paragraphs 1 to 20, wherein the membrane is a fluoropolymer membrane.

[0042] 22. The method as described in paragraph 21, wherein the fluoropolymer membrane is polytetrafluoroethylene (PTFE).

[0043] 23. The method as described in any of paragraphs 1 to 22, wherein the elastic material comprises bromobutyl rubber.

[0044] 24. The method of any one of paragraphs 1 to 23, wherein the inner surface of the membrane is treated prior to being applied to the outer surface portion of the liner to promote adhesion to the outer surface portion.

[0045] 25. The method as described in paragraph 24, wherein the inner surface of the membrane is corona treated.

[0046] 26. The method as described in paragraph 24, wherein the inner surface of the membrane is chemically treated.

[0047] 27. The method of any one of paragraphs 1 to 26, wherein the dimensional tolerance of the liner that can be used in the method is selected from ±100 micrometers, ±50 micrometers, ±35 micrometers, ±25 micrometers, ±20 micrometers, ±15 micrometers, ±10 micrometers, ±5 micrometers or ±3 micrometers.

[0048] 28. The method as described in any of paragraphs 1 to 27, wherein light masking (LO) or microfluidic imaging (MFI) is used for measurement, and the pad has fewer than 300 particles of 2 micrometers in size or larger.

[0049] 29. A matching syringe and plunger system, comprising:

[0050] (a) A tubular syringe barrel;

[0051] (b) a plunger, said plunger being located within the syringe barrel and capable of longitudinal reciprocating movement within the barrel; and

[0052] (c) A gasket attached to the distal end of the plunger; the gasket comprising a body made of an elastic material 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, wherein the gasket is characterized by one or more continuous channels formed according to a method comprising the following steps:

[0053] (i) Insert a portion of one end of the mandrel into the opening of the cavity;

[0054] (ii) Secure the pad to the mandrel;

[0055] (iii) Positioning the mandrel and the fixed pad near the laser; and

[0056] (iv) While rotating the mandrel and the fixed pad along the longitudinal axis of the mandrel, a laser beam emitted from the laser is applied to one or more selected locations on the surface portion of the film residing on the circumferential outer surface portion of the pad to create one or more continuous channels in the film that extend around the entire circumference of the circumferential outer surface of the pad.

[0057] 30. The system as described in paragraph 29, wherein the gasket is attached to the plunger by press-fit assembly.

[0058] 31. The system as described in paragraph 30, wherein the syringe barrel contains injectable fluid on the distal side of the liner.

[0059] 32. The system described in any one of paragraphs 29 to 31 has a container closure integrity (CCI) with a defect rate not exceeding 6 sigma.

[0060] 33. The system as described in any one of paragraphs 29 to 32, wherein the plunger and the attached gasket have a release force between 4 Newtons (N) and 20 Newtons.

[0061] 34. The system of any one of paragraphs 29 to 33, wherein the plunger and the attached gasket have a sliding force between 4 Newtons (N) and 20 Newtons.

[0062] 35. The system as described in paragraph 33 or 34, wherein the loosening force or the sliding force changes by less than about 10-30% over a two-year storage life.

[0063] 36. The system of any one of paragraphs 29 to 35, wherein the syringe barrel includes a wall having an inner surface coated with a lubricating layer, the lubricating layer having an atomic ratio of 1 atom Si: 0.5 to 2.4 atoms O: 0.6 to 3 atoms C as measured by X-ray photoelectron spectroscopy (XPS).

[0064] 37. The system as described in paragraph 36, wherein the syringe barrel further comprises a three-layer coating between the inner surface of the wall and the lubricating coating, wherein the three-layer coating comprises a bonding coating, a barrier coating, and a pH-protective coating; wherein

[0065] (a) The bonding coating comprises SiO x C y or SiNxC y , where x is about 0.5 to about 2.4 and y is about 0.6 to about 3, the connecting coating has an outer surface facing the inner surface of the wall, and the connecting coating has an inner surface facing the inner cavity of the syringe barrel;

[0066] (b) The barrier coating comprises SiO x Where x is 1.5 to 2.9, the barrier coating is 2 nm to 1000 nm thick, the barrier coating has an outer surface facing the inner surface of the connecting coating, and the barrier coating has an inner surface facing the inner cavity of the syringe barrel; and

[0067] (c) The pH-protective coating comprises SiO x C y or SiN x C y , where x is about 0.5 to about 2.4 and y is about 0.6 to about 3, the pH protective coating has an outer surface facing the inner surface of the barrier coating and an inner surface facing the inner cavity of the syringe barrel.

[0068] 38. The system as described in paragraph 36 or 37, wherein the lubricating layer is capable of reducing one or both of the viscous and sliding friction of the gasket in the cylinder compared to one or both of the viscous and sliding friction of the gasket in the cylinder without the lubricating layer.

[0069] 39. The system as described in any one of paragraphs 29 to 38, wherein the membrane is a fluoropolymer membrane.

[0070] 40. The system as described in any one of paragraphs 29 to 39, wherein the fluoropolymer membrane is polytetrafluoroethylene (PTFE).

[0071] 41. The system as described in any of paragraphs 29 to 40, wherein, when assembled to form a prefilled syringe, one or more of the channels improve the container closure integrity of the syringe components compared to a otherwise substantially similar prefilled syringe that does not include channels generated by the method.

[0072] 42. The system as described in paragraph 41, wherein the improvement is an extended shelf life.

[0073] 43. The system as described in paragraph 41 or 42, wherein the improvement is measured by a vacuum decay leak detection method.

[0074] 44. The system as described in paragraph 41 or 42, wherein the improvement is measured by a liquid CCI test method.

[0075] 45. A matching syringe and plunger system as described in any of paragraphs 29 to 44, wherein the syringe barrel has a wall, the wall including an inner surface defining a generally cylindrical inner cavity, and the barrel has an inner diameter;

[0076] The gasket has a leading surface, a side surface, a trailing portion, and an outer diameter;

[0077] The gasket is configured to be received within any of the cylinders, the outer diameter of the gasket being located within the inner diameter of the cylinder and movable relative to the inner diameter of the cylinder; and

[0078] During assembly, the sizes of the system's cylinder and gasket are respectively set to provide a spacing between the minimum inner diameter of the cylinder and the maximum outer diameter of the gasket, the spacing deviating from the nominal spacing by no more than: ±100 micrometers, ±50 micrometers, ±35 micrometers, ±25 micrometers, ±20 micrometers, ±15 micrometers, ±10 micrometers, ±5 micrometers, or ±2 micrometers.

[0079] 46. ​​A padding comprising:

[0080] (a) The body is made of an elastic material, the body having a circumferential surface portion and an internal cavity defined by an inner surface portion of the pad and being open at one end.

[0081] (b) a membrane, said membrane being at least located on the circumferentially outer portion of the liner; and

[0082] (c) One or more continuous channels in the membrane, the channels extending outward around the entire circumference of the subject;

[0083] The gasket said therein has one or more of the following characteristics:

[0084] (i) Container closure integrity (CCI) with a defect rate not exceeding 6 sigma when assembled in a matched syringe and plunger system;

[0085] (ii) When assembled in a matching syringe and plunger system, the loosening force is between 4 Newtons (N) and 20 Newtons;

[0086] (iii) Sliding force between 4 Newtons (N) and 20 Newtons when assembled in a matching syringe and plunger system;

[0087] The loosening force or the sliding force changes by less than about 10-30% over a two-year storage life. Attached Figure Description

[0088] Figure 1 A cross-sectional view of a syringe 10 is shown, which includes a syringe barrel 12 assembled with a liner 14 attached to a plunger 26.

[0089] Figure 2 It shows Figure 1A partial detailed view of the syringe shows the inner diameter (ID) of the barrel 12 and the outer diameter (OD) of the liner 14, the barrel and liner being matched within a predetermined tolerance between them. The view also shows a membrane 16 on the outer surface of the liner core 18 and continuous channels 20 residing in the membrane on a circumferentially outer surface portion of the liner core 18, the channels 20 surrounding the liner 14. The channels have lips 22 and 24, as... Figure 3B As shown.

[0090] Figure 3A It shows along Figure 2 A schematic cross-sectional view taken by section line 3A-3A shows a liner core 18 with an internal cavity (IC), a membrane 16, and a channel 20 located in the surface of the membrane and surrounding the circumferential outer surface portion of the liner 14 (in some embodiments, the channel 20 extends through the membrane into the outer surface of the liner (not shown)). Figure 3B It shows Figure 3A A partial detailed view of the structure shows one embodiment of channel 20 and the lips 22 and 24 on the respective sides of channel 20.

[0091] Figure 4A The figure shows an assembly of a liner 14 and a mandrel 28 inserted into the inner cavity of the liner. The figure also depicts the application of a laser beam at an angle to the outer portion of a membrane 16 residing on the circumferential outer surface portion of the liner 14, which is fixed to the mandrel 28, as the mandrel 28 and the liner 14 rotate along the longitudinal axis of the mandrel, to create a continuous channel 20 in the membrane 16 residing on the circumferential outer portion of the liner 20. Figure 4B It shows along Figure 4A A schematic cross-sectional view of one embodiment of the gasket, taken by section line 4B-4B, shows a mandrel 28 fixed in the internal cavity of the gasket, a membrane 16, and a channel 20 residing on and surrounding the outer surface of the membrane 16 on the circumferential outer surface portion of the gasket 20. In other embodiments, the channel extends through the membrane and into the outer surface of the gasket.

[0092] Figure 5A A liner 14 with a membrane 16 is shown, in which channels 20 are provided. Figure 5B It shows Figure 5A A partial detailed view of the structure shows an embodiment of a channel 20 in the surface of the membrane (with lips 22 and 24 on corresponding sides of the channel 20) and various dimensions (peak width, axial width, laser cutting depth, and radial depth) of the channel 20 and the lips 22 and 24. In other preferred embodiments, the channel 20 extends into the outer surface of the liner (not shown).

[0093] According to any embodiment, the following reference numerals are used in the accompanying drawings:

[0094]

[0095]

[0096] definition

[0097] In the context of this disclosure, the following definitions and abbreviations are used:

[0098] Unless otherwise stated, according to any embodiment, the word "comprising" does not exclude other elements or steps, and the indefinite article "a / an" does not exclude a plurality. Whenever a parameter range is indicated, it is intended to disclose the given parameter value that limits the range and all parameter values ​​falling within the range. The reference herein to "about" a value or parameter includes (and describes) an embodiment for that value or parameter itself. For example, a description referring to "about X" includes a description of "X". A numerical range includes the number that defines the range. As used herein, the term "about" allows for a variation of ±10% within the range of significant figures.

[0099] In describing aspects or embodiments related to alternative Markush groups or other groupings, this application includes not only the entire group listed as a whole, but also each individual member of that group and all possible subgroups of the main group, as well as the main group lacking one or more of its members. This application also contemplates the explicit exclusion of any one or more group members in the implemented disclosure.

[0100] This document describes exemplary methods and materials, but similar or equivalent methods and materials may also be used in practice or testing in various aspects and embodiments. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0101] To facilitate understanding of this disclosure, certain terms are defined first. These definitions should be read in accordance with the remainder of this disclosure and as understood by one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Additional definitions are set forth throughout the detailed description.

[0102] As used herein, the term "syringe" is broadly defined to include cartridges, injection pens, and other types of cartridges or reservoirs adapted to assemble with one or more other components to provide a functional syringe. "Syringe" is also broadly defined to include related articles providing a mechanism for dispensing contents, such as an autoinjector. Preferably, "syringe" can include a pre-filled syringe. "Syringe" as used herein can also be applied to vaccine dispensing syringes that include a product space for containing a vaccine. "Syringe" as used herein can also be applied to diagnostic devices, such as sampling devices that include a medical cartridge pre-filled with a diagnostic agent (e.g., contrast dye) or the like. In a broader sense, "syringe" as used herein is any medical cartridge that, when assembled with one or more other components (e.g., a liner and a plunger), acts as a container / dispenser for a flowable product. While this disclosure is not necessarily limited to syringes with a specific volume, consideration is given to syringes with an inner lumen having an empty volume of, for example, 0.5 mL to 50 mL, optionally 1 mL to 10 mL, optionally 0.5 mL to 5 mL, optionally 1 mL to 3 mL. The syringe disclosed herein includes a hollow cylindrical syringe barrel 12, a plunger 26 assembled with and reciprocating within the syringe barrel 12, and a liner 14 attached to the distal end of the plunger 26. See also Figure 1 .

[0103] As used herein, in the context of this disclosure, the term "shim" refers to a shaped part or ring made of an elastic material that can be used for a space between two opposing inner surfaces of a mechanically sealed syringe barrel. The shim is preferably cylindrical with a short axis. The shim has a circumferential surface portion that will maintain substantially airtight and liquidtight contact with the inner peripheral surface of the syringe barrel. The shim disclosed herein comprises a body made of an elastic material and a membrane residing at least on the circumferential surface of the body, the shim having a circumferential surface portion and an internal cavity (IC) at its center, defined by the inner surface of the shim and open at one end. See also Figure 2 and Figure 3A In a preferred embodiment, the internal cavity of the gasket has no threads.

[0104] The “elastic material” can be a rubber or an elastomer. In particular, preferred types of rubber include butyl rubber, chlorinated butyl rubber, and brominated butyl rubber. Other types of elastic materials can include thermosetting rubbers and dynamically crosslinkable thermoplastic elastomers, which have crosslinking sites that make them heat-resistant. These polymer components of such elastomers include ethylene-propylene-diene rubber and butadiene rubber.

[0105] As used herein, the term "film" refers to a material that resides at least on the circumferential outer surface portion of the body of the liner. Preferably, it is substantially coated or resides on all outer surfaces of the liner. The film may have an optional thickness of less than 100 micrometers (μm), optionally about 10-30 micrometers, about 15-35 micrometers, or about 20-50 micrometers. Most preferably, the thickness of the film is about 20 micrometers. The film can be made of a wide variety of different materials, 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 due to their excellent slidability and chemical stability. There are no particular restrictions on the type of membrane that can be placed on the surface of the main body of the liner, as long as the membrane can prevent substances from migrating from the cross-linked rubber (the main body) and has slidability (i.e., a lower coefficient of friction) compared to the main body of the liner.

[0106] Optionally, the membrane may contain a CPT fluoropolymer. CPT is a modified perfluoroalkoxy (PFA) that typically involves adding PCTFE side chains to the PFA backbone during polymerization.

[0107] Optionally, additives may also be added to the membrane material, such as additives that improve adhesion between the membrane and the underside of the liner to form a liquid-sealed section and / or reduce friction between that section and the sidewall of the syringe barrel. Additionally, according to some embodiments, adhesion-promoting coatings or methods, such as corona treatment or chemical treatment, may be employed. Corona treatment or air plasma is a surface modification technique that uses low-temperature corona discharge plasma to alter surface properties. Corona plasma is generated by applying a high voltage to electrodes with pointed tips. For some applications, it may be desirable to co-extrude different materials to form the membrane. For example, co-extruded membrane compositions may include cyclic olefin copolymers (COC) with Aclar, polyethylene (PE) with Aclar, and FEP with PE, as well as other combinations.

[0108] As used herein, the term "mandrel" refers to a device or tool whose distal end can be attached to a base that holds the mandrel body 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, which can be inserted into and secured within the internal cavity (corresponding to the female portion) of a liner. In some embodiments, the mandrel is a shaped strip of metal or steel, such as a cylindrical rod. The proximal end of the mandrel can be continuous with the mandrel body, or can have a circumferential portion smaller or larger than the distal section of the mandrel. In a preferred embodiment, the proximal end of the mandrel is secured to the liner using a "press-fit assembly," wherein the liner is secured to the mandrel by friction after the parts are pushed together, rather than by any other fastening method (e.g., threaded connection). In some embodiments, at least a portion of the mandrel portion inserted into the internal cavity of the liner has a diameter larger than the inner diameter of the cavity. "Securing the pad" to the mandrel means ensuring that the pad is fixed or fastened to the proximal end of the mandrel so as not to yield, loosen, or move independently of the mandrel. The pad 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 the secured pad near the laser means fixing the base of the mandrel relative to the laser beam at the desired location so that the base of the mandrel will be in a rigid, non-moving position during the laser beam process disclosed herein. However, the mandrel will still be able to rotate along its longitudinal axis. See also Figure 4A .

[0109] As used herein, the term "channel" refers to a cut formed in a film residing on the surface of a liner by laser cutting. The term "channel" may be used interchangeably with the term "cut." In this disclosure, the term "cut" may also refer to the process of using one or more laser beams to form a notch or spacer in a film residing at least on a circumferentially outer surface portion of the liner. In some embodiments, the channel is cut into a surface portion of the film. In a more preferred embodiment, the channel extends through the film into the outer surface of the liner. One or more such channels may be created, each channel surrounding the liner. When more than one channel is present, the channels are preferably axially spaced apart from each other. Each channel has two lips. The term "lip" refers to the structure formed along both sides of the channel formed by laser beam cutting due to the accumulation of film material. Figure 3B and Figure 5B Channel lips 22 and 24 are shown. Each lip is a raised rib positioned to seal against the inner surface of the tube. Thus, each channel has two lips comprising two sealing ribs or peaks. In this disclosure, the terms “lip,” “rib,” “peak,” and “micro-protrusion” are used interchangeably.

[0110] The laser cut and the resulting channel are characterized by various dimensions, including laser cutting depth, radial depth, peak width, axial width, and peak height. "Laser cutting depth" is measured downwards from the uncut surface of the liner film to the lowest point of the channel groove. See also Figure 5B The laser cutting depth of one or more channels is independently selected from the following ranges: 20-80 micrometers, 30-60 micrometers, 40-50 micrometers, 50-60 micrometers, 40-45 micrometers, 45-50 micrometers, 50-55 micrometers, and 55-60 micrometers. "Radial depth" is measured from the uncut outer surface of the liner to the lowest groove in the channel. See also Figure 5B The radial depth of one or more channels can be independently selected from the following ranges: 0 to 100 micrometers, 5 to 50 micrometers, 10 to 30 micrometers, and 15 to 25 micrometers. "Peak width" is the distance between two peaks on the two lip edges on either side of the channel. Peak width is measured from the top of the peak. See also Figure 5B The peak width can be one of the following ranges: 200-1,000 micrometers, 275-550 micrometers, 300-400 micrometers, and 450-500 micrometers.

[0111] The circumferentially continuous channel disclosed herein has axially opposed "first sidewalls and second sidewalls" and a "base plate". Depending on the membrane thickness and the depth of the cut, the base plate of the channel may be the membrane surface, or more preferably the gasket surface. The "axial width" is measured across the channel base plate from the first sidewall to the second sidewall. In other words, the "axial width" is measured across the channel from one end to the other at the baseline level of the membrane or gasket (i.e., at the level of the uncut outer surface). The sidewalls of one or more channels independently have an axial width in one of the following ranges: 1 to 100 micrometers, 5 to 50 micrometers, 10 to 30 micrometers, and 15 to 25 micrometers.

[0112] "Peak height" is measured from the surface of the uncut liner film up to the highest peak of the lip formed by the laser beam along the central axis of the peak (i.e., perpendicular to the surface of the film). The peak height of the lip on one or more channels is independently selected from one of the following ranges: 10-100 micrometers, 15-60 micrometers, 20-50 micrometers, or 30-40 micrometers.

[0113] As used herein, “container closure integrity” or “CCI” refers to the ability of a container closure system (e.g., a plunger attached to a liner disposed in a syringe barrel, preferably a prefilled syringe barrel) to provide protection and maintain efficacy and sterility of the sterile product contained in the container throughout its shelf life. In some embodiments, container closure integrity is related to the sealing performance of the syringe system disclosed herein. By providing physical breaks in the membrane to prevent defects in the membrane (e.g., delamination, tearing, or wrinkling) that adversely affect the seal integrity between the liner and the syringe, one or more channels formed in the membrane by a laser are expected to improve the CCI of the plunger attached to the liner when assembled into a prefilled syringe. Container closure integrity (CCI) must be maintained substantially throughout the entire shelf life of the syringes disclosed herein. CCI is an important characteristic of prefilled syringes for parenteral drug products contained within the syringe. A key element of CCI is maintaining a sterile barrier. The improved methods of this disclosure for creating one or more channels in the membrane reduce the likelihood of CCI failure (disruption of sterility) and / or contribute to extended shelf life.

[0114] As used herein, the term "release force" refers to the force required to initiate movement of a plunger attached to a liner within a syringe (e.g., in a pre-filled syringe). It is the maximum force required to break the static friction of the plunger attached to the liner. In the context of this disclosure, release force is synonymous with "plunger force," "plunger release force," "release force," "initiating force," and "Fi."

[0115] As used herein, the term "sliding force" refers to the force required to maintain plunger movement within the syringe barrel (when the plunger is attached to the liner of this disclosure) once static friction is overcome (e.g., during suction or dispensing). In the context of this disclosure, sliding force is synonymous with "thrust," "plunger sliding force," "holding force," and "Fm."

[0116] As used herein, the terms “release force” and “slip force” are collectively referred to as “BLGF force,” which refers to the various forces of the plunger and attached liner of this disclosure. The BLGF force can be measured using any test known in the art (e.g., ISO 7886-1:1993). For example, the BLGF force can be tested by filling the syringe of this disclosure with 1 ml of liquid (e.g., water) and then applying a vacuum to the stop. The plunger force can be tested using a plastic threaded rod at a speed of 300 mm / min. In this disclosure, the improved method of creating channels on the surface of the liner prevents plunger force aging (i.e., the increase in release force over time). The matched syringe-plunger system of this disclosure maintains a release force and slip force between 4 Newtons (N) and 20 Newtons, which change by less than about 10%–30% over a two-year shelf life. The method of this disclosure provides consistent release and slip forces by combining manufacturing process control with a 100% inspection system.

[0117] As used herein, the term "viscous" refers to a phenomenon, an industry term for adhesion between the plunger (attached to the liner) and the syringe barrel, which needs to be overcome in order to disengage the plunger from the barrel and allow it to begin moving. The term "sliding friction" or "kinetic friction" refers to the resistance generated when two objects slide against each other. Sliding friction is intended to prevent movement of the objects. In this disclosure, a lubricating layer within the syringe barrel reduces one or both of the viscous and sliding friction of the liner within the barrel, compared to one or both of the viscous and sliding friction of the liner in a barrel without lubrication.

[0118] As used herein, the terms “dimensional tolerance,” “dimensional accuracy,” or “dimensional consistency” refer to the degree of control over the dimensions of a part (Quality Management for the Technology Sector (2000) 142-158). Dimensional tolerance is the permissible limit of variation in the physical dimensions of the various parts disclosed herein, such as gaskets and syringe barrels. “Tolerance” is the permissible variation in any given size of a gasket or syringe barrel disclosed herein that allows for proper functioning of the syringe system. In other words, dimensional tolerance is the permissible variation in the dimensions of the syringe or gasket disclosed herein that does not affect one or more of the following characteristics: container closure integrity, BLGF force, sealing performance, leakage characteristics, slippage, etc. Dimensional tolerances for gaskets that can be used in the methods disclosed herein are selected from ±100 micrometers, ±50 micrometers, ±35 micrometers, ±25 micrometers, ±20 micrometers, ±15 micrometers, ±10 micrometers, ±5 micrometers, or ±3 micrometers. The term “nominal spacing” in the syringe system disclosed herein is related to dimensional tolerance. During assembly, the sizes of the cylinder and gasket in the system disclosed herein are respectively set such that the distance between the minimum inner diameter of the cylinder and the maximum outer diameter of the gasket deviates from the nominal distance by no more than: ±100 micrometers, ±50 micrometers, ±35 micrometers, ±25 micrometers, ±20 micrometers, ±15 micrometers, ±10 micrometers, ±5 micrometers, or ±2 micrometers. Detailed Implementation

[0119] In some embodiments, this disclosure will now be described more fully with reference to the accompanying drawings. However, this disclosure may be implemented in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are examples and have the full scope indicated by the language of the claims. Similar reference numerals throughout the drawings refer to similar or corresponding elements.

[0120] Laser process examples

[0121] Figure 4A This is a simplified diagram of a laser processing procedure according to one embodiment of this disclosure. (See reference) Figure 4A A laser beam is applied at a desired angle to the circumferential surface portion of a pad 14 fixed to a mandrel 28. To form a channel in the circumferential surface portion of the pad, the laser beam source is fixed relative to the circumferential surface portion of the pad 14, while the film 16 resides on the outer surface of the pad. The laser beam is applied to the circumferential surface portion as the pad 14, fixed to the mandrel 28, rotates about its longitudinal axis. Therefore, the laser beam can be applied at any angular position on the circumferential surface portion at a predetermined incident angle α, thereby uniformly forming a channel.

[0122] When the laser beam is applied obliquely to the circumferential surface portion, the pad rotates in the rotational direction, causing the circumferential surface portion to move away from the laser beam application position (in... Figure 4A In the middle, the pad rotates clockwise.

[0123] By performing the laser processing of this embodiment of the present disclosure, channels are formed substantially uniformly in the film, more preferably extending into the circumferential surface portion of the pad, and simultaneously, outer edge portions 22 and 24 are formed. Figure 5B ).

[0124] Syringe and plunger system embodiment

[0125] exist Figure 1 This document illustrates an exemplary embodiment of a matched syringe and plunger system according to this disclosure, the plunger system including a liner 14 and a plunger 26 constructed according to one aspect of this disclosure. The terms "distal" and "proximal" generally refer to a spatial or positional relationship relative to a given reference point, where "proximal" is a position at or relatively closer to that reference point, and "distal" is a position farther from that reference point. When applied herein to plunger 26, for example, the relevant reference point is, for example, the bottom end of plunger 26, i.e., the distal end attached to liner 14. When applied herein to syringe barrel 12, for example, the relevant reference point is, for example, the bottom end of barrel 12, i.e., the distal end attached to the delivery catheter or syringe.

[0126] The syringe 10 typically has a conventional construction and material (preferably plastic), comprising a hollow barrel 12 having a central longitudinal axis A. The barrel has an inner surface 14 and is configured to retain an injectable liquid therein. A syringe or delivery conduit is located at the distal end of the barrel and is in fluid communication with the barrel. The plunger 26 also typically has a conventional construction and material. The gasket 14 disclosed herein is attached to the distal end of the plunger.

[0127] Gasket manufacturing and laser cutting process

[0128] In some embodiments of this disclosure, the gasket comprises two materials: a bromobutyl rubber-based gasket and a membrane, preferably a PTFE membrane, residing on the outer surface. Examples of bromobutyl rubber include Sumitomo LAG 5010-50 and West 4023. In a preferred embodiment, the PTFE membrane substantially covers the outer surface of the gasket. Gasket manufacturing includes the following processes, which are part of some embodiments of this disclosure:

[0129] (a) Molding: The PTFE membrane is treated to promote adhesion to the bromobutyl rubber of the liner. A typical treatment is corona treatment. In some embodiments, chemical treatment may also be used. The PTFE membrane is placed into a multi-cavity liner mold. Bromobutyl rubber is poured / injected into the multi-cavity mold. The mold is closed, and the PTFE membrane and bromobutyl rubber form the liner. The mold is opened, and the liner is removed from the mold. The resulting liner has a substantially uniform wall thickness and comprises both rubber and PTFE. The liner is trimmed by die-cutting to remove excess material. In some embodiments, the multi-cavity mold produces a liner without threaded connections in the internal cavities.

[0130] (b) Laser cutting of PTFE or other films: The improved method disclosed herein includes the steps of: (1) inserting a portion of one end of a mandrel into an open end of a liner cavity of a liner manufactured in step (a); (2) securing the liner to the mandrel; (3) positioning the mandrel and the secured liner near a laser; and (4) while rotating the mandrel and the secured liner along the longitudinal axis of the mandrel, applying a laser beam emitted from a precision laser to one or more selected locations on a surface portion of the film residing on a circumferential outer surface portion of the liner to create one or more continuous channels in the film extending around the entire circumference of the circumferential outer surface of the liner. This process creates one or more continuous channels circumferentially in the PTFE or other film on the outer surface of the liner. The accuracy of the channels created by the laser beam is directly related to the securing of the liner to the mandrel, the position of the laser beam, and the dimensional tolerance of the liner used in the process.

[0131] One or more channels are created, forming physical spaces within the PTFE or other membrane on the liner. Specifically, without being bound by theory, it is assumed that the laser treatment melts the PTFE or other membrane and pushes the PTFE material to both sides of the channel. During the laser treatment, the PTFE or other membrane material “builds up” on both sides of the channel, thus forming two sealing ribs or peaks (micro-protrusions). The PTFE or other membrane sealing ribs on both sides of the channel are able to maintain CCI—both a liquid barrier and a sterile barrier. It is assumed that the PTFE membrane thickness is uniform and “defect-free”; however, the height and angle of the sealing ribs depend on the alignment and position control of the laser beam (relative to the rotating liner on the mandrel). The greatest sources of variation in the sealing ribs are attributed to the PTFE or other membrane: (1) variations in membrane thickness and (2) defects in the membrane (e.g., blockages).

[0132] Furthermore, when forming the initial membrane, the fluoropolymer membrane is typically stretched during the manufacturing process. This stretching process creates microchannels or micropores (the terms "microchannel" or "micropore" are used interchangeably in this specification) within the membrane, the size and dimensions of which vary depending on the specific manufacturing conditions. In at least some cases, these microchannels or micropores are believed to provide a path along the fluoropolymer or other membrane from the back of the liner of the pre-filled syringe (outside the syringe seal) to the lumen of the syringe containing the material to be filled. This reduces the CCI of the matched syringe-plunger system and shortens its shelf life.

[0133] While cutting one or more channels into the membrane can mitigate some of the degradation of container closure integrity and shortened shelf life caused by these microchannels, the process of creating the channels can itself lead to other problems that degrade CCI and shelf life. For example, it is undesirable to be bound by theory; unless the liner is properly secured during the laser cutting process, it may sag on its outer surface or otherwise deform, resulting in inconsistencies and variations within the channels. Furthermore, unless the liner and channels are carefully and individually inspected after production, the failure rate of the liner when used in syringe plunger systems will be unacceptable.

[0134] The improved processes, liner, and syringe-plunger system disclosed herein overcome these problems. Furthermore, the rigorous testing processes disclosed herein ensure a low liner failure rate when used in the syringe-plunger system.

[0135] An improved liner inspection system: After liner manufacturing and, in some embodiments, after the laser processing disclosed herein, the inspection of liner characteristics includes, but is not limited to, the following: (1) dimensional checks of the overall height and outer diameter of the liner; (2) camera inspection of the shape of the sealing ribs; (3) camera inspection of the laser cut, e.g., verifying 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 membrane, examining for evidence of wrinkles, tears, or peeling from the rubber (insufficient adhesion). Further tests are also performed to verify the characteristics of the syringe and liner system disclosed herein, such as container closure integrity test (CCIT), plunger release force and slip force test, aseptic assurance, and particulate test.

[0136] Gasket Inspection (Die-cut and Micro-protrusions): A vision system is used for online inspection of plungers (100% inspection). Simac (Netherlands) manufactures an example of a high-speed plunger inspection system. The camera inspection system has the following properties: (1) 13 pistons / second; (2) support for a wide range of plunger colors; (3) performance of top, bottom, external, and internal surface inspections; (4) inspection of micro-protrusions; (5) inspection of stamping and shape defects; (6) 100% quality control with a minimum defect detection of 100μm. Non-conforming parts are sorted in separate containers and statistically tracked. Conforming parts are accurately counted and automatically packaged.

[0137] Laser micrometer dimensional measurement: This measures the dimensional consistency of each finished pad disclosed herein. Preferably, this is an online 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 to be measured. The part blocks the laser, creating a shadow that lasts for a duration proportional to the size of the part. Optics in a receiver collect the unblocked laser beam and focus it onto a phototube. The output of the phototube is analyzed by electronics to detect the precise time it takes for the laser to cross the edge of each part. Software converts the timing data into meaningful measurements.

[0138] Sorting: Using dimensional measurements, the gaskets disclosed herein can be sorted to ensure that each gasket has a specific dimensional tolerance. The tolerance may be ±100 micrometers, more specifically ±50 micrometers, more specifically ±35 micrometers, more specifically ±25 micrometers, more specifically ±20 micrometers, more specifically ±15 micrometers, more specifically ±10 micrometers, more specifically ±5 micrometers, and more specifically ±3 micrometers.

[0139] The dimensions of the pre-filled syringe barrel are measured in a similar manner to ensure a precise and consistent fit between the syringe and the liner. This allows for precise control of liner compression in the assembled syringe. Quality attributes of the assembled syringe include, but are not limited to: (1) container closure integrity measures obtained by dye penetration, (2) container closure integrity measures obtained by vacuum decay methods, and (3) plunger force profile (Fi / Fm) consistency (aging and batch-to-batch variability).

[0140] In some embodiments, the lubricated liner disclosed herein maintains container closure integrity with a defect failure rate of at least 6 sigma. System elements may include: 100% inspection of the molded plunger; 100% inspection of the laser-cut notches or channels of the plunger fluoropolymer; 100% inspection of the plunger diameter; 100% measurement of the syringe barrel ID; and a low-stretch syringe barrel.

[0141] In some embodiments of the improved laser process disclosed herein, the following are subject to 100% verification: (a) the depth around the periphery of the liner fixed to the stainless steel mandrel; and (b) the shape of the membrane edge formed by the laser cut or channel using a servo motor to control laser movement. In some embodiments, plasma and / or chemical treatments are used to optimize the adhesion of the membrane to the rubber liner.

[0142] The container closure integrity (CCI) test can be performed using a vacuum decay leak detection method, in which a vacuum is maintained within the test volume and the pressure rise is measured over time. A sufficiently large pressure rise is an indication of inflow into the system, which is evidence of a leak. Optionally, the vacuum decay test is performed in two separate cycles. The first cycle is dedicated to detecting large leaks for a very short duration. A relatively weak vacuum is used for the first cycle because a large pressure difference is not required to detect a large pressure rise if a large leak is detected. If a large leak is present, using the first cycle as described helps to shorten the overall test time. If no leak is detected in the first cycle, a second cycle is run, which conforms to the ASTM F2338-09 standard test method for non-destructive detection of leaks in packaging using the vacuum decay method. The second cycle begins with a system evaluation to reduce the signal-to-noise ratio in the pressure rise measurement. A relatively strong vacuum is maintained for a longer period of time in the second cycle to increase the chance of detecting a pressure rise in the system.

[0143] Example

[0144] Example 1: Liquid CCI Test Method

[0145] The syringe and liner system of this disclosure are filled with water, and a vacuum load is applied to the stop. The syringe needle is stored at 4°C with the needle facing upwards. At specific time points (0 days, 1 day, 4 days, 7 days, 1 month, and 3 months), each syringe is removed, allowed to reach room temperature, and then visually inspected for signs of water ingress into the space between the ribs of the stop. A written description of each failure is recorded, and a photograph of each failure is taken. The leakage characteristics of the syringe of this disclosure are compared with those of other syringes with liner membranes (such as laminated membranes). Compared with syringes not produced using the improved laser and inspection process of this disclosure, the syringe of this disclosure exhibits superior CCI over time.

Claims

1. A method for creating one or more continuous channels in a membrane residing at least on a circumferential outer surface portion of a liner, the liner comprising a body made of an elastic material having a circumferential outer surface portion and an internal cavity at its center, the cavity being defined by an inner surface portion of the liner and open at one end, wherein the internal cavity of the liner is not threaded, the method comprising the steps of: (a) Insert a portion of one end of the mandrel into the open end of the cavity; (b) The gasket is fixed to the mandrel by press fitting assembly; (c) Positioning the mandrel and the fixed pad near the laser; and (d) While rotating the mandrel and the fixed pad along the longitudinal axis of the mandrel, a laser beam emitted from the laser is applied to one or more selected locations on the surface portion of the film residing on the circumferential outer surface portion of the pad to create one or more continuous channels in the film that extend around the entire circumference of the circumferential outer surface of the pad.

2. The method as described in claim 1, wherein, Prior to step (d), the thickness of the film on the surface of the pad is 10-30 micrometers, 15-35 micrometers, 20-50 micrometers, or 20 micrometers.

3. The method as described in claim 1 or 2, wherein, The membrane possesses one or more of the following properties: good slidability and chemical stability.

4. The method as described in claim 1 or 2, wherein, The membrane can prevent components from migrating from the elastic material of the liner.

5. The method of claim 4, wherein, At least a portion of the mandrel portion inserted into the internal cavity of the liner has a diameter greater than the inner diameter of the cavity.

6. The method as described in claim 1 or 2, wherein, When more than one continuous channel is generated, the continuous channels are axially spaced apart.

7. The method as described in claim 1 or 2, wherein, The one or more continuous channels have axially opposed first and second sidewalls, and a base plate.

8. The method of claim 7, wherein, Each of the one or more continuous channels has an axial width selected from 1-100 micrometers, 5-50 micrometers, 10-30 micrometers, or 15-25 micrometers between the first and second sidewalls.

9. The method as claimed in claim 1 or 2, wherein, Each of the one or more continuous channels independently has a radial depth selected from 0-100 micrometers, 5-50 micrometers, 10-30 micrometers, or 15-25 micrometers.

10. The method as claimed in claim 1 or 2, wherein, Each of the one or more continuous channels independently has a laser cutting depth selected from 20-80 micrometers, 30-60 micrometers, 40-50 micrometers, 50-60 micrometers, 40-45 micrometers, 45-50 micrometers, 50-55 micrometers, or 55-60 micrometers.

11. The method as claimed in claim 1 or 2, wherein, The one or more continuous channels extend through the membrane into the outer surface portion of the liner.

12. The method of claim 7, wherein, The one or more continuous channels include a first circumferentially extending lip, which is positioned adjacent to a first sidewall of the continuous channel and extends radially over the membrane.

13. The method of claim 12, wherein, The one or more continuous channels further include a second circumferentially extending lip, the second circumferentially extending lip being positioned adjacent to the second sidewall and extending radially over the membrane.

14. The method of claim 13, wherein, The first circumferentially extended lip margin and the second circumferentially extended lip margin independently have peak heights selected from 10-100 micrometers, 15-60 micrometers, 20-50 micrometers or 30-40 micrometers.

15. The method of claim 13, wherein, The first and second circumferentially extending lip edges of each of the one or more continuous channels independently have peak widths selected from 200-1,000 micrometers, 275-550 micrometers, 300-400 micrometers, or 450-500 micrometers.

16. The method of claim 13, wherein, Each of the first circumferentially extending lip and the second circumferentially extending lip includes a membrane material.

17. The method of claim 13, wherein, Each of the first circumferentially extending lip and the second circumferentially extending lip includes a membrane material that is removed from the continuous channel by the laser beam during the generation of the continuous channel.

18. The method of claim 13, wherein, At least one of the first circumferentially extending lip and the second circumferentially extending lip can be positioned within the tubular syringe barrel to form a seal against the inner surface of the tubular syringe barrel.

19. The method as claimed in claim 1 or 2, wherein, The position of the laser relative to the mandrel and the fixed pad is controlled by a servo motor.

20. The method of claim 1 or 2, wherein, The membrane is a fluoropolymer membrane.

21. The method of claim 20, wherein, The fluoropolymer membrane is polytetrafluoroethylene (PTFE).

22. The method as claimed in claim 1 or 2, wherein, The elastic material includes bromobutyl rubber.

23. The method as claimed in claim 1 or 2, wherein, The inner surface of the membrane is treated before being applied to the outer surface portion of the liner to promote adhesion to the outer surface portion.

24. The method of claim 23, wherein, The inner surface of the membrane is corona-treated.

25. The method of claim 23, wherein, The inner surface of the membrane is chemically treated.

26. The method as claimed in claim 1 or 2, wherein, The dimensional tolerances of the pads that can be used in the method are selected from ±100 micrometers, ±50 micrometers, ±35 micrometers, ±25 micrometers, ±20 micrometers, ±15 micrometers, ±10 micrometers, ±5 micrometers, or ±3 micrometers.

27. The method of claim 1 or 2, wherein, Measurements were performed using light-blocking (LO) or microfluidic imaging (MFI), and the pad contained fewer than 300 particles of 2 micrometers in size or larger.

28. A matching syringe and plunger system, comprising: (a) A tubular syringe barrel; (b) A plunger located within the syringe barrel and capable of longitudinal reciprocating within the syringe barrel; as well as (c) A gasket attached to the distal end of the plunger; the gasket comprising a body made of an elastic material 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, wherein the internal cavity of the gasket is unthreaded, wherein the gasket is characterized by one or more continuous channels formed according to a method comprising the following steps: (i) Insert a portion of one end of the mandrel into the open end of the cavity; (ii) The gasket is fixed to the mandrel by press fitting assembly; (iii) Position the mandrel and the fixed pad near the laser; and (iv) While rotating the mandrel and the fixed pad along the longitudinal axis of the mandrel, a laser beam emitted from the laser is applied to one or more selected locations on the surface portion of a membrane residing on the circumferential outer surface portion of the pad to create one or more continuous channels in the membrane that extend around the entire circumference of the circumferential outer surface of the pad.

29. The system of claim 28, wherein, The syringe barrel contains injectable fluid on the distal side of the liner.

30. The system of claim 28 or 29, having a container closure integrity (CCI) with a defect rate not exceeding 6 sigma.

31. The system as claimed in claim 28 or 29, wherein, The plunger and the attached gasket have a release force between 4 Newtons (N) and 20 Newtons.

32. The system of claim 31, wherein, The plunger and the attached gasket have a sliding force between 4 Newtons (N) and 20 Newtons.

33. The system of claim 32, wherein, The loosening force or the sliding force changes by less than 10-30% over a two-year storage life.

34. The system as claimed in claim 28 or 29, wherein, The syringe barrel includes a wall having an inner surface coated with a lubricating layer, which, as measured by X-ray photoelectron spectroscopy (XPS), has an atomic ratio of 1 atom Si: 0.5 to 2.4 atoms O: 0.6 to 3 atoms C.

35. The system of claim 34, wherein, The syringe barrel further includes a three-layer coating between the inner surface of the wall and the lubricating layer, wherein the three-layer coating includes a bonding coating, a barrier coating, and a pH protection coating; in (a) The bonding coating comprises SiO x Cy or SiN x C y Where x is 0.5 to 2.4 and y is 0.6 to 3, the connecting coating has an outer surface facing the inner surface of the wall, and the connecting coating has an inner surface facing the inner cavity of the syringe barrel; (b) The barrier coating comprises SiO x Where x is 1.5 to 2.9, the barrier coating is 2 nm to 1000 nm thick, the barrier coating has an outer surface facing the inner surface of the connecting coating, and the barrier coating has an inner surface facing the inner cavity of the syringe barrel; and (c) The pH-protective coating comprises SiO x C y or SiN x C y , where x is 0.5 to 2.4 and y is 0.6 to 3, the pH protective coating has an outer surface facing the inner surface of the barrier coating and an inner surface facing the inner cavity of the syringe barrel.

36. The system of claim 34, wherein, Compared to one or both of the viscous and sliding friction of the liner in the syringe barrel without the lubricating layer, the lubricating layer can reduce one or both of the viscous and sliding friction of the liner in the syringe barrel.

37. The system of claim 28 or 29, wherein, The membrane is a fluoropolymer membrane.

38. The system of claim 37, wherein, The fluoropolymer membrane is polytetrafluoroethylene (PTFE).

39. The system of claim 28 or 29, wherein, Compared to a pre-filled syringe that is otherwise substantially similar but does not include the continuous channels produced by the method, one or more of the continuous channels improve the container closure integrity of the syringe components when assembled to form a pre-filled syringe.

40. The system of claim 39, wherein, The improvement is an extension of the shelf life.

41. The system of claim 39, wherein, The improvement was measured using a vacuum decay leakage detection method.

42. The system of claim 39, wherein, The improvement was measured using a liquid CCI test method.

43. The matched syringe and plunger system as described in claim 28 or 29, wherein, The syringe barrel has a wall, the wall including an inner surface defining a generally cylindrical inner cavity, and the syringe barrel has an inner diameter; The gasket has a leading surface, a side surface, a trailing portion, and an outer diameter; The liner is configured to be received within the syringe barrel, the outer diameter of the liner being located within the inner diameter of the syringe barrel and movable relative to the inner diameter of the syringe barrel; and During assembly, the size of the syringe barrel and the liner of the system are respectively set to provide a distance between the minimum inner diameter of the syringe barrel and the maximum outer diameter of the liner, the distance deviating from the nominal distance by no more than: ±100 micrometers, ±50 micrometers, ±35 micrometers, ±25 micrometers, ±20 micrometers, ±15 micrometers, ±10 micrometers, ±5 micrometers or ±2 micrometers.

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