Method of sterilizing pre-filled syringe and sterilized surgical kit

Abstract

The invention relates to a method for sterilizing a pre-filled syringe using ethylene oxide (EtO) and a sterilized surgical kit. The method comprises the following steps: providing an injector pre-filled with a sterilization sensitive solution; placing the pre-filled syringe in an EtO sterilizable package having one or more other medical devices; sealing an EtO sterilizable package having a pre-filled syringe and at least one other medical device therein and then performing an EtO sterilization cycle; performing an EtO sterilization procedure cycle on an EtO sterilizable package comprising a pre-filled syringe and at least one other medical device; and an EtO sterilization phase of initiating an EtO sterilization procedure cycle of the EtO sterilizable package including the pre-filled syringe and the at least one other medical device in the processing chamber. The methods disclosed herein do not produce many possible unacceptable side effects of EtO gas ingress.

Description

[0001] This application is a divisional application of the Chinese Patent Application No. 201780033848.6, filed on May 22, 2017, entitled "Method of Manufacturing Non-glass Prefilled Containers", with the same inventors. TECHNICAL FIELD

[0002] The present invention relates to an ethylene oxide ("EtO") gas sterilization method for sterilizing non-glass containers at least partially prefilled with materials sensitive to certain sterilization techniques without causing EtO gas to enter the prefilled containers, including but not limited to containers prefilled with saline (0.9% NaCl saline, heparinized saline, or lidocaine). BACKGROUND

[0003] Syringes and other medical containers have been used for many years. However, such containers have typically been made of glass. Gradually, as plastic materials were discovered, some containers, including syringes, began to be offered in plastic form. In recent history, many plastic syringe manufacturers, medical device manufacturers, and / or pharmaceutical companies began to offer prefilled plastic containers, including vials and syringes, with fluid materials, such as saline, heparinized saline, or lidocaine. However, these manufacturers discovered that these materials are sensitive to certain sterilization techniques. For example, when saline contents in plastic containers are exposed to ethylene oxide ("EtO") gas sterilization, IV flush solutions, pharmaceuticals, vaccines, or other fluid materials containing saline solutions can undergo changes in their respective compositions or properties, such as an undesirable change in pH of the saline solution. In addition, the potency of heparinized saline and / or lidocaine can be adversely affected, and EtO gas residuals and / or residual toxic byproducts can be generated when the solution is exposed to certain sterilization techniques after the filling is completed.

[0004] Accordingly, prefilled syringes and other containers made of plastic materials, such as polypropylene, have been found to cause various complications. For example, the United States Pharmacopeia ("USP") guidelines require that physiological saline solutions (i.e., 0.9% NaCl) in prefilled syringes only have a pH between 4.5 and 7.0 to be suitable for human use. One complication that has been identified as frequently occurring with known prefilled containers is an undesirable change in pH after ethylene oxide gas (EtO) sterilization. PH has been identified as an indicator of EtO ingress, such that if the pH of the fluid within the syringe has changed to outside of the accepted USP standard limits (typically +, or higher), then one or more other parameters suitable for human use (discussed in further detail below) also exceed the standard limits.

[0005] Commercially available prior art pre-filled saline and heparinized saline syringes and vials for IV flush were obtained for testing against a test protocol designed and performed for evaluating the state of the art of pre-filled plastic containers, such as syringes and vials. Control samples that were not EtO sterilized and 11 groups of EtO sterilized samples were tested. After the EtO sterilization process was completed, all samples were tested for pH levels. The testing showed that the commercially available samples showed undesirable pH changes such that the pH of the saline after EtO sterilization was outside the USP allowed range. Each test group provided 10 samples from a different prior art manufacturer. The average pH change amount for the control samples indicated an unacceptable pH change which resulted in the pH of the saline being outside the mandatory pH range of 4.5 to 7.0:

[0006]

[0007] This undesirable change determined that EO entered the syringe / container during the EtO sterilization process.

[0008] However, it is desirable to package a pre-filled syringe or other container containing a sterilization sensitive fluid material with other medical procedure tools and / or equipment that require sterilization in a medical procedure tray, kit, pouch or other package. For example, a conveniently packaged, all-in-one kit (e.g., a surgical or procedure kit) can include a pre-filled syringe along with surgical instruments, gloves, bandaging supplies, sterile wipes, etc. (all of which require EtO sterilization) necessary to perform a given medical procedure. In the case of adding a pre-filled syringe containing a sterilization sensitive fluid material to such a conveniently packaged kit, one known method of avoiding the problems created by using plastic pre-filled syringes or other pre-filled containers is to use glass containers and glass syringes because glass effectively prevents the undesirable effects of EtO entering the fluid material as determined above.

[0009] However, while glass containers have proven to be suitable barriers for achieving EtO sterilization, glass containers have certain limitations that make the selection of this material undesirable. For example, glass containers are fragile. As a result, there is a risk of the sterilization sensitive material eroding the surface of the glass material, or the glass can shatter and contaminate the material therein. For another example, micro-cracks in the glass can allow EO penetration and / or the glass container can explode during the vacuuming of a deep sterilization cycle. Other problems resulting from the brittleness of glass include the breaking of the syringe if dropped. While broken glass can be cleaned up, if the syringe is dropped during surgery in the operating room, such clean up can require the closure of the operating room (a huge economic loss to the facility) to reestablish a sterile field, and a delay in patient care. In addition, glass is much more expensive to manufacture than plastic and has inherent limitations related to the geometry, size and complexity of the container. In addition to having to be particularly careful to avoid breakage, due to the weight of the material, transporting glass containing sterilization sensitive material therein and transporting used glass syringes after use is much more expensive than plastic. Finally, glass syringes have the added problem that an integrated medical industry standard luer tip cannot be formed for the glass syringe. Instead, an adapter must also be provided to incorporate the luer fitting, adding cost.

[0010] One method to address the known EtO sterilization limitations inherent to plastic containers is to sterilize empty plastic syringes or other empty plastic containers and then fill the plastic containers with a sterile fluid (introducing the sterile fluid into a clean room or a sterile environment). The filled syringes are then packaged in a non-sterile bag. This method provides a "pathway for sterile fluid" but the exterior of the syringe is not sterile itself. More specifically, the exterior of the syringe / container is not sterile. As a result, the syringe / container must be packaged separately from the rest of the procedure kit, creating two different SKU numbers, which can complicate inventory tracking and cause inconvenience and inefficiency for the end clinical user. In one example, a non-sterile pre-filled container is attached to the outside of a sterile kit after the kit is sterilized, sometimes referred to as a "sidecar" package, creating a secondary non-sterile kit consisting of a non-sterile pre-filled container and a sterile kit. While this combined kit can reduce inventory tracking, the added step of packaging the plastic containers separately and attaching them to the sterilized kit makes manufacturing and assembly more time consuming and expensive. In addition, there is a risk that the sidecar package can come off and be lost in the medical facility, which can then result in unnecessary waste and delay of the procedure while the material is found.

[0011] In addition, for a fully wrapped "pick-up" surgical kit of sterile tray inner, the syringe / container components are not within the wrapped assembly. Rather, after the wrap / drape is opened in the sterile field, these syringe / container components must be individually unwrapped and assembled onto the surgical drape.

[0012] Another known method to address the known EtO sterilization limitations inherent to plastic containers is to fill the empty plastic syringe / container with a fluid material that can be introduced as a sterile fluid in a clean room or a sterile environment, as described above. The filled plastic syringe / container can then be autoclaved, which will ensure that a sterile fluid and fluid pathway are created. However, the exterior of the syringe / container remains non-sterile and can be packaged as described above.

[0013] Further, when non-sterile components must be handled separately from the packaging, maintaining aseptic technique during the clinical procedure becomes more challenging. This can impact the order of actions required to complete a given procedure; or, in some cases, the number of physicians required to complete the procedure. For example, during the procedure, a nurse must open the non-sterile packaging outside the sterile field, and once the physician accesses the syringe and / or container, the procedure must be adjusted to maintain aseptic technique.

[0014] As another alternative, the filled "sterile fluid pathway" syringe / container can be steam sterilized. After steam sterilization, the syringe / container is placed in a foil package that is impermeable to EtO gas, and then it is introduced into the procedure kit, which is EtO sterilized along with the foil package. The foil package prevents EtO gas within the procedure kit from passing through the foil package, thereby preventing the EtO gas from interacting with the fluid material within the syringe / container. However, this process is also time consuming and expensive because it requires two separate sterilization processes. Further, in use, it requires the clinician to open multiple packages and move them to the appropriate location in the sterile field during the procedure, and to properly dispose of the packaging components without compromising the integrity of the sterile field.

[0015] In another alternative, a pre-filled syringe / container containing a sterile solution (but the exterior of the syringe is not sterile) is packaged in a sleeve that can be attached to a cap or bag of the kit. Once packaged, the sleeve can be autoclaved so that the packaged syringe / container is already sterile. However, this setup requires an additional person to open the package to place the syringe / container into the sterile field. This setup does not allow for the syringe / container to be placed into a procedure kit that can be EtO sterilized. SUMMARY

[0016] It is desirable to address one or more of these limitations of the known glass containers, plastic containers, packaging kits, and / or methods disclosed herein. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 A side view of an exemplary syringe assembly is shown;

[0018] Figure 2The section cut along line 2-2 is shown. Figure 1 A cross-sectional view of the syringe assembly;

[0019] Figure 3A It shows the relationship with Figure 1 A side view of an exemplary plunger assembly used in conjunction with a syringe assembly;

[0020] Figure 3B It shows the relationship with Figure 3A A side view of an exemplary plunger tip used in conjunction with a plunger;

[0021] Figure 4A It shows Figure 1 A side view of the barrel of an exemplary syringe assembly;

[0022] Figure 4B It shows Figure 4A An enlarged view of an exemplary neck of the cylinder;

[0023] Figure 4C It shows Figure 4A An enlarged view of the alternative structure near the end of the cylinder;

[0024] Figure 5 A side view of an exemplary vial is shown;

[0025] Figure 6A A perspective view of the end cap assembly is shown;

[0026] Figure 6B It shows Figure 6A A perspective view of the end cap insert of the end cap assembly;

[0027] Figure 7A yes Figure 6A A cross-sectional view of the end cap assembly; and

[0028] Figure 7B yes Figure 7A A plan view of the end cap assembly; and

[0029] Figure 8 This is a flowchart illustrating the flow paths of various products used in the EtO sterilization process for each group. Detailed Implementation

[0030] Exemplary embodiments are now illustrated in detail with reference to the accompanying drawings. Although the drawings illustrate specific embodiments, they are not necessarily drawn to scale and certain features may be exaggerated to better illustrate and explain the innovative aspects of the embodiments. Furthermore, the embodiments described herein are not intended to be exhaustive or otherwise limit to the exact forms and constructions shown in the drawings and disclosed herein.

[0031] In one exemplary configuration, the pre-filled container system may be embodied as a syringe assembly having a barrel, a plunger, and an end cap. A chamber may be formed within the barrel between the plunger and the end cap, and this chamber may be configured to contain sterile-sensitive materials, such as saline or heparinized saline. The syringe assembly may be formed from various materials and / or solutions that allow the syringe assembly to be packaged and sterilized together with a surgical kit containing other items necessary for performing a medical procedure. For example, as determined by medical professionals such as nurses, surgeons, and other operating room staff, such a kit may be tailored to a specific procedure and may include items suitable for and required for that specific procedure, such as instruments, medications, antiseptics, and dressing supplies. For convenience and to reduce inventory burden (e.g., tracking), it is preferable that individual items are not packaged separately. In another exemplary configuration, the container with the chamber may be formed from various materials and / or solutions that allow the container to be packaged and sterilized together with a surgical kit containing other items necessary for performing a medical procedure.

[0032] As another key advantage, the availability of a sterile convenience kit allows operating room staff to maintain established aseptic techniques while performing surgical procedures, eliminating the need to individually remove syringes from their separate packaging and position the syringes / containers in a sterile area.

[0033] For health and hygiene purposes, it may be desirable and necessary to sterilize and prepare all items within the kit for use by medical professionals. During manufacturing, items within the kit may be sterilized to eliminate live bacteria or other microorganisms present inside or outside the kit, as well as inside and outside any component items within a sterile kit. Known sterilization methods may include EtO sterilization, autoclaving, or other methods such as radiation. In one embodiment, terminal sterilization is used as the sole sterilization step during the assembly and manufacture of the packaging kit. However, as mentioned above, the EtO gas used during terminal sterilization can alter the composition of sterilization-sensitive materials within the syringe and / or container.

[0034] Therefore, in one exemplary setting, such as Figure 1 As shown, the syringe assembly 100 may include a barrel 105, a plunger 110, and an end cap 115. Figure 6A (As shown in the diagram). When the plunger 110 and end cap 115 are assembled to the cylinder 105, the interior of the cylinder 105 can mate with the distal end 113 of the plunger 110 and the end cap 115 to define a chamber 230 (in... Figure 4AThe chamber 230 can include any number of solutions (i.e., materials) therein (best seen in FIG. 2). Examples of preferred solutions include, but are not limited to, sodium chloride (e.g., 0.9% NaCl saline), heparinized saline (various amounts of heparin content), lidocaine, or other liquid pharmaceuticals used for infusion or catheter lumen line flushing. The solutions can also include active ingredients, such as vaccines, pharmaceuticals, probiotics, diagnostic compositions, etc. Typically, the chamber contents are sterile liquid solutions; either by aseptic fill process or by terminal sterilization after fill by providing a sterile fluid path. When packaged in an operating kit, these solutions can be adversely affected by the terminal kit sterilization process (e.g., EtO sterilization as described above). However, to ensure that all contents of the completed operating kit are sterile, kit sterilization is necessary.

[0035] As described above, the contents of the plastic container can be compromised during the kit sterilization process, and thus, the solutions contained therein can be affected and considered "sterilization sensitive." For example, EtO sterilization can include subjecting the filled syringe assembly 100 to EtO gas. The use of EtO gas is effective and an acceptable procedure to kill any microorganisms and ensure that the assembly 100 is sterilized prior to use. However, as recognized by the Federal Drug Administration (FDA), EtO gas can alter the composition of sterilization sensitive solutions. Therefore, as set forth in the regulatory notice published by the FDA in the Federal Register, Vol. 43, No. 122, pp. 27474-27483 (Proposed June 23, 1978) (to be codified at 21 CFR §§ 221 and 821) ("Ethylene Oxide, 2-Chloroethanol, and Ethylene Glycol - Proposed Maximum Residue Limits and Maximum Exposure Levels") (hereby incorporated by reference in its entirety), the amount of residual ethylene oxide (EO) gas, 2-chloroethanol (ECH), and ethylene glycol (EG) toxic byproducts present in an injectable pharmaceutical must be strictly controlled. For injectable pharmaceuticals, the FDA guidance document recommends that the residual EO and ECH not exceed 10 ppm, and the residual EG not exceed 20 ppm. Additionally, the FDA guidelines also set forth a daily maximum exposure level requirement. More specifically, for EO, the daily maximum exposure level is 30 μg / kg / day for up to 30 days. For ECH, the daily maximum exposure level is 15 μg / kg / day for up to 30 days. For EG, the daily maximum exposure level is 2.5 mg / kg / day for up to 30 days. Although the above proposed limits for residual EO, ECH, and EG were never published as final rules, these limits have been used and accepted by the industry and government as a matter of fact regulation for nearly 40 years.

[0036] With specific reference to sodium chloride injection, the United States Pharmacopeia (USP) - National Formulary provides test standards for acceptable pH in such solutions. More specifically, the pH should be in the range of 4.5-7.0 (Test No. 791). The inventors of the present application have determined that a shift in pH outside of this range is an indication of undesirable EO entering the chamber 230 or container holding the sterilization sensitive material of the syringe. For example, as described in the Background section, testing of samples prior to undergoing EtO sterilization treatment produced a baseline pH that was well within the USP range of 4.5-7.0. However, once these prior art samples were subjected to the prior art EtO sterilization technique, the pH shifted outside of the UPS range, reflecting that the solution within the container had been altered.

[0037] The USP also provides acceptable pH ranges for other injectable solutions contemplated by the present application, such as lidocaine hydrochloride and epinephrine injection (pH in the range of 3.3-5.5), lidocaine hydrochloride injection (pH in the range of 5.0-7.0), and heparin lock flush solution (pH in the range of 5.0-7.0).

[0038] While the above USP standards are directed to the material within the chamber 230, the syringe assembly 100 itself is also subject to maximum residue limits. More specifically, syringes are classified as medical devices and are subject to ANSI / AAMI / ISO 10993-7:2012 "Biological Evaluation of Medical Devices - Part 7: ETO Sterilization Residuals." For those medical devices that are subjected to EtO sterilization techniques, the residual EO gas in the device must be less than or equal to 4 mg / device, while the residual ECH toxic byproduct must be less than or equal to 9 mg / device. Currently, there are no standards for residual EG toxic byproducts.

[0039] To provide a syringe assembly 100 that meets the above FDA requirements and related ISO standards, as explained in further detail below, the syringe assembly 100 provides that the chamber 230 creates an effective barrier between the sterilizing gas and the solution such that the solution remains substantially unchanged within the chamber 230 during and after sterilization. For example, in one exemplary setup, the pH of the solution remains within a range of about 4.5-7.0 in accordance with the term "substantially unchanged." The inventors of the present application have determined that a slight change in the pH of the solution that results in a pH that remains within a range of about 4.5-7.0 after sterilization indicates that the sterilization technique did not cause the EtO gas to enter the solution through any known entry points and paths of the assembly 100 (through the barrel, any rubber interface, any silicone lubricant, interface areas (end cap)) and thus did not adversely affect the solution contained within the chamber 230. Thus, the solution remains within acceptable specifications for manufacturing, marketing, and using the device. These unexpected results were discovered by the inventors after conducting numerous tests using different plastic materials for the assembly 100 in conjunction with variations in sterilization cycle parameters (discussed in further detail below). For another example, if the solution remains substantially unchanged after being subjected to sterilization, then the device and solution still meet the regulatory requirements for manufacturing, marketing, and using the drug product, i.e., also have no more than 10 ppm of residual EO gas and ECH toxic byproducts and no more than 20 ppm of residual EG toxic byproducts.

[0040] In the exemplary construction of the syringe assembly 100, as Figure 1 To Fig. 3, the plunger 110 can include a plunger body 130 that extends along the axis A and has the base 120 at one end and a stopper mounting portion 125 disposed at an opposite end of the plunger body 130. The stopper mounting portion 125 is configured to receive the plunger stopper 127. The plunger body 130 can be made of a lightweight material. As explained in further detail below, the material of the plunger body 103 has multiple options since the plunger body 103 is not in contact with the solution disposed in the barrel 230. In one exemplary setup, the plunger body 103 can be made of polypropylene, which is low cost and lightweight.

[0041] In one exemplary construction, the stopper mounting portion 125 includes an extension element 131 that extends distally from the plunger body 130. The extension element 131 has a diameter that is slightly smaller than the diameter of the plunger body 130. A mounting flange 133 is secured to a distal end of the extension element 131. This construction provides a mounting channel 135 between the mounting flange 133 and the distal end of the plunger body 130. For example, as Figure 2 shown, the mounting channel 135 is configured to receive the annular retainer 155 of the stopper 127.

[0042] As Figure 3BAs best shown, the stopper 127 can include a cylindrical portion 140 and an end portion 145, which can have a tapered shape. The cylindrical portion 140 can also include at least one wiper 150 extending radially about the cylindrical portion 140. As noted above, in one exemplary arrangement, the stopper 125 can be connected to the extension element 131 of the plunger body 130 via a retainer 155. In one exemplary arrangement, as shown, the attachment mechanism 155 includes a ring-shaped retainer 155 that extends inwardly from the outer surface and is configured to frictionally engage within the mounting channel 135 of the extension element 131. However, it should be appreciated that other connection structures can be contemplated. For example, a suitable attachment mechanism can include male and female connection mechanisms whereby the stopper 125 can define an opening (not shown) configured to receive a post (not shown) that extends outwardly along the axis A of the plunger body 130 to frictionally engage the stopper 125. Further, a suitable attachment mechanism 155 can also include an adhesive, for example, a glue can be used. Additionally or alternatively, other mechanisms can be used, for example, a threaded mechanism, a grommet mechanism, etc. Figure 3B

[0043] The stopper 125 can have a relatively high modulus of elasticity and can be formed from one or more materials, including high barrier thermoplastic elastomers. Exemplary elastomers can include, but are not limited to, butyl rubber or bromobutyl rubber. For example, the stopper 125 can also be coated with a silicone lubricant having a suitably selected centistoke viscosity to increase the barrier properties to EO ingress. Additionally, a suitable coating can provide smooth operating / sliding friction during a variety of EtO sterilization cycle parameters during which many environmental pressure changes are imposed on the assembly 100 without unintended plunger movement.

[0044] The base 120 of the plunger 110 can be formed to co-extend with the plunger body 130 and thus include similar materials. In one exemplary arrangement, the plunger body 130 is configured to taper inwardly from a first diameter Dl to a second diameter D2 at the proximal end 129 of the plunger body 130. This configuration serves to limit the movement of the plunger body 130 within the barrel 105. The base 120 is sized to be larger than the first diameter Dl so as to provide a land area for activating the movement of the plunger 130 within the barrel 105 during use. As noted above, during sterilization, at least a portion of the base 120 and the plunger body 130 can be exposed to EtO gas. However, the plunger body 130 and the base 120 are not in contact with the sterilization sensitive material within the chamber 230. Thus, at least one of the base 120 and the plunger body 130 can be formed from a less expensive plastic, for example, polypropylene or polycarbonate.

[0045] As Figure 2 and Figure 4A ​As shown, the barrel 105 includes a first end 180, a second end 185, and a barrel body 190 extending therebetween. The barrel body 190 can form a cylindrical shape extending along the axis A. The first end 180 can be an open end configured to receive the plunger 110 to provide a fluid-tight seal. The second end 185 can include a barrel neck 195. In one example arrangement, the neck 195 can include a male luer 200 defining an opening 205.

[0046] The barrel 105 can also include a mechanical engagement system or barrel flange 210 extending radially inward from an inner surface of the barrel 105 proximate the first end 180. More specifically, as shown, a cross-sectional thickness of the inner surface of the barrel 105 adjacent the first end 180 of the barrel 105 can be greater than a cross-sectional thickness of the inner surface toward a center axis extending through the barrel 105. With this arrangement, the barrel flange 210 is formed. During EtO sterilization, a positive pressure differential can be created within the barrel 105 (relative to the pressure outside the barrel, which can be negative). This pressure differential can exert a force on the plunger 110 attempting to force the plunger 110 out of the barrel 105 and leak fluid from the barrel 105. The barrel flange 210 can be configured to engage the wiper 150 of the stopper 125 and / or an outer periphery of the plunger flange 170 to prevent the plunger 110 from being completely expelled from the barrel 105. Other example mechanical engagements can include one or more protrusions on the inner surface of the barrel 105 sufficient to prevent expulsion of the plunger 115. For example, as shown, in one arrangement, the inner surface of the barrel 105 can also include an inwardly extending annular stop 210'. Figure 4A Figure 4C As shown, in one arrangement, the inner surface of the barrel 105 can also include an inwardly extending annular stop 210'.

[0047] The stopper 125 has an outer diameter that is slightly larger than the inner diameter of the barrel 105. While the stopper 125 will compress when introduced into the barrel 105, the barrel flange 210 or annular stop 210' will prevent the stopper 125 from being withdrawn from the barrel 105 as a portion of the annular retainer 155 will be in contact with the barrel flange 210 and annular stop 210'.

[0048] In one example method, after filling the chamber 230 with solution, air bubbles are intentionally left in the barrel. The air bubbles facilitate a large pressure differential and outward force on the plunger 110 during sterilization when the EtO sterilization cycle uses a deep vacuum. In another example method, the chamber 230 is free of air bubbles. As noted above, the selection of the silicone lubricant parameters can also affect plunger movement.

[0049] ​A gripping flange 235 is provided on the exterior of the first end of the cylinder 105. The gripping flange 235 extends radially outward about the open first end 180 so as to be larger than the diameter of the cylinder 105. In one exemplary configuration, the gripping flange 235 extends all the way around the open first end 180. In another exemplary configuration, the gripping flange 235 is configured to have gaps between the land areas. Both configurations allow a user to grip the cylinder 105 as the plunger 130 moves inward within the chamber 230.

[0050] Cylinder 105 can be made of one or more plastic materials. However, in one exemplary configuration, cylinder 105 is formed of cyclic olefin polymer (COP) and / or cyclic olefin copolymer (COC) materials. These polymers are similar to glass because they have high impermeability, high moisture barrier properties, and low absorbency. However, unlike glass, COC and COP materials are not easily broken and do not have the weight and transportation issues associated with glass. Cylinder 105 may be coated with a material to increase barrier properties, such as silica or alumina. In another embodiment, cylinder 105 may be uncoated. Additionally or alternatively, cylinder 105 may be formed of a material with high transparency, allowing for visual inspection of the contents of the cylinder. Cylinder 105 may also be made of a material with low water vapor permeability (in one embodiment, less than about 0.5 g / m³ at atmospheric pressure per 330 micrometers thickness). 2 / day, to minimize moisture transfer through the container walls), low oxygen permeability (in one embodiment, less than about 500 cm per 80 micrometers thickness at atmospheric pressure). 3 / m 2 The material is formed to minimize gas transmission through the container wall, has high heat resistance to autoclaving temperatures (in one embodiment, the heat resistance is effective for standard autoclaving temperatures), and minimizes at least one of the following: leaching, elution, extraction, absorption, or adsorption.

[0051] The barrel 105 may be configured to receive the plunger 110 at a first end 180. A stopper 125 of the plunger 110 may be inserted at the first end 180. The stopper 125, together with the end cap 115, may be configured to form a chamber 230 within the barrel 105. As described above, the stopper 125 may have a high elastic modulus of stiffness, and the wiper 150 may form a mating surface with the interior of the barrel 105. Therefore, the stopper 125 may allow the plunger 110 to move along axis A within the barrel 105 and also form a seal within the barrel 105 to prevent any material from leaving the chamber 230. Furthermore, the tapered mating surface between the barrel 105 and the stopper 125 may also be used to prevent blood absorption by preventing the plunger assembly 110 from bouncing upwards after administration, once the pre-filled syringe has been administered to the patient.

[0052] ReferenceFigures 6A-7B In one example arrangement, the end cap 115 can be configured as a female connector 220 configured to receive a mating male connector 200 extending from the barrel 105. The end cap 115 can be configured to seal the syringe assembly 100 to help form a chamber 230 within the barrel 105. In one example arrangement, the end cap 115 includes an insert 300 disposed in a housing member 302. Because the housing member 302 does not contact material disposed within the chamber 230, the housing member 302 can be composed of a substantially rigid material, such as polycarbonate or other suitable plastic. The insert 300 includes a base member 304 and a neck 306. The base member 304 is disposed within a cavity 308 formed by inner flanges 310 extending inwardly from an inner surface 312 of the housing member 302. In one example arrangement, the inner flanges 310 have upwardly extending lips 314 that extend annularly around the insert 300 to lock the insert 300 into the housing member 302. The inner flanges 310 are spaced apart from one another such that a void region 316 is formed between adjacent flanges 310. Although not shown, in one example arrangement, the inner surface 312 can include threads.

[0053] The insert 300 is manipulated such that the base member 304 is disposed within the cavity 308 and retained within the housing member 302 by the inner flanges 310. With the insert 300 mechanically secured to the housing member 302, the housing is disposed over the barrel neck 195 such that the insert 300 is inserted into the barrel neck 195 in a manner in which the male connector 200 is received within the channel 318 of the insert by a press fit. The positioning member 320 is disposed within an opening formed within the male connector 200. The base member 304 engages and seals a top surface of the barrel neck 195. In one example arrangement, the inner surface 312 can include threads that mate with corresponding threads disposed on an outer surface of the barrel neck 195 to lock the end cap 115 to the barrel 105.

[0054] As explained, the chamber 230 can be configured to contain a sterilization sensitive material. Accordingly, a portion of the end cap 115 can be in contact with the material during sterilization, transport, and storage of the syringe. In the case where the syringe assembly 100 is packaged in a package, such as a surgical kit, a needle for insertion into the barrel neck 195 can also be packaged in the kit.

[0055] End cap 115 can be made of any number of materials. Exemplary materials can include polycarbonate with sufficient barrier properties. For example, a plastic such as polypropylene coated on at least a portion of end cap 115 with a high barrier material (e.g., butyl rubber) can be used. In comparison to cartridge 105 and plug 125, the surface area of end cap 115 exposed to the material in chamber 230 is relatively small. Accordingly, the portion exposed to the material can be coated, while the remainder of end cap 115 can not be coated.

[0056] In another exemplary arrangement (not shown), the end cap can be entirely composed of butyl rubber and include a neck and base member. The outer diameter of the base member is configured to be larger than the outer diameter of the neck region. A channel similar to channel 318 is provided within the neck region. The channel is also defined by an open end and a closed end. A positioning element similar to positioning member 320 can be fixedly provided at the closed end of the channel.

[0057] In operation, the neck region is inserted into the cartridge neck in a manner such that the male connector is received within the channel by a press fit. The positioning member is disposed within the opening formed within the male connector 200. The base member fits against and seals the top surface of cartridge neck 195.

[0058] Referring to Figure 7A and Figure 7B , which is another exemplary arrangement; end cap 115" includes a butyl rubber insert 300 disposed in a housing member 302. Since housing member 302 does not contact the material disposed within chamber 230, housing member 302 can be composed of a substantially rigid material such as polycarbonate or other suitable plastic. Insert 300 includes a base member 304 and a neck 306. Base member 304 is disposed within a cavity 308 formed by inner flanges 310 that extend inwardly from an inner surface 312 of housing member 302. In one exemplary arrangement, inner flanges 310 have upwardly extending lips 314 that extend annularly around insert 300 to lock insert 300 into housing member 302. Inner flanges 310 are spaced apart from one another such that void regions 316 are formed between adjacent flanges 310. Although not shown, in one exemplary arrangement inner surface 312 can include threads.

[0059] Figure 5An exemplary vial 240 is shown that includes a stopper 245 and a cap 250. The vial 240 can be formed of COC or COP (much like the barrel 105), and the stopper 245 can include a region formed of a thermoplastic elastomer (e.g., butyl rubber). The stopper 245 can fit within a neck of the vial 240. The cap 250 can surround a top of the vial 240. Similar to the syringe assembly 100 above, the vial 240 can include a sterilization sensitive material. During sterilization, pressure can be built up within the vial, and the cap 250 can be configured at the top of the vial against at least a portion of the stopper 245 to prevent the stopper 245 from being ejected from the vial 240 during the pressure increase.

[0060] As described above, the exterior of the syringe assembly 100 and / or the vial 240 (or other container) can be sterilized with other items within a surgical suite by various sterilization techniques (e.g., EtO sterilization and / or autoclaving). Prior to sterilization, individual components of the syringe assembly 100 and the vial 240 (e.g., the barrel 105, the plunger 110, the end cap 115, etc.) can be manufactured in a clean room environment. Additionally or alternatively, each component can be sterilized prior to assembly. When the components are partially assembled, the chamber 230 can be filled with a material. In one embodiment, the stopper 125 of the plunger 110 can be inserted at the first end 180 of the barrel 105, and the material can be filled at the opening 205 prior to attaching the end cap 115 to the barrel neck 195. The end cap 115 can then be attached to the barrel 105 at the barrel neck 195, thereby sealing the material within the chamber 230. In another embodiment, the end cap 115 can first be connected to the barrel neck 195 via a connector fitting, and the material can be filled at the first end 180 prior to the plunger 110 being inserted into the barrel 105. Once the chamber 230 is filled and the plunger 110 is inserted, the syringe assembly 100 can be sterilized.

[0061] For example, the assembly 100 / vial 240 or other container can be placed in an autoclave. By subjecting the syringe assembly 100 / vial 240 or other container to highly saturated steam, the exterior of the assembly can be sterilized. In addition, due to the high temperature of the solution in the container, the interior of the components that are not exposed to the steam will also be sterilized. Once the syringe assembly 100 / vial 240 or other container is removed from the autoclave, the exterior of the assembly 100 / vial 240 or other container can become non-sterile; however, the fluid and fluid path remain sterile. The syringe assembly 100 / vial 240 or other container can be packaged individually (as a single dose syringe / container or multiple syringes / containers in a single package) or in combination with the remaining contents of the kit. The individual packages or the entire kit can then be sterilized by EtO sterilization. Thus, the exterior of the assembly 100 / vial 240 or other container is sterilized. For those arrangements that include packaging the syringe assembly 100 / vial 240 or other container with the remaining kit items together, the exterior of the assembly 100 / vial 240 or other container can be sterilized simultaneously with the other kit components. Due to the specific properties of the barrel 105, plunger 110, stopper 125, and end cap 115, the material within the chamber 230 is not altered or affected by the sterilization process.

[0062] In another alternative arrangement, once the syringe assembly 100 is removed from the autoclave, the syringe assembly 100 (with or without the sterilization sensitive material) can be placed in its own pouch with one or more vials 240 / containers containing the sterilization sensitive material. The packaged combination syringe assembly 100 and vials 240 / containers can then be subjected to an EtO sterilization procedure. Finally, it should be understood that the present invention also contemplates that vials and / or containers (e.g., vials 240) constructed of COP or COC materials and having a suitable butyl rubber border can be packaged individually (or in a surgical kit) and subjected to EtO sterilization without adversely affecting the sterilization sensitive material.

[0063] Advantageously, the pre-filled container system can be packaged with other materials that require final sterilization as part of the manufacturing process and need not be packaged separately with materials having high barrier properties (e.g., sealed foil wrap).

[0064] The inventors have discovered that by using COP or COC for the barrel of the syringe (and / or vial 240 or other container) and employing suitable sterilization protocols, the solution disposed within the chamber 230 does not have undesirable pH changes after being subjected to a suitable final sterilization procedure. More specifically, the inventors have developed a series of sterilization protocols that were tested on an exemplary arrangement of a prototype manufactured with a COP barrel and end cap manufactured with polypropylene and having a chlorobutyl rubber insert.

[0065] An exemplary EtO sterilization cycle that the inventors have developed for successfully EtO sterilizing pre-filled syringes (which is also applicable to other containers / vials, including single dose administration delivery devices) has a number of processes, but generally can be broken down into the basic four groups of processes and / or parameters: 1) pre-treatment or preconditioning; 2) chamber washing and conditioning; 3) sterilization and 4) evacuation. A first implementation of the processes / parameters of the pre-treatment group of the exemplary EtO sterilization cycle is given in Table 1 below:

[0066] Table 1

[0067] Category Cycle Stage Cycle Set Point Allowable Range Pre-treatment Minimum temperature prior to conditioning Not Applicable 40-125℉ Pre-treatment Conditioning Temperature 100℉ 90-130℉ Pre-treatment Conditioning Humidity 60％ 45-95％ Pre-treatment Conditioning Time (hours) Not Applicable 6-96 Pre-treatment Product Relative Humidity % Not Applicable 45-85％ Pre-treatment Product Temperature Not Applicable 45-125℉

[0068] The processes of the pre-treatment group are designed to precondition the syringes / vials / containers to make any bacteria "active" or "excited" so that any bacteria / microbes grow and are more susceptible to the EtO gas. To this end, the processes of the pre-treatment group seek to raise the temperature and humidity to precondition the syringes / vials / containers and their contents. In one implementation, the processes of the pre-treatment group begin with the syringes / vials / containers being placed in a pre-conditioning area (e.g., a space or chamber) set at a minimum temperature. Alternatively, the pre-treatment step can also be performed in the sterilization chamber that is used for the other parameters of the sterilization cycle, which will be described in further detail below. In one exemplary setup, the minimum initial starting temperature can be in the range of 40-125 °F. In one particular embodiment, the initial starting temperature can be room temperature, i.e., about 70 °F.

[0069] The temperature of the pre-conditioning area is then raised from the initial starting temperature to a pre-conditioning temperature. In one exemplary setup, the temperature ranges within about 90-130 °F. In another exemplary setup, the pre-conditioning temperature can range from 90-110 °F. In one particular embodiment, the pre-treatment temperature is set to 100 °F.

[0070] The humidity is also raised in the processes of the pre-treatment group. More specifically, the pre-conditioning humidity in the pre-treatment area is raised to a range of 45-85% relative humidity. In another exemplary setup, the pre-conditioning humidity is raised to a range of 45-95%. In one particular embodiment, the pre-conditioning humidity is set to 60%.

[0071] To properly incubate any bacteria / microorganism, the syringes / containers are held in the pre-conditioning area / chamber for a pre-treatment duration. This duration is dependent on the temperature of the product and the humidity of the product to achieve an approximate temperature and humidity of the space / chamber. In one exemplary setup, the syringes / containers are held in the pre-treatment space / chamber for a time ranging between 6 hours to 96 hours. In another exemplary setup, the syringes / containers are held in the pre-treatment space / chamber for a time ranging between 18-96 hours. The temperature of the syringes / containers is in the range of 45-125 °F prior to the syringes / containers being subjected to the sterilization process (and can be moved to the sterilization chamber as explained in further detail below). In another exemplary configuration, after pre-conditioning, the syringes / containers are in the range of 90-110 °F.

[0072] Additionally, after pre-conditioning, in one exemplary setup, the relative humidity of the syringes / containers is in the range of 45-85%. In another exemplary setup, the relative humidity of the syringes / containers is in the range of 45-95%.

[0073] Once the treatment / parameters of the pre-treatment group are complete, the syringes / containers are exposed to or subjected to the chamber wash and conditioning, if required. The first implementation of the treatment / parameters of the chamber wash and conditioning group of the EtO sterilization cycle is given in Table 2 below:

[0074] Table 2

[0075] Category Cycle Stage Cycle Set Point Allowable Range Wash / Conditioning Treatment Temperature 115℉ 85-130℉ Wash / Conditioning Initial Pumpdown 6 inches of mercury 1.0-24.0 inches of mercury Wash / Conditioning Gross Leak Test Chamber 5 minutes 5-60 minutes Wash / Conditioning Fill Pressure Change Not Applicable .5-3.0 inches of mercury Wash / Conditioning Hold Pressure Not Applicable 2.3-14 inches of mercury Wash / Conditioning Dwell Time Not Applicable 15-120 minutes Wash / Conditioning Relative Humidity at End of Dwell Time Not Applicable 47.6-91.9％ Wash / Conditioning N2 Pressure 28.0 inches of mercury Up to 30.5 inches of mercury Wash / Conditioning Second Pumpdown 6 inches of mercury 1.0-24.0 inches of mercury Wash / Conditioning Repeat N2 Pumpdown 2 0-4 Wash / Conditioning Fill Pressure Change 1.5 inches of mercury 0.5-3.0 inches of mercury Wash / Conditioning Hold Pressure 6.5 inches of mercury 2.3-14.0 inches of mercury Wash / Conditioning Dwell Time 75 minutes 15-120 minutes

[0076] The treatment / parameters of the wash / conditioning group are performed to remove a majority (>97% in one exemplary setup) of the air from the chamber so that the EO gas / air mixture is not explosive. Additionally, the treatment / parameters of the wash / conditioning group are performed to add moisture and heat to the area / chamber so that when the EO gas is injected into the chamber, the bacteria / microorganism exposed to the pre-treatment steps above will be eliminated. Once the syringes / containers are properly sealed in the appropriate area, the temperature of the area / chamber is raised to the sterilization temperature. In one exemplary setup, the sterilization temperature is raised to be in the range of 85-130 °F. In another exemplary setup, the sterilization temperature is raised to be in the range of 105-125 °F. In yet another exemplary setup, the target temperature of the sterilization temperature is 115 °F.

[0077] The sterilization zone is subjected to an evacuation process to remove air from the syringe / container while the temperature is being raised to the sterilization temperature. In one exemplary setup, the evacuation process applies a vacuum pressure in the range of 1-24 inches of mercury. In another exemplary setup, the initial evacuation process applies a vacuum pressure of about 6 inches of mercury. In yet another exemplary setup, the initial evacuation process applies a vacuum pressure of about 10 inches of mercury. Acceptable tolerance for the vacuum pressure is 0.5 inches of mercury.

[0078] Once the evacuation process reaches the desired set point, e.g., 10 inches of mercury, the vacuum is turned off and a leak test is performed to verify that the sterilization zone is properly sealed. If the evacuation pressure remains at the set point within acceptable tolerance during the leak test, then the wash / conditioning process proceeds to the pressure injection step. However, if the leak test fails, then any failed seals of the sterilization zone must be checked and the pre-treatment procedure must be repeated for the syringe / container. In one exemplary setup, the leak test is performed in the range of 5-60 minutes. In one particular embodiment, the leak test is performed for 5 minutes.

[0079] If the leak test is satisfactory, in one exemplary optional embodiment, moisture can be introduced into the syringe / container, e.g., by raising the relative humidity of the sterilization zone until the pressure within the sterilization zone rises to a predetermined pressure limit or reaches a desired relative humidity set point according to a direct measurement (i.e., if the sterilization zone includes one or more sensors that indicate relative humidity). If the pressure injection step is omitted, then the next process step is the injection of nitrogen into the sterilization zone, discussed below.

[0080] For the moisture injection, in one embodiment, the sterilization zone (including the syringe) is injected with moisture to a target relative humidity range of 0.5-3.0 inches of mercury to achieve a predetermined hold pressure. In one exemplary setup, the hold pressure can be in the range of 2.3-14.0 inches of mercury. Once the desired hold pressure is achieved, the relative humidity level is maintained for a predetermined dwell time. In one exemplary setup, the dwell time is in the range of 15-120 minutes. Once the dwell time has passed, the relative humidity of the sterilization zone is confirmed. The inventors have determined that a relative humidity in the range of 47.6-91.9% is acceptable. If the pressure injection fails, then the cycle is aborted.

[0081] After the moisture injection (or after the leak test if the moisture injection is omitted), nitrogen is next injected into the sterilization zone under pressure. In one exemplary setup, the nitrogen is injected up to 30.5 inches of mercury. In another exemplary setup, the nitrogen is injected up to about 28 inches of mercury. In another exemplary setup, the nitrogen is injected in the range of 26-27 inches of mercury.

[0082] Next, the sterilization zone undergoes a second evacuation process. In one exemplary setup, the sterilization zone is subjected to a vacuum pressure in the range of 1-24 inches of mercury. In another exemplary setup, the sterilization chamber is subjected to a vacuum pressure set point of about 6 inches of mercury. In another exemplary setup, the sterilization zone is subjected to a vacuum pressure set point of about 10 inches of mercury. The inventors have determined that a tolerance of 0.5 inches of mercury is acceptable for the second evacuation process.

[0083] Following the nitrogen evacuation process, the nitrogen pressure / evacuation process outlined above can be repeated, but is not required. For example, in one exemplary setup, the nitrogen pressure / evacuation process is repeated 1-4 times. In another exemplary setup, the nitrogen pressure / evacuation process is repeated about 2 times. In another exemplary setup, the nitrogen pressure / evacuation process is repeated 3 times.

[0084] Following the nitrogen evacuation process, more water vapor can be introduced into the sterilization zone to increase the relative humidity level. In one exemplary setup, the sterilization zone (including the syringe / container) is injected with moisture to a target relative humidity range of 0.5-3.0 inches of mercury. In another embodiment, the sterilization zone is injected with moisture to a target humidity of 1.5 inches of mercury to achieve a predetermined hold pressure. In one exemplary setup, the hold pressure can be in the range of 2.3-14.0 inches of mercury. In another exemplary setup, the target hold pressure can be in the range of 10-14 inches of mercury. In other exemplary setups, the target hold pressure can be 6.5 or 11.5. Once the desired hold pressure is achieved, the relative humidity level is maintained for a predetermined dwell time. In one exemplary setup, the dwell time is in the range of 15-120 minutes. In another exemplary setup, a dwell time of 75.0 minutes has been found to be acceptable.

[0085] Once the chamber wash and conditioning set of processes is complete, then the syringe / container is subjected to an EtO sterilization process. A first implementation of the EtO sterilization set of processes and parameters for the EtO sterilization cycle is given in Table 3 below:

[0086] Table 3

[0087] Category Cycle Stage Cycle Set Point Allowable Range EtO Sterilization EtO Fill 20 inches of mercury 10.7-29.9 inches of mercury EtO Sterilization EtO Concentration after EtO Fill 710 mg / L 150-800 mg / L EtO Sterilization Nitrogen Blanket 27 inches of mercury 25.5-30 inches of mercury EtO Sterilization Sterilization Dwell Time 4 hours 1-24 hours EtO Sterilization Sterilization Dwell Temperature 102℉ 102-140 EtO Sterilization EtO Make-up 1 0-10

[0088] The EtO sterilization set of processes begins with the introduction of EtO gas into the sterilization zone until a predetermined pressure level is achieved. In one exemplary setup, the pressure level is in the range of about 10.7-29.9 inches of mercury. In another exemplary setup, the target pressure level is 20 inches of mercury. In yet another exemplary setup, the target pressure level is 19 inches of mercury.

[0089] Next, the EtO concentration within the sterilization zone is verified to have a preset target level after EtO injection. In one exemplary setup, a suitable target range is 150-800 mg / L. In another exemplary setup, the target range is about 315-474.5 mg / L. In one exemplary setup, it is desirable to set the target at 421.7 mg / L. Alternatively, biological indicators can be used to verify the EtO concentration within the sterilization chamber.

[0090] Once the EtO concentration is achieved, a nitrogen atmosphere can be introduced. In one exemplary setup, the target range for the nitrogen atmosphere is up to 30 inches of mercury. In another exemplary setup, a suitable target range can be between 25.5-27.0 inches of mercury.

[0091] The EtO concentration within the sterilization zone is maintained at a set temperature for a suitable dwell time. In one exemplary setup, the dwell temperature is in the range of 102-140 °F. Alternatively, the dwell temperature can be in the range of 110-125 °F. The dwell time can be in the range of 1-24 hours. In another embodiment, the dwell time can be in the range of 4-8 hours. In another exemplary setup, a dwell time of 4 hours is used.

[0092] During the dwell time, if the EtO concentration is below a predetermined set point, additional EtO can be injected until the EtO concentration can be maintained above the set point for the minimum dwell time. During the EtO sterilization procedure, EtO injection can be performed up to 10 times.

[0093] Once the EtO sterilization cycle is complete, the syringes / containers are subjected to a wash and post-exposure process. A first embodiment of the wash and post-exposure cycle's process / parameters are given in Table 4 below:

[0094] Table 4

[0095]

[0096] The wash and post-exposure cycle's process / parameters begin with the withdrawal of the EtO gas and nitrogen gas from the sterilization zone to remove the EtO gas from the sterilization zone. In one exemplary setup, a vacuum pressure in the range of 1-24 inches of mercury is applied to the sterilization zone. The inventors of the present application have found that a vacuum pressure of 6 inches of mercury is a suitable vacuum level. The evacuation pressure is applied for 1 to 30 minutes.

[0097] Next, nitrogen gas is injected into the sterilization chamber under pressure. In one exemplary setup, the nitrogen gas is injected until 30.5 inches of mercury. In another exemplary setup, the nitrogen gas is injected at about 27 inches of mercury. In another exemplary setup, the nitrogen gas is injected in the range of 27-28 inches of mercury. The nitrogen gas injection is performed for 1 to 30 minutes. This process can be repeated up to 4 times. In one exemplary setup, the nitrogen gas injection is repeated three times.

[0098] After the nitrogen gas injection is complete, the sterilization area is evacuated to an evacuation pressure. In one exemplary setup, a vacuum pressure of about 1-24 inches of mercury is applied. In another exemplary setup, a vacuum pressure of 6 inches of mercury has been found to be acceptable. In yet another embodiment, a vacuum pressure of 10 inches of mercury has been found to be acceptable.

[0099] Next, the sterilization area undergoes an air wash step. Air is injected at a pressure up to 30.5 inches of mercury. In one exemplary setup, the air wash pressure ranges between 27-28 inches of mercury. The sterilization area is air washed for 1 to 30 minutes. The air wash can be repeated up to 6 times. In one exemplary setup, the air wash can be repeated 3 times. In another exemplary setup, the air wash process can be repeated 4 times.

[0100] After the air wash is complete, the sterilization area is opened to atmosphere, and the product pallet containing the pre-filled syringes can be removed and taken to aeration facilities within the manufacturing facility, which is described in further detail below. Alternatively, the product pallet can remain in the sterilization area. In one exemplary setup, the aeration temperature within the aeration area of the facility can range from 95-120 °F. The product pallet can be aerated for 24-120 hours.

[0101] Referring to Figure 8 The construction of the sterilization protocol will now be discussed. More specifically, Figure 8 The flowchart in FIG. 1 represents an alternative product flow (i.e., syringes, vials, or other items) for the sterilization protocols discussed herein. For ease of illustration, the product flow will be described in the context of EtO sterilization of syringes, but it should be understood that the protocol described below can be applied to other containers containing sterilization sensitive materials.

[0102] In a first setup, represented by solid arrows A, the pre-treatment / pre-conditioning set of processes begins with the placement of the syringes (or set of syringes) in a pre-conditioning area within the facility. Then, the pre-treatment / pre-conditioning set of processes are all performed in the pre-conditioning area. Once the pre-treatment / pre-conditioning set of processes is complete, then the syringes are moved to the sterilization chamber / area. Once in the sterilization chamber / area in the product flow A, the syringes are subjected to the chamber wash / conditioning, sterilization, and evacuation sets of processes. Finally, the syringes can be moved to an aeration area to aerate the syringes.

[0103] In another alternative set-up, the processing of all groups (i.e., pre-processing / pre-conditioning, chamber washing / conditioning, sterilization, and evacuation, including venting) can be done in a single area or chamber as an "all-in-one" process. The product flow is represented in FIG. 1 by element B. Figure 8

[0104] As another alternative set-up, represented by dash C, the product flow includes processing of the pre-processing / pre-conditioning group in a pre-processing area / chamber. Once completed, the syringe is moved to a sterilization chamber / area where the processing of the remaining groups (i.e., chamber washing / conditioning, sterilization, and evacuation, including venting) is performed.

[0105] In the product flow set-up represented by dash-dot D, the syringe undergoes processing of the pre-processing / pre-conditioning group and the chamber washing / conditioning and sterilization groups at the same location (e.g., in the sterilization chamber / area). Once the evacuation of the chamber / area is completed, the syringe is then moved to the venting area of the facility.

[0106] The product flow set-up represented by product flow paths E-H includes repeating certain aspects of the processing of each group. More specifically, the product flow path represented by alternating dots and dashes E includes first subjecting the syringe to the pre-conditioning group in a pre-conditioning area. Next, the syringe is moved to a sterilization chamber where the processing of the pre-conditioning group is repeated and the processing of the chamber washing / conditioning, sterilization, and evacuation (including venting) groups is completed. The syringe is then moved to the venting area of the facility and can be vented again.

[0107] In the product flow set-up represented by dash-dot F, the syringe is first subjected to the pre-processing group in a pre-conditioning area. Next, the syringe is moved to a sterilization chamber where the processing of the chamber washing / conditioning, sterilization, and evacuation groups is performed. The syringe is then moved to the venting area of the facility and can be vented again.

[0108] The product flow set-up represented by long-dash G includes first subjecting the syringe to the pre-processing group in a pre-conditioning area. Next, the syringe is moved to a sterilization chamber / area where the pre-processing group is repeated and the processing of the chamber washing / conditioning, sterilization, and evacuation groups is performed in the sterilization chamber / area. The syringe is then moved to the venting facility and can be vented.

[0109] An additional alternative product flow set-up is represented by double-dot-dash H. In this set-up, the syringe is subjected to the pre-processing group in a pre-conditioning area. Next, the syringe is moved to a sterilization chamber where the syringe is then subjected to another pre-processing / pre-conditioning step, and the syringe is subjected to the chamber washing / conditioning, sterilization, and evacuation groups, including venting.​

[0110] A series of test samples were prepared to verify the effectiveness of the sterilization procedures described above. The sample size for testing included a total of 60 pre-filled syringe assemblies 100, which were divided into six groups of 10 syringe assemblies 100. Each chamber 230 of the individual syringe assemblies 100 included a chamber 230 of a barrel 105 filled with 5 mL of saline, with an end cap 115 secured to the end of the barrel 105. One group of 10 syringe assemblies 100 was selected as a control sample (identified as Group 1) and set aside without performing any sterilization procedures.

[0111] A second group of 10 syringe assemblies 100 was designated as Group 2. The syringes of Group 2 were exposed to two EtO sterilization cycles (discussed in further detail below).

[0112] A third group of 10 syringe assemblies 100 was designated as Group 3. The syringe assemblies 100 of Group 3 were exposed to steam sterilization only.

[0113] A fourth group of 10 syringe assemblies 100 was designated as Group 4. The syringe assemblies 100 of Group 4 were exposed to steam sterilization and two EtO sterilization cycles (as described below).

[0114] A fifth group of 10 syringe assemblies 100 was designated as Group 5. The syringe assemblies 100 of Group 5 were exposed to one EtO sterilization cycle (as described below).

[0115] A final group of 10 syringe assemblies 100 was designated as Group 6. Group 6 was exposed to steam sterilization and one EtO sterilization cycle (as described below).

[0116] The pH of the NaCl saline solution from each syringe in Groups 1-6 was tested using an acceptable test protocol to determine the pH reading to the accuracy of ±0.02 pH. The EO and ECH residuals of the NaCl saline solution from the control group (Group 1) and each of Groups 2, 4, and 6 were tested using an acceptable test protocol (e.g., using gas chromatography with a flame ionization detector). The average test results for each group are given in Table 5 below:

[0117] Table 5

[0118]

[0119] As can be seen from the above table, the pH change was within an acceptable range, such that the pH level was well within the USP requirements. More specifically, the pH of the solution in Groups 2-6 all fell within the range of 4.5-7.0. In addition, the residual EO and ECH were also well within the FDA requirements. More specifically, the EO residual results were below the limit of 4 mg / device, and the ECH residual results were below the limit of 9 mg / device.

[0120] The present invention provides manufacturing methods, EtO sterilization processes and cycles, parameters and ranges for the regulatory compliant production and EtO gas sterilization of polymer pre-filled containers (e.g., syringes) and vials (post-fill and autoclave). Suitable materials for such pre-filled containers include 0.9% NaCl saline, heparinized saline or other liquids. Proper application of the above complex methods results in the resulting sterile pre-filled containers without EtO gas ingress into the EtO sensitive fluid within the container. The methods disclosed herein do not produce many possible unacceptable side effects of EtO gas ingress, such as: pH variation outside the range of 4.5 to 7.0; residues of toxic byproducts such as EO-EC-EG; 0.9% NaCl potency variation of more than ±5%; changes in contents (mL) due to plunger movement and leakage caused by one or more of the 30+ EtO sterilization process cycle parameters being selected improperly. The discovery of these disclosed methods enables the inclusion of non-glass pre-filled containers (e.g., syringes and vials) that can be safely placed into standard, gas permeable medical procedure sterile trays (i.e., convenience trays), kit bags without packaging (i.e., no additional user, inconvenient protective ETO barrier over-pack foil, etc.), or can be packaged with other components, or the container can be packaged alone, and when removed from their packaging or picked up from a sterile procedure tray by the operating technician, can withstand EtO sterilization and be ready for infusion directly.

[0121] With respect to the processes, systems, methods, etc. described herein, it should be understood that, although the steps of such processes etc. have been described as occurring according to a certain order, such processes could be implemented with the aforementioned steps performed in an order other than as described herein. It also should be understood that certain steps could be implemented in parallel, that additional steps could be added, or that certain steps could be omitted. In other words, the descriptions of processes herein are provided for the purpose of illustrating certain implementations, and should in no way be construed so as to limit the claimed application.

[0122] Accordingly, it is to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments and applications other than the examples provided would be apparent upon reading the above description. The scope of the invention should be determined, not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full range of equivalents to which such claims are entitled. It is anticipated that future developments will occur in the technologies discussed herein and that the disclosed systems and methods will be incorporated into such future embodiments. In short, the present application is intended to cover all modifications of this application that fall within the scope of the claims, together with their full range of equivalents.

[0123] Unless expressly indicated otherwise herein, all terms used in the claims are intended to have their broadest reasonable constructions and common meaning understood by those skilled in the art. In particular, the use of singular forms, such as "a", "an", "the", "said", and the like, should be understood to refer to one or more of the indicated element, unless the context clearly dictates otherwise by the recitation of "only one" or "exactly one" or like language.

Claims

1. A method for sterilizing a pre-filled syringe using ethylene oxide (EtO), the method comprising: A syringe pre-filled with a sterile-sensitive solution, wherein the initial solution pH range is 4.5-7.0 and is adversely affected by exposure to EtO; Place the pre-filled syringe in an EtO sterilizable package containing one or more other medical devices; The EtO sterilizable package containing a pre-filled syringe and at least one other medical device is sealed, and then an EtO sterilization cycle is performed. An EtO sterilizable packaging comprising a pre-filled syringe and at least one other medical device is subjected to an EtO sterilization procedure cycle, the EtO sterilization procedure cycle comprising: a pretreatment phase to induce microbial growth on the pre-filled syringe; and a washing and conditioning phase to remove air from a processing chamber containing the packaging comprising the pre-filled syringe and at least one other medical device, wherein the washing and conditioning phase comprises raising the temperature of the processing chamber to a conditioning temperature of 85-130℉; and An EtO sterilization phase is initiated in an EtO sterilizable package, which includes a pre-filled syringe and at least one other medical device, within a processing chamber to sterilize the pre-filled syringe. The EtO sterilization phase provides EtO exposure, which, upon experiencing such EtO exposure, additionally alters the pH of the sterilization-sensitive solution to outside the initial solution pH range of 4.5–7.

0. During the completion of the EtO sterilization cycle, the pH of the resulting sterilization-sensitive solution is maintained within the initial solution pH range of 4.5-7.

0.

2. A surgical kit sterilized with ethylene oxide (EtO), comprising: EtO-sterilized syringes containing a sterile-sensitive solution with a pH suitable for injection into the human body, said sterile-sensitive solution being adversely affected by exposure to EtO; EtO sterilized packaging containing a syringe and one or more other medical procedure components; The sterilized surgical kit has been cyclically sterilized using an EtO sterilization process, which maintains the sterile sensitive solution in a syringe suitable for injection into the human body. This EtO sterilization process cycle includes: A pretreatment phase is initiated on the surgical kit to induce microbial growth on the surgical kit. A washing and conditioning phase is initiated for the surgical kit to remove air from both the syringe and the treatment chamber containing the surgical kit. This washing and conditioning phase includes raising the temperature of the treatment chamber to a conditioning temperature of 85-130℉. An EtO sterilization phase is initiated for the surgical kit to sterilize it. This EtO sterilization phase provides EtO exposure, which, upon undergoing such exposure, additionally alters the pH of the sterilization-sensitive solution to a pH suitable for injection into the human body. The surgical kit is subjected to a washing and post-exposure treatment to remove EtO gas from the treatment chamber.

3. The method according to claim 1, wherein, The EtO sterilizable packaging includes a surgical kit.

4. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, The one or more medical devices include a program tray with a pre-filled syringe fixed therein.

5. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, The one or more medical devices mentioned include surgical instruments, drugs, disinfectants, and dressings.

6. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, The pretreatment stage includes increasing the temperature and humidity of the treatment chamber for at least 6 hours.

7. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, The syringe barrel is formed of at least one of cyclic olefin polymer (COP) and cyclic olefin copolymer (COC).

8. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, The sterilization-sensitive solution comprises at least one of saline, heparinized saline, and lidocaine.

9. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, The sterilization-sensitive solution contains at least one of lidocaine hydrochloride, epinephrine, and heparin.

10. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, The EtO sterilization process cycle also includes: While raising the temperature to the set temperature, the evacuation process is initiated; and Perform a leak test for a predetermined duration of 5-60 minutes.

11. The method of claim 10, further comprising introducing moisture into the processing chamber to a target range of 0.5-3.0 inches of mercury relative humidity to achieve a predetermined holding pressure, wherein, The predetermined holding pressure is maintained for a residence time of 15-120 minutes.

12. The method of claim 11, further comprising injecting nitrogen gas into the processing chamber under pressure.

13. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, When the EtO sterilization cycle is completed, the residual levels of ethylene oxide and 2-chloroethanol in the sterilization-sensitive solution do not exceed 10 ppm.

14. The method of claim 1 or the sterilized surgical kit of claim 2, wherein, When the EtO sterilization cycle is completed, the residual ethylene glycol level in the sterilization-sensitive solution does not exceed 20 ppm.

15. The sterile surgical kit according to claim 2, wherein, The pretreatment stage includes raising the temperature and humidity of the pre-conditioned area where the surgical kit is located to predetermined levels to induce microbial growth.

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