Methods for enhanced sterilization of packaged, pre-filled syringes and contents of the pre-filled syringe

Abstract

Methods are disclosed for enhanced terminal sterilization of packaged, pre-filled syringes containing drug solutions. The methods utilize a sequence of autoclave steps - including vacuum application, dynamic steam pulsing, and controlled counterpressure - to sterilize both the syringe and its enclosing semipermeable pouch without compromising structural integrity or drug quality. The vacuum removes air from the secondary7 space within the pouch, while steam pulsing ensures thorough penetration. Counterpressure is applied to prevent plunger movement caused by internal expansion. The process concludes with drying and cooling phases. The methods maintain sterility to a sterilization assurance level (SAL) of 10 6 and are suitable for use with a range of syringe and packaging materials. The resulting product is sterile field ready, single-use compliant, and structurally intact. These techniques are adaptable to various sterilization times and temperatures, ensuring flexibility across drug formulations and syringe configurations.

Description

TITLE METHODS FOR ENHANCED STERILIZATION OF PACKAGED, PRE-FILLED SYRINGES AND CONTENTS OF THE PRE-FILLED SYRINGE CROSS-REFERENCE(S)

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 671,982, filed on July 16, 2024. The entire contents of the provisional application are hereby incorporated by reference. FIELD OF THE INVENTION

[0002] The invention relates to methods for enhanced sterilization of packaged, pre- filled syringes. More specifically, the invention provides methods for sterilizing a packaged, pre-filled syringe and its contents, all of which are terminally sterilized, ready to use, sterile field ready, enhanced to enforce compliance to single use, and sterilized to a sterilization assurance level of 10-6. BACKGROUND OF THE INVENTION

[0003] Autoclaves, also known as steam sterilizers, operate on the basic principle of steam sterilization, i.e., autoclaving. An autoclave utilizes four criteria, namely steam, temperature, pressure, and time. The autoclaving process uses saturated steam and entrained water. Autoclaves are commonly used in healthcare settings to sterilize medical devices. The items to be sterilized are placed inside a pressure vessel, commonly referred to as the chamber of the autoclave. An autoclave uses steam under pressure to kill harmful bacteria, viruses, fungi, and spores on items. The items are heated to an appropriate sterilization temperature and pressure for a given amount of time. The moisture in the steam efficiently transfers heat to the items to destroy the protein structure of the bacteria, viruses, fungi, and spores, thereby sterilizing the items.

[0004] In general, there are several phases or steps to the autoclave process. In the conditioning phase, air must be removed from the chamber. Depending on the type of autoclave used, the air can be removed from the chamber using a vacuum system, with a series of steam flushes and pressure pulses, or the use of steam to displace air in the chamber. In the exposure (or sterilization phase), steam is continuously introduced into the chamber to increase the pressure and temperature inside the chamber to a predetermined level. The items are then held at the sterilization temperature and pressure for a fixed amount of time required to sterilizethem. After completion of sterilization, the steam is removed, and the chamber is depressurized to allow the items in the load to dry.

[0005] Autoclaving is a safe and effective method of sterilization in the healthcare field. Autoclaving achieves sterilization much quicker and with less damage to autoclaved materials in comparison to other sterilization methods. For example, dry heat sterilization is less effective than autoclaving because the heat must be applied for a longer duration without the benefit of moisture, i.e., steam, to transfer energy in the form of heat to kill any type of microorganism. Autoclaving is safer and less damaging to the autoclaved materials in comparison to low temperature or chemical sterilization methods using ethylene oxide gas, hydrogen peroxide, ozone, gas plasma, gaseous chlorine dioxide, ionizing radiation, pulsed light, or chemical sterilants.

[0006] While the benefits of autoclaving are well-recognized, there are drawbacks to autoclaving pre-filled syringes, as well as packaged, pre-filled syringes. During the autoclave process, the applied heat will cause a liquid, e.g., drug solution, inside the syringe to expand, which creates force sufficient to move the plunger and its stopper relative to the internal surface of the barrel of the syringe. This can draw unwanted air and / or moisture inside the barrel of the syringe, which contaminates and dilutes the drug solution. The heat applied during autoclaving can degrade the structural integrity of the material of the semipermeable package and of the syringe and its components. For example, the rubber tip of the plunger and / or slip agent (if present) can be damaged in a way, which adversely affects the ability of a plunger to slide properly within the barrel or makes the plunger loose. The heat can also deform other parts of the syringe like the barrel or hub, thereby rendering the syringe and its contents unusable. The heat and pressure can also degrade the drug solution or cause chemicals to leach or be extracted from the syringe material or from the slip agent, into the drug solution, which can generate unwanted particulate matter in the drug solution. Autoclaving semipermeable materials like a package, e.g., peelable pouch, for a pre-filled syringe can leave unwanted, contaminating moisture in the secondary space between the inside of the package and the exterior of the syringe.

[0007] Pre-filled syringes are growing in preference over conventional needle and vial delivery systems because pre-filled syringes preserve drug sterility, limit drug waste due to overfilling, improves needlestick safety, simplifies the administration process, and reduces the likelihood of dosing errors.

[0008] Accordingly, there is a need for methods for enhanced sterilization of a pre- filled syringe including its contents, i.e., drug solution, in addition to the semipermeable package enclosing the pre-filled syringe, without movement of the plunger of the syringe or material degradation of the semipermeable container, the syringe in whole or in part, or the drug solution in the syringe. There is a further need for a method for sterilizing a packaged, pre-filled syringe that is terminally sterilized, ready to use, sterile field ready, enhanced to enforce compliance to single use, and sterilized to a sterilization assurance level of 10-6. SUMMARY OF THE INVENTION

[0009] To achieve solutions for the foregoing needs and to provide other advantages, and according to the purpose of the invention as embodied and described herein, the invention provides methods for enhanced sterilization of a pre-filled syringe including its contents, i.e., drug solution, in addition to the semipermeable package enclosing the pre-filled syringe. The invention prevents movement of the plunger of the syringe, as well as degradation of the material of the semipermeable container, the syringe (in whole or in part), or the drug solution in the syringe. The invention also prevents deformation of the syringe (in whole or in part), as well as chemical leaching or extraction from the syringe material or slip agent, any of which can generate unwanted particulate matter in the drug solution.

[0010] The invention provides a method for providing a pre-filled syringe that is sterile field ready. The method comprises the steps of: (1) exposing a semipermeable pouch enclosing the pre-filled syringe having a plunger to the following sequence of steps in a chamber of an autoclave: (a) applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space (or void) within the semipermeable pouch; (b) applying a dynamic steam rising pulse to introduce water vapor into the secondary space (or void) within the semipermeable pouch; and (c) sterilizing the semipermeable pouch, the secondary space, the pre-filled syringe, and drug solution at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the pouch by completion of the sterilization time; (2) applying a drying temperature to the chamber for a drying time at ambient air pressure; and (3) cooling the chamber to a temperature less than the drying temperature.

[0011] The invention provides a method for sterilizing a primary container prefilled with a drug solution, an interior surface of a semipermeable secondary container enclosing theprimary container, and the void between the primary container and the interior surface of the secondary container. The method comprises the steps of: (1) exposing the semipermeable secondary container enclosing the primary container to the following sequence of steps in a chamber of an autoclave: (a) applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space (or void) within the semipermeable secondary container; (b) applying a dynamic steam rising pulse to introduce water vapor into the secondary space (or void) within the semipermeable secondary container; and (c) sterilizing the internal surface of the semipermeable secondary container, the primary container, the secondary space (or void), and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure, wherein all moisture is removed from the secondary space (or void) within the semipermeable secondary container by completion of the sterilization time; (2) exposing the chamber to a drying temperature for a drying time at ambient air pressure; and (3) cooling the chamber below the sterilization temperature.

[0012] The invention provides a manufacturing process for sterilizing a pre-filled syringe having a plunger that is packaged in a semipermeable container. The method comprises (1) autoclaving the pre-filled syringe packaged in the semipermeable container according to the following sequence of steps: (a) applying a vacuum to a chamber of the autoclave to depressurize the chamber and remove air from a secondary space (or void) within the semipermeable container; (b) applying a dynamic steam rising pulse to introduce water vapor into the secondary space (or void) within the semipermeable container; and (c) sterilizing the pre-filled syringe and its contents packaged in the semipermeable container at a sterilization temperature for a sterilization time while applying counter pressure in the chamber to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space (or void) within the semipermeable container by completion of the sterilization time; (2) applying a drying temperature to the chamber for a drying time at ambient air pressure; and (3) cooling the chamber to a temperature less than the drying temperature.

[0013] The invention provides a method for terminally sterilizing a syringe prefilled with a drug solution. The method comprises: (1) exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to the following sequence of steps in a chamber of an autoclave: (a) applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space (or void) within the semipermeable pouch; (b) applying a dynamic steam rising pulse to introduce water vapor into the secondary space (or void) within the semipermeable pouch; and (c) terminally sterilizingthe semipermeable pouch, the syringe, the void, and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space (or void) within the pouch by completion of the sterilization time; (2) applying a drying temperature to the chamber for a drying time at ambient air pressure; and (3) cooling the chamber to a temperature less than the drying temperature.

[0014] The invention provides a method for providing a ready-to-use syringe prefilled with a drug solution. The methods comprises: (1) exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to the following sequence of steps in a chamber of an autoclave: (a) applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space (or void) within the semipermeable pouch; (b) applying a dynamic steam rising pulse to introduce water vapor into the secondary space (or void) within the semipermeable pouch; and (c) sterilizing the semipermeable pouch, the syringe, the secondary space (or void), and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the pouch by completion of the sterilization time; (2) applying a drying temperature to the chamber for a drying time at ambient air pressure; and (3) cooling the chamber to a temperature less than the drying temperature.

[0015] The invention provides a method for sterilizing a syringe prefilled with a drug solution that assures single use compliance with the drug solution. The method comprises: (1) exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to the following sequence of steps in a chamber of an autoclave: (a) applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space (or void) within the semipermeable pouch; (b) applying a dynamic steam rising pulse to introduce water vapor into the secondary space (or void) within the semipermeable pouch; and (c) sterilizing the semipermeable pouch, the syringe, the secondary space (or void), and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the pouch by completion of the sterilization time; (2) applying a drying temperature to the chamber for a drying time at ambient air pressure; and (3) cooling the chamber to a temperature less than the drying temperature.

[0016] In a non-limiting embodiment, the vacuum pressure is about 0.10 bar abs.

[0017] In a non-limiting embodiment, the dynamic steam rising pulse is at a vacuum value of 0.90 bar abs.

[0018] In non-limiting embodiments, the sterilization temperature is in a range of 121 to 130 degrees Celsius. The sterilization temperature can be 121, 126, or 130 degrees Celsius.

[0019] In non-limiting embodiments, the sterilization time is in a range of about 1 to about 10 minutes. The sterilization time is 1 minute, 3 minutes, or 10 minutes.

[0020] The sterilization temperature influences sterilization time. Sterilization temperature and sterilization time are selected while considering the F0 cycle, which is based on the concept of thermal equivalence. The F0 value represents the equivalent minutes of sterilization at 121.1 degrees Celsius, where the F0 value is the accumulated lethality in minutes at 121.1 degrees Celsius. In application, an F0 value of 10 minutes equates to 10 minutes of actual exposure at 121.1 degrees Celsius during the sterilization phase of the method. Further, an F0 value of 10 minutes equates to approximately 3 minutes of actual exposure at 126 degrees Celsius. Finally, an F0 value of 10 minutes equates to approximately 1 minute of actual exposure at 130 degrees Celsius. In a non-limiting embodiment, the sterilization temperature is 121 degrees Celsius, and the sterilization time is about 10 minutes. In another non-limiting embodiment, the sterilization temperature is 126 degrees Celsius, and the sterilization time is about 3 minutes. In a further non-limiting embodiment, the sterilization temperature is 130 degrees Celsius, and the sterilization time is about 1 minute.

[0021] The counter pressure is selected to counteract internal pressure of the drug solution caused by heat exposure at the sterilization temperature and prevent movement of the plunger relative to the syringe. In a non-limiting embodiment, the counterpressure is about 1,20 kilopascals.

[0022] The drying temperature can be in a range of about 105 to about 120 degrees Celsius.

[0023] The semipermeable pouch maintains its structural integrity after exposure to the sequence of steps of the methods disclosed. In a non-limiting embodiment, the semipermeable pouch is a peel open pouch.

[0024] The syringe maintains its structural integrity throughout exposure to the sequence of the steps of the methods disclosed. In non-limiting embodiments, the syringe is made from polypropylene, polycarbonate, cyclic olefin polymer, cyclic olefin copolymer, glass, or metal. The syringe has a plunger and can have a luer lock or a luer slip, all of whichmaintains its structural integrity after exposure to the sequence of steps of the methods disclosed.

[0025] The syringe is pre-filled with a drug solution. The drug solution can be a compounded product. The drug solution is terminally sterilized after exposure to the sequence of steps of the methods disclosed.

[0026] In embodiments of the invention, the semipermeable pouch, the syringe, and the drug solution prefilled in the syringe have a sterilization assurance level of 10-6upon completion of the sequence of steps of the methods disclosed.

[0027] In summary, the solutions of the invention provide autoclave methods to terminally sterilize a primary container, i.e., pre-filled syringe, and its contents, i.e., a drug solution, along with a secondary container, i.e., semipermeable package enclosing the primary container, including the secondary space (or void) present between the primary container and the secondary container. This results in a packaged, prefilled syringe and its contents that is (1) enhanced to terminal sterilization, (2) ready to use, (3) sterile field ready, (4) enhanced to enforced compliance to “single use”, and (5) sterilized to a sterilization assurance level of 10-6. These advantages are derived from the unique sequence and conditions of temperature, time, steam (moisture), and pressure (positive and negative) applied during the steps of the method, along with selection of materials used for the semipermeable pouch and syringe and its components. BRIEF DESCRIPTION OF THE FIGURES

[0028] Additional aspects, features, and advantages of the invention, as to its methods will be understood and become clearer when the invention is considered in view of the following brief description of the figures made in conjunction with the accompanying drawings, wherein:

[0029] Figure 1 is a flow chart illustrating the general flow of the methods of the invention.

[0030] Figure 2 is a graph of the pressure in bars and time in minutes for one embodiment of the disclosed method applied to a BD Polycarbonate syringe.

[0031] Figure 3 is a graph of the temperature in Celsius and time in minutes for five embodiments of the disclosed method applied to a BD Polycarbonate syringe.DETAILED DESCRIPTION OF THE INVENTION

[0032] Illustrative and alternative embodiments of methods for enhanced sterilization of packaged, pre-filled syringes are described in detail with reference being made to the figures of this application. While similar aspects of embodiments of the invention are featured throughout this disclosure, these similarities may be repeated within the context of the various embodiments of the invention.

[0033] Referring to Figure 1, the method fits within a broader process for providing a terminally sterilized pre-filled syringe containing a drug solution, and package enclosing the pre-filled syringe. The broader process includes (1) formulating the drug solution and then drawing the drug solution into a syringe to reach a target volume, e.g., 3 mL format pre-filled syringes; (2) subjecting the pre-filled syringe to standard quality control assessments including, but not limited to, visual inspection and testing required for use of the pre-filled syringe; (3) placing the pre-filled syringe inside an overwrap, e.g., semipermeable package; (4) sterilizing the wrapped pre-filled syringe in an autoclave according to the specific program parameters to reach terminal sterilization; (5) performing post-sterilization testing and inspection; (6) packaging the terminally sterilized wrapped pre-filled syringes in any amount of batches in boxes; (7) warehousing the boxes filled with the terminally sterilized, pre-filled syringes; and (8) shipping the boxes filled with the terminally sterilized, pre-filled syringes to delivery points.

[0034] The solutions provided by the invention include autoclave methods to terminally sterilize a primary container, i.e., pre-filled syringe, and its contents, i.e., a drug solution, along with a secondary container, i.e., semipermeable package enclosing the primary container, including the secondary space (or void) between the primary container and the secondary container. This results in a packaged, prefilled syringe and its contents that is (1) enhanced to terminal sterilization, (2) ready to use, (3) sterile field ready, (4) enhanced to enforced compliance to “single use”, and (5) sterilized to a sterilization assurance level of 10-6. These advantages are derived from the unique sequence and conditions of temperature, time, steam (moisture), and pressure (positive and negative) applied during the sequence of steps of the method, along with the selection of materials used for the semipermeable pouch, the syringe and its components, and the drug solution.

[0035] The invention provides a method for terminally sterilizing a syringe prefilled with a drug solution. The method comprises: (1) exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to the following sequence of steps in a chamber of an autoclave: (a) applying a vacuum to the chamber of the autoclave todepressurize the chamber and remove air from a secondary space (or void) within the semipermeable pouch; (b) applying a dynamic steam rising pulse to introduce water vapor into the secondary space (or void) within the semipermeable pouch; and (c) terminally sterilizing the semipermeable pouch, the syringe, the secondary space (or void), and the drug solution at a sterilization temperature for a sterilization time, while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space (or void) within the pouch by completion of the sterilization time; (2) applying a drying temperature to the chamber for a drying time at ambient air pressure; and (3) cooling the chamber to a temperature less than the drying temperature.

[0036] The syringe is the primary container for the drug solution. In non-limiting embodiments of the invention, the syringe is configured with typical components including a barrel, plunger with a rubber stopper or seal and possibly a slip agent, and a hub, which can be a luer lock or a luer slip. The syringe can be made of any material capable of maintaining its structural integrity throughout exposure to the pressures and temperatures used in the sequence of steps of the methods disclosed. In maintaining structural integrity, the materials must not leach chemicals or particulates into the drug solution contained in the syringe. In non-limiting embodiments, and except for the natural or synthetic rubber stopper or seal of the plunger, the syringe can be made from polyethylene, polypropylene, polycarbonate, cyclic olefin polymer, cyclic olefin copolymer, glass, or metal. Any syringe is suitable for use with the methods of the invention so long as it is made from appropriate materials. For syringes with a slip agent, the slip agent must be selected on the basis to withstand degradation due to the heat applied during the process and, also, not contaminating the drug solution by providing unwanted particulate matter. Examples of suitable slip agents include, but are not limited to, silicone, inert silicone, oleamide, and cross-linked and bonded silicone. The syringe must also be configured to be stored and transported after exposure to the sequence of steps of the methods.

[0037] Non-limiting examples of syringes include the Beckton Dickison (BD) 3 mL Luer Lock syringes (polypropylene or polycarbonate) and the Terumo 3 mL syringe (polypropylene), all with new IMI cap configurations. The BD syringe has a silicone slip agent, which does not degrade during exposure to the conditions of the method.

[0038] In non-limiting embodiments, any size syringe can be selected for use based on dosage type and format for use as a pre-filled syringe containing a drug solution. The drug solution can be any therapeutic solutions or suspension meant to be injected into the body and which is capable of withstanding chemical or molecular degradation from exposure to thepressures and temperatures of the sequence of steps for the methods of the invention. The drug solution can be any injectable medications, vaccines, and other medical substances. In an embodiment, the drug solution can be compounded from two or more regulated products to achieve specific characteristics for use in application. Compounded drugs may be mixed and / or diluted in outsourcing facilities subject to current good manufacturing practice (CGMP) requirements or by a licensed pharmacist, a federal facility, or a physician, in accordance with the conditions of section 503A and 503Bof the FD&C Act.

[0039] Non-limiting examples of drug solutions include any pharmaceutical solution such as, small molecule (e.g., DNA, RNA, antibodies, peptides, etc.), biologic, chemotherapeutic, therapeutic, vaccine, ophthalmic solutions, organic compound, and the like, all of which are capable of withstanding degradation during exposure to the conditions of the method.

[0040] In a non-limiting embodiment, the syringe is selected to be a pre-filled syringe for 3 mL volume format for use with a drug solution such as, an ophthalmic product.

[0041] The semipermeable package is a secondary container for the primary container, i.e., the syringe, and its contents, i.e., the drug solution. The semipermeable container is configured to be self-sealing to contain the primary container. When enclosing a primary container, the semipermeable container defines an interior space between the inner surface of the semipermeable container and the exterior surface of the primary container. The semipermeable container can be made from any material that maintains its structural integrity after exposure to the sequence of steps of the methods disclosed. The semipermeable container can be made from any semipermeable material, e.g., high density polyethylene (Tyvek), medical grade paper, non-woven material like polypropylene, polyethylene terephthalate (PET) or polyester film applied to medical grade paper or Tyvek, which allows penetration of steam to the items placed inside the container, i.e., pre-filled syringe and its contents, and, after sterilization, the semipermeable material maintains the sterility of the processed item. Any semipermeable container is suitable for use with the methods of the invention so long as it is made from appropriate materials. The semipermeable container must be configured to maintain sterility of the items placed inside the container, i.e., pre-filled syringe and its contents, during storage and transport.

[0042] In a non-limiting embodiment, the semipermeable container is a self-sealing, peel open pouch. An example of a semipermeable container includes the Henry Schein self- seal, sterilization Tyvek pouch.

[0043] According to embodiments of the invention, the method comprises exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to a sequence of steps in a chamber of an autoclave. The autoclave can be an advanced steam sterilizer having a vacuum pump configured for steam pulsing for effective steam penetration through a load to achieve terminal sterilization. The autoclave must be capable of sterilization of aqueous solutions in sealed containers, like, for example, the Fedegari air steam mixture autoclave (FOAF). The vacuum pump can be configured to create a pre-vacuum to efficiently remove air from the sterilization chamber and the load itself. By evacuating ambient air within the chamber, this ensures thorough sterilization so that high-temperature steam can be pulsed to penetrate and sterilize areas otherwise occupied by air. This vacuum function is crucial for ensuring complete steam penetration in the most challenging items including complex instruments with hollow spaces, wrapped items, and surgical packs. The autoclave uses steam pulsing to remove air effectively from the chamber to allow for deep penetration of steam into the load to reach terminal sterilization of the semipermeable pouch and the syringe and its contents.

[0044] According to embodiments of the invention, the sequence of steps includes applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from the secondary space (or void) within the semipermeable pouch. The application of a vacuum ensures removal of ambient air from the chamber and the secondary space within the semipermeable pouch.

[0045] In a non-limiting embodiment, the vacuum pressure is about 0.10 bar abs.

[0046] According to embodiments of the invention, and after applying the vacuum to the chamber, the sequence of steps includes then applying dynamic steam rising pulse to introduce water vapor, i.e., steam, into the secondary space within the semipermeable pouch. This ensures adequate penetration of steam inside the secondary space (or void) of the semipermeable pouch for the next step.

[0047] In a non-limiting embodiment, the dynamic steam rising pulse is at a vacuum value of 0.90 bar abs.

[0048] According to embodiments of the invention, and after applying dynamic steam pulsing to the chamber, the sequence of steps includes then terminally sterilizing the semipermeable pouch, the secondary space (or void), the syringe, and the drug solution at a sterilization temperature for a sterilization time under pressure. During this step, it is critical to apply a sufficient counter pressure to prevent movement of the plunger relative to the barrel ofthe syringe. All moisture is removed from the secondary space (or void) within the pouch upon completion of the sterilization time.

[0049] The sterilization temperature is related to the sterilization time. In non-limiting embodiments, the sterilization temperature is in a range of 121 to 130 degrees Celsius. The sterilization temperature can be 121, 126, or 130 degrees Celsius. In non-limiting embodiments, the sterilization time is in a range of about 1 to about 10 minutes. The sterilization time can be 1 minute, 3 minutes, or 10 minutes depending on the sterilization temperature. In a non-limiting embodiment, the sterilization temperature is 121 degrees Celsius, and the sterilization time is about 10 minutes. In another non-limiting embodiment, the sterilization temperature is 126 degrees Celsius, and the sterilization time is about 3 minutes. In a further non-limiting embodiment, the sterilization temperature is 130 degrees Celsius, and the sterilization time is about 1 minute.

[0050] Sterilization temperature and sterilization time are selected while considering the F0 cycle, which is based on the concept of thermal equivalence. The F0 value represents the equivalent minutes of sterilization at 121.1 degrees Celsius, where the F0 value is the accumulated lethality in minutes at 121.1 degrees Celsius. In application, an F0 value of 10 minutes equates to 10 minutes of actual exposure at 121.1 degrees Celsius during the sterilization phase of the method. Further, an F0 value of 10 minutes equates to approximately 3 minutes of actual exposure at 126 degrees Celsius. Finally, an F0 value of 10 minutes equates to approximately 1 minute of actual exposure at 130 degrees Celsius.

[0051] The counter pressure is selected to counteract internal expansive pressure of the drug solution caused by heat exposure at the sterilization temperature and prevent movement of the plunger relative to the syringe. In a non-limiting embodiment, the counterpressure is about 1,20 kilopascals.

[0052] According to embodiments of the invention, and after completion of the sterilization, the method comprises applying a drying temperature to the chamber for a drying time at ambient air pressure. The drying temperature can be in a range of about 105 to about 120 degrees Celsius.

[0053] According to embodiments of the invention, and after completion of the drying step, the method comprises cooling the chamber to a temperature less than the drying temperature. The terminally sterilized semipermeable containers with pre-filled syringes can be removed from the autoclave and packaged into boxes for storage and later shipment to the destination.

[0054] Sterility of any product is defined by the probability of a viable microorganism on the product after it has been sterilized, which is referred to as a sterility assurance level. A sterility assurance level is normally expressed as 10-n, as a quantitative value to assure sterility. There is greater assurance of sterility with a lower SAL. For example, a 10-6SAL is lower than a 10-3SAL, whereby a 10-6SAL provides a greater assurance of sterility. An SAL of 10-6is frequently used for the terminal sterilization of medical devices and pharmaceutical injections. An SAL of 10-6has a probability of 1 in 1,000,000 of finding a non-sterile unit. While the probability of sterility can never be reduced to zero, i.e., a 100% assurance level, and still have product for use, it can be and is expected to be reduced to very low numbers. In embodiments of the invention, the semipermeable pouch, the syringe, and the drug solution prefilled in the syringe have a sterilization assurance level of 10-6upon completion of the sequence of steps of the methods disclosed.

[0055] EXAMPLES

[0056] The following examples demonstrate the implementation of the disclosed methods for terminal sterilization of packaged, pre-filled syringes. These examples are provided for illustrative purposes only and are not intended to limit the scope of the invention.

[0057] Figure 2 depicts the pressure profile of a BD polycarbonate syringe during autoclaving. Specifically, a BD 3 mL polycarbonate Luer Lock syringe, prefilled with a representative ophthalmic drug solution, was placed inside a semipermeable, peel-open sterilization pouch composed of Tyvek® material. The packaged syringe was then subjected to the sterilization cycle in a Fedegari air-steam mixture autoclave, which provides programmable control over temperature, vacuum stages, steam pulsing, and chamber pressure. The purpose of this example is to describe the pressure dynamics throughout the sterilization process and demonstrate how the method preserves the physical integrity, including but not limited to zero plunger movement during and after the sterilization, of both the syringe and its contents.

[0058] As shown in Figure 2, the sterilization cycle proceeded through a series of controlled pressure stages over time. The cycle began with a deep vacuum phase, where the pressure inside the chamber was reduced to approximately 0.10 bar absolute. This vacuum step served to efficiently evacuate air from both the autoclave chamber and the internal void between the syringe and the interior surface of the semipermeable pouch. Removing this air is critical to facilitate thorough steam penetration and eliminate insulating air pockets that would otherwise interfere with uniform sterilization.

[0059] Following the vacuum stage, the cycle transitioned to a dynamic steam pulsing phase. During this stage, a rising pulse of saturated steam was introduced into the chamber. The pressure increased in a controlled manner, reaching approximately 0.90 bar absolute. The pulsed introduction of steam not only saturated the chamber but also actively displaced residual air from difficult-to-reach spaces within the pouch. This ensured full contact between steam and all surfaces of the syringe and pouch interior.

[0060] In certain embodiments disclosed above, but not shown in Figure 2, during the steam introduction phase, once pressure reached approximately 0.90 bar absolute – about being plus or minus 0.05 bar absolute – the pressure was then reduced by up to 0.1 bar absolute for a short duration such as less than five, three, or one minute. This temporary reduction in pressure facilitates redistribution of steam and further promotes uniform penetration throughout the load. Following this brief reduction, the chamber pressure increased back to about 0.90 bar absolute in preparation for the sterilization phase.

[0061] During the sterilization phase, chamber pressure was further increased and precisely maintained to apply a counterpressure sufficient to oppose internal expansion pressure from the heated drug solution within the syringe. This counterpressure, which reached approximately 1.20 kilopascals, prevented movement of the plunger within the syringe barrel. Pressure was held constant during the sterilization hold time, while temperature and time parameters were varied depending on the selected cycle, as discussed below and depicted in Figure 3.

[0062] Upon completion of the sterilization phase, the chamber entered the drying phase. Steam was evacuated from the chamber, and the pressure returned to ambient levels. Drying occurred at a temperature between 110 and 115 degrees Celsius under ambient air pressure. This allowed for the removal of residual moisture from the pouch and syringe surfaces without introducing deformation or thermal degradation. Finally, the chamber was cooled below the drying temperature, and the sterilized product was removed.

[0063] Throughout the cycle, pressure changes were carefully monitored and confirmed via instrumentation and process data recorded in the autoclave's programmable logic controller. The resulting pressure curve in Figure 2 reveals a smooth and controlled sequence of pressure transitions with no evidence of destabilizing spikes or mechanical shock.

[0064] Post-cycle inspection revealed no evidence of plunger displacement, deformation of the syringe or packaging, or drug solution degradation. The syringe maintained its structural and functional integrity, and the peel-open pouch remained intact and properlysealed. This example demonstrates that the disclosed sterilization method, through its precise control of vacuum and counterpressure stages, can effectively sterilize a pre-filled syringe while preventing mechanical compromise.

[0065] To demonstrate the thermal dynamics of the disclosed sterilization method and its adaptability across different cycle configurations, five sterilization runs were performed using BD 3 mL polycarbonate Luer Lock syringes prefilled with a representative ophthalmic drug solution. Each syringe was enclosed in a semipermeable Tyvek® peel-open pouch and subjected to autoclaving using the disclosed method. All five runs utilized a sterilization temperature of 121 degrees Celsius but employed different heating profiles and exposure times to reach an equivalent microbial lethality, with an F₀ value of 10 minutes.

[0066] Figure 3 illustrates the temperature versus time profiles for these five runs. The chart shows that, while the peak sterilization temperature was consistent across all runs (121^°C), the timing and slope of the temperature ramp-up and hold phases varied. These variations were designed to explore how different thermal delivery patterns affect the process efficiency and product stability while still meeting sterility targets.

[0067] In certain runs, the autoclave temperature ramped quickly to 121^°C and held that temperature for a sustained period, reaching the F₀ target through prolonged steady exposure. In others, the system approached 121^°C more gradually and held for longer durations to achieve the same cumulative lethality. One run displayed a two-stage temperature rise with a brief plateau before final ramp-up to 121^°C, which was followed by a shorter hold time – demonstrating that the lethality requirement can be met through a more distributed thermal dose.

[0068] Each temperature profile confirmed that the autoclave chamber achieved uniform and stable temperature control throughout the sterilization phase. The hold segments of each run maintained 121^°C consistently without significant overshoot or fluctuation, ensuring a reliable environment for terminal sterilization of the packaged syringe and its contents.

[0069] Following the sterilization phase in all five runs, the chamber transitioned to a drying phase at a temperature between approximately 110 and 115^°C, under ambient air pressure. The drying step lasted approximately 20 minutes and facilitated complete removal of residual moisture from the interior surfaces of the pouch and the exterior of the syringe. The chamber was then cooled below the drying temperature before product removal.

[0070] Again, post-process inspection confirmed the structural integrity of the syringes and packaging in all five runs. The plungers remained properly seated, the syringe barrels and hubs were free from deformation, and the drug solution appeared clear and free of particulates or discoloration. Biological indicators confirmed that a sterility assurance level (SAL) of 10⁻⁶ was consistently achieved.

[0071] These results, as shown in Figure 3, demonstrate that the disclosed method can be tailored through variations in ramp-up time and hold duration while maintaining a constant sterilization temperature of 121^°C. The flexibility in thermal profiling allows the method to accommodate different drug formulations and packaging materials without compromising sterilization efficacy or product stability.

[0072] While the subject matter has been disclosed with reference to specific embodiments, it will be apparent that other embodiments and variations can be devised by those skilled in the art without departing from the true spirit and scope of the subject matter described herein. The appended claims include all such embodiments and equivalent variations.

Claims

What is claimed is:

1. A method for providing a pre-filled syringe that is sterile field ready, the method comprising: exposing a semipermeable pouch enclosing the pre-filled syringe having a plunger to the following sequence of steps in a chamber of an autoclave: applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space within the semipermeable pouch; applying a dynamic steam rising pulse to introduce water vapor into the secondary space within the semipermeable pouch; and sterilizing the semipermeable pouch, the secondary space, and the pre-filled syringe at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the pouch by completion of the sterilization time; applying a drying temperature to the chamber for a drying time at ambient air pressure; and cooling the chamber to a temperature less than the drying temperature.

2. The method of claim 1 wherein the semipermeable pouch is a peel open pouch.

3. The method of claim 1 wherein the semipermeable pouch maintains its structural integrity after exposure to the sequence of steps.

4. The method of claim 1 wherein the pre-filled syringe has a luer lock or a luer slip.

5. The method of claim 4 wherein the luer lock or a luer slip maintains its structural integrity after exposure to the sequence of steps.

6. The method of claim 1 wherein the pre-filled syringe is made from polypropylene, polycarbonate, cyclic olefin polymer, cyclic olefin copolymer, glass, or metal.

7. The method of claim 1 wherein the pre-filled syringe contains a drug solution.

8. The method of claim 7 wherein the drug solution is terminally sterilized after exposure to the sequence of steps.

9. The method of claim 1 wherein the vacuum pressure is about 0.10 bar abs.

10. The method of claim 1 wherein the dynamic steam rising pulse is at a vacuum value of 0.90 bar abs.

11. The method of claim 1 wherein the sterilization temperature is in a range of 121 to 130 degrees Celsius.

12. The method of claim 11 wherein the sterilization temperature is 121 degrees Celsius.

13. The method of claim 1 wherein the sterilization time is in a range of about 1 to about 10 minutes.

14. The method of claim 13 wherein the sterilization time is 10 minutes.

15. The method of claim 1 wherein the sterilization temperature is 121 degrees Celsius, and the sterilization time is about 10 minutes.

16. The method of claim 1 wherein the sterilization temperature is 126 degrees Celsius, and the sterilization time is about 3 minutes.

17. The method of claim 1 wherein the sterilization temperature is 130 degrees Celsius, and the sterilization time is about 1 minute.

18. The method of claim 1 wherein the counterpressure is about 1.20 kilopascals.

19. The method of claim 1 wherein the drying temperature is in a range of about 105 to about 120 degrees Celsius.

20. A method for sterilizing a primary container prefilled with a drug solution and an interior surface of a semipermeable secondary container enclosing the primary container, the method comprising: exposing the semipermeable secondary container enclosing the primary container to the following sequence of steps in a chamber of an autoclave:applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space within the semipermeable secondary container; applying a dynamic steam rising pulse to introduce water vapor into the secondary space within the semipermeable secondary container; and sterilizing the semipermeable secondary container, the secondary space, the primary container, and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure, wherein all moisture is removed from the secondary space within the semipermeable secondary container by completion of the sterilization time; exposing the chamber to a drying temperature for a drying time at ambient air pressure; and cooling the chamber below the sterilization temperature.

21. The method of claim 20 where the primary container is a pre-filled syringe having a plunger.

22. The method of claim 21 wherein the pre-filled syringe is made from polypropylene, polycarbonate, cyclic olefin polymer, cyclic olefin copolymer, glass, or metal.

23. The method of claim 21 wherein the pre-filled syringe, the drug solution, and the semipermeable secondary container are terminally sterilized.

24. The method of claim 21 wherein counter pressure is selected to counteract internal pressure of the drug solution caused by heat exposure at the sterilization temperature and prevent movement of the plunger relative to the syringe.

25. The method of claim 21 wherein the syringe maintains structural integrity throughout exposure to the sequence of steps.

26. The method of claim 20 wherein the semipermeable secondary container is a peel open pouch.

27. The method of claim 20 wherein the semipermeable secondary container maintains structural integrity throughout exposure to the sequence of steps.

28. A manufacturing method for sterilizing a pre-filled syringe having a plunger that is packaged in a semipermeable container, the method comprising: autoclaving the pre-filled syringe packaged in the semipermeable container according to the following sequence of steps: applying a vacuum to a chamber of the autoclave to depressurize the chamber and remove air from a secondary space within the semipermeable container; applying a dynamic steam rising pulse to introduce water vapor into the secondary space within the semipermeable container; and sterilizing the pre-filled syringe packaged in the semipermeable container and the secondary space at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the semipermeable container by completion of the sterilization time; applying a drying temperature to the chamber for a drying time at ambient air pressure; and cooling the chamber to a temperature less than the drying temperature.

29. The method of claim 28 wherein the pre-filled syringe is made from polypropylene, polycarbonate, cyclic olefin polymer, cyclic olefin copolymer, glass, or metal.

30. The method of claim 28 wherein the pre-filled syringe contains a drug solution.

31. The method of claim 30 wherein counter pressure is selected to counteract the internal pressure of the drug solution caused by heat applied at the sterilization temperature and prevent movement of the plunger.

32. The method of claim 28 wherein the syringe maintains structural integrity throughout exposure to the sequence of steps.

33. The method of claim 28 wherein the semipermeable container is a peel open pouch.

34. The method of claim 28 wherein the semipermeable container maintains structural integrity throughout exposure to the sequence of steps.

35. A method for terminally sterilizing a syringe prefilled with a drug solution, the method comprising: exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to the following sequence of steps in a chamber of an autoclave: applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space within the semipermeable pouch; applying a dynamic steam rising pulse to introduce water vapor into the secondary space within the semipermeable pouch; and terminally sterilizing the semipermeable pouch, the secondary space, the syringe, and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the pouch by completion of the sterilization time; applying a drying temperature to the chamber for a drying time at ambient air pressure; and cooling the chamber to a temperature less than the drying temperature.

36. The method of claim 35 wherein the semipermeable pouch, the syringe, and the drug solution have a sterilization assurance level of 10-6upon completion of the sequence of steps.

37. A method for providing a ready-to-use syringe prefilled with a drug solution, the method comprising: exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to the following sequence of steps in a chamber of an autoclave: applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space within the semipermeable pouch; applying a dynamic steam rising pulse to introduce water vapor into the secondary space within the semipermeable pouch; andsterilizing the semipermeable pouch, the secondary space, the syringe, and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the pouch by completion of the sterilization time; applying a drying temperature to the chamber for a drying time at ambient air pressure; and cooling the chamber to a temperature less than the drying temperature.

38. A method for sterilizing a syringe prefilled with a drug solution that assures single use compliance with the drug solution, the method comprising: exposing a semipermeable pouch enclosing the syringe prefilled with the drug solution and having a plunger to the following sequence of steps in a chamber of an autoclave: applying a vacuum to the chamber of the autoclave to depressurize the chamber and remove air from a secondary space within the semipermeable pouch; applying a dynamic steam rising pulse to introduce water vapor into the secondary space within the semipermeable pouch; and sterilizing the semipermeable pouch, the secondary space, the syringe, and the drug solution at a sterilization temperature for a sterilization time while applying counter pressure to prevent movement of the plunger relative to the syringe, wherein all moisture is removed from the secondary space within the pouch by completion of the sterilization time; applying a drying temperature to the chamber for a drying time at ambient air pressure; and cooling the chamber to a temperature less than the drying temperature.

Images